Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases: Volume I: Liver, Skin, Thyroid, Rheumatic & Myopathic Diseases 9811919453, 9789811919459

Citation preview

Mitesh Kumar Dwivedi N. Amaresan E. Helen Kemp Yehuda Shoenfeld   Editors

Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases Volume I: Liver, Skin, Thyroid, Rheumatic & Myopathic Diseases

Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases

Mitesh Kumar Dwivedi • N. Amaresan • E. Helen Kemp • Yehuda Shoenfeld Editors

Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases Volume I: Liver, Skin, Thyroid, Rheumatic & Myopathic Diseases

Editors Mitesh Kumar Dwivedi C.G. Bhakta Institute of Biotechnology Uka Tarsadia University Surat, Gujarat, India

N. Amaresan C.G. Bhakta Institute of Biotechnology Uka Tarsadia University Surat, Gujarat, India

E. Helen Kemp Department of Oncology and Metabolism University of Sheffield Sheffield, UK

Yehuda Shoenfeld Zabludowizc Center for Autoimmunity Sheba Medical Center Tel-Hashomer, Israel

ISBN 978-981-19-1945-9 ISBN 978-981-19-1946-6 https://doi.org/10.1007/978-981-19-1946-6

(eBook)

# The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Foreword

Within this volume, each of the chapters presents perspectives on the interplay of the microbiome with host cellular and molecular defenses. These reviews revisit fundamental questions that date to the contributions of Paul Ehrlich, who first conceptualized the risks to the host of autoimmune disease (Ehrlich 1900). Each of these reviews seeks to illuminate how our interdependence with our resident internal microbiome communities reinforces, or at times degrades, the capacity of the adaptive immune system to discriminate self from non-self, and for the innate immune system to regulate and efficiently resolve inflammatory responses. Studies of the microbial world became the discipline of medical microbiology, which was founded for the identification of microbes that cause infection by direct invasion usually of solitary pathogens. Hence, traditional microbiology techniques focus on isolating and characterizing the comparative few species that are known causes of infections, while the vast majority of bacterial species are little known and currently non-cultivable. Yet, there is increasing awareness of how the metabolic and immunologic features of chronic medical conditions are affected by more subtle distortions and outgrowths of microbes that are not commonly directly invasive. Arguably, the first observation of a disease triggered by an infection that triggered dysregulated immune mediated tissue devoid was reported over two centuries ago, by Wells who described “post scarlatinal dropsy” (Wells 1812). Here, Wells is referring to the rash of scarlet fever that is induced following infection by streptococcal strains expressing with erythrogenic toxin, while dropsy refers to severe peripheral edema resulting from severe nephrotic syndrome (i.e., proteinuria can v

vi

Foreword

result from glomerular injury). Overtime this renal disease has been shown to reflect an often serious, yet sterile immune complex-mediated glomerulopathy, now termed acute post streptococcal glomerulonephritis (APSGN) (Rodriguez-Iturbe and Batsford 2007). In these cases, evidence of preceding streptococcal infectionbased serum antibodies to extracellular streptococcal antigens can be the smoking gun. Sadly, in many parts of the world, ASPGN and rheumatic fever are still common sequalae of minor pharyngeal and cutaneous streptococcal infections in developing countries where antibiotics are a luxury for many. While our understanding of immune pathogenesis is still incomplete, it has been postulated that these postinfection diseases involve cross-reactive immune recognition by host lymphocytes between bacterial antigens and the self-antigens, which either reside in or are locally deposited via immune complexes formed in glomeruli, due to molecular mimicry [reviewed in (Albert and Inman 1999)]. “Microbiome” refers to the entire habitat, including all of the microorganisms in a defined environment, and the term was coined only 20 years ago (Lederberg and McCay 2001). Humans each harbor microbiota communities that consist of 10–100 trillion symbiotic microbial cells (Turnbaugh et al. 2007). Historically, the field of microbiome research emerged from environmental microbiome research (microbial ecology) and provides an interdisciplinary platform for many fields, from food science, plant pathology, and agriculture, to biotechnology, mathematics (informatics, statistics, modeling), and especially human medicine. The explosive growth of this young field was propelled by opportunities provided by next-generation DNA sequencing (with metagenomic 16S rRNA amplicon analysis enabling robust culture-independent microbiota profiling). Subsequent advances in sensitive and quantitative instrumentation for metabolomic analyses have been joined by other advanced methodologies to enable elucidation of nuanced variations and functions of these complex communities. Hundreds of bacterial species have now been newly identified and these populate our every exposed surface, inside and out. In our bodies, the largest communities populate the lining of the gut tube, with diverse communities adapted to different anatomic stretches from the oral cavity to the anus, as well as from the gut lumen to the mucosal surfaces that in health provide barriers to host invasion. These communities of commensal microbial organisms together have a 100-fold or greater number of genes than the human genome, which potentially provide a tremendous range of metabolic pathways that shift based on nutritional opportunity or host stress. We co-evolved with these microbiota communities that are essential for maintaining health. The immune system is kept in balance by the microbiome, and in health the microbiome is in dynamic balance by the immune system. Moreover, microbiota imbalance in an increasing number of maladies is being characterized as a reflection of genetic inheritance and the adverse influence of the Western diet comprised of processed foods and poorly understood food additives. Commensal microbes, with their own orthologues of the conserved basic machinery of life and antigenic products, also represent the functional equivalent of early sparring partners for the host immune system. Early immune exposure, which results in selection and expansion of a repertoire of T cell and B cell clones, is essential for

Foreword

vii

effective early immune development (Greiling et al. 2018; Wesemann et al. 2013). Microbiota communities also affect the control of inflammatory responses and produce soluble immune regulatory mediators like short-chain fatty acids (SCFAs), which influence immune modulation, control anabolic processes, serve as an energy source for colonocytes, and are precursor metabolites for lipogenesis and gluconeogenesis (Correa-Oliveira et al. 2016; Wong et al. 2006). Of these SCFA, butyrate is essential in controlling inflammation responses and serving as the main energy source for gut epithelial cells (Tedelind et al. 2007; Roy et al. 2006). The microbiome also affects the generation of pro-inflammatory Th17 cells arising in the gut that traffic to affected tissue (Evans-Marin et al. 2018). Microbial factors can also expand or downregulate anti-inflammatory regulatory T cells (Tregs) or activate different dendritic cell (DC) subsets and innate-like lymphocytes, and at times molecular mimicry with microbial factors drives autoimmune responses, with many variations thereof and beyond. In an increasing number of clinical diseases, pathology has been correlated with broad imbalances (dysbiosis) in community composition, but it can be enigmatic whether these alterations are a cause, or a secondary effect. While there are only a handful of cases in which specific microbes have been implicated as causal, powerful paradigms have been learned from Candidatus Savagella, commonly known as segmented filamentous bacteria (SFB), a common murine gut commensal. While in many murine strains SFB does not induce a strong phenotype, in a predisposed murine strain SFB contributes to the development of inflammatory arthritis, and in other mice SFB expansions instead contribute to the production of anti-nuclear autoantibodies (Van Praet et al. 2015). SFB are also inducers of RORγt(+) Th17 cells that potentiate autoimmune tissue injury (Lecuyer et al. 2014). SFB has therefore become the prototype symbiont species that in some settings directly contributes to autoimmune pathogenesis, akin to opportunistic pathogens, hence the term pathobiont. The identification and characterization of a bona fide pathobiont may lead to the development of new targeted therapeutic agents that do not have broad effects throughout the immune system and general metabolic balance of the host. From our own studies of patients with systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, we found the most severely affected individuals often have expansions of the gut commensal Ruminococcus gnavus of the genus Blautia and the family Lachnospiraceae. In fact, R. gnavus is a prevalent member of the gut microbial community within the Firmicutes division (Qin et al. 2010; Kraal et al. 2014), and R. gnavus was one of the 57 species detected in more than 90% of human fecal samples by metagenomic sequencing (Qin et al. 2010). This anaerobic species has genetic features that distinguish and separate its genome and genes from other members of the genus and family. R. gnavus blooms have been implicated as triggers of flares of lupus nephritis (LN), and such affected individuals are of diverse ethnicity in studies in the US (Azzouz et al. 2019). R. gnavus expansions have also been recently documented to be prominent in untreated LN patients in China (Chen et al. 2020). The affected hosts are of diverse ethnicity, which may represent a surrogate for genetic inheritance, and could suggest that host

viii

Foreword

T cell immune recognition in a narrow MHC-restricted fashion is unlikely to be a primary mediator in a postulated host–pathobiont relationship. It furthermore remains to be elucidated whether R. gnavus strain-associated genome variation, and possible differences that affect release of virulence factors, stokes associated flares of autoimmune disease. While this overview is far from a complete inventory of each of the topics that are touched upon by the contributions within this volume, it should also be acknowledged that there is often a common thread that disturbances in the balance within the gut microbiome affect the intestinal barrier function. The balance of bacterial species in local residence can affect the integrity of this barrier, with regulatory roles for the endogenous peptides of the zonulin ligand–receptor pathway that control the generation of tight junctions between colonic epithelial cells (Troisi et al. 2021). There can be powerful systemic immune consequences, as defects in intestinal barrier function can result in translocation of bacteria, and release of pro-inflammatory products (e.g., endotoxin and lipopeptides), into peripheral lymphoid tissues, the liver, and other sites (Manfredo Vieira et al. 2018; Azzouz et al. 2019). Increased intestinal permeability, commonly referred to as a “leaky gut,” has been therefore blamed for a panoply of inflammatory disorders. Taken together, the chapters in this volume focus on the current state of the art of investigations focused of the microbiome–host relationship in liver, skin, thyroid, rheumatic and myopathic disease, and the application of multiple dimensions of technology that are now being applied. No doubt by the date of publication the frontier of these investigations will already have greatly advanced, and a future volume will be needed in the near future. References Albert LJ, Inman RD (1999) Molecular mimicry and autoimmunity. N Engl J Med, 341, 2068-74. Azzouz D, Omarbekova A, Heguy A, Schwudke D, Gisch N, Rovin BH, Caricchio R, Buyon JP, Alekseyenko AV, Silverman GJ (2019) Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal. Ann Rheum Dis, 78, 947-956. Chen BD, Jia XM, Xu JY, Zhao LD, Ji JY, Wu BX, Ma Y, Li H, Zuo XX, Pan WY, Wang XH, Ye S, Tsokos GC, Wang J, Zhang X (2020) An Autoimmunogenic and Proinflammatory Profile Defined by the Gut Microbiota of Patients With Untreated Systemic Lupus Erythematosus. Arthritis Rheumatol. Correa-Oliveira R, Fachi JL, Vieira A, Sato FT, Vinolo MA (2016) Regulation of immune cell function by short-chain fatty acids. Clin Transl Immunology, 5, e73. Ehrlich P (1900) On immunity with a special reference to cell life. Proc R. Soc Lond, 66, 424-448. Evans-Marin H, Rogier R, Koralov SB, Manasson J, Roeleveld D, van der Kraan PM, Scher JU, Koenders MI, Abdollahi-Roodsaz S (2018) MicrobiotaDependent Involvement of Th17 Cells in Murine Models of Inflammatory Arthritis. Arthritis Rheumatol, 70, 1971-1983.

Foreword

ix

Greiling TM, Dehner C, Chen X, Hughes K, Iniguez AJ, Boccitto M, Ruiz DZ, Renfroe SC, Vieira SM, Ruff WE, Sim S, Kriegel C, Glanterik J, Chen X, Giardi M, Degnan P, Costenbader KH, Goodman AL, Wolin SL, Kriegel MA (2018) Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus. Sci Transl Med, 10. Kraal L, Abubucker S, Kota K, Fischbach MA, Mitreva M (2014) The prevalence of species and strains in the human microbiome: a resource for experimental efforts. PLoS One, 9, e97279. Lecuyer E, Rakotobe S, Lengline-Garnier H, Lebreton C, Picard M, Juste C, Fritzen R, Eberl G, McCoy KD, Macpherson AJ, Reynaud CA, Cerf-BensussanN, Gaboriau-Routhiau V (2014) Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses. Immunity, 40, 608-20. Lederberg JM, McCay AT (2001) Ome sweet 'omics: a genealogical treasury of words. The Scientist, 15. Manfredo Vieira S, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, Khan N, Costa FRC, Tiniakou E, Greiling T, Ruff W, Barbieri A, Kriegel C, Mehta SS, Knight JR, Jain D, Goodman AL, Kriegel MA (2018) Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science, 359, 1156-1161. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Dore J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, Meta HITC, Bork P, Ehrlich SD, Wang J (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature, 464, 59-65. Rodriguez-Iturbe B, Batsford S (2007) Pathogenesis of poststreptococcal glomerulonephritis a century after Clemens von Pirquet. Kidney Int, 71, 1094–1104. Roy CC, Kien CL, Bouthillier L, Levy E (2006) Short-chain fatty acids: ready for prime time? Nutr Clin Pract, 21, 351–366. Tedelind S, Westberg F, Kjerrulf M, Vidal A (2007) Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J Gastroenterol, 13, 2826–2832. Troisi J, Venutulo G., Terraciano C, Carri MD, Di MiccoI S, Landolfi A, Fasano A (2021) The therapeutic use of the zonulin inhibitor AT-1001 (Larazotide) for a variety of acute and chronic inflammatory diseases. Curr Med Chem. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI (2007) The human microbiome project. Nature, 449, 804–810. Van Praet JT, Donovan E, Vanassche I, Drennan MB, Windels F, Dendooven A, Allais L, Cuvelier CA, van de Loo F, Norris PS, Kruglov AA, Nedospasov SA, Rabot S, Tito R, Raes J, Gaboriau-Routhiau V, Cerf-Bensussan N, Van De Wiele T, Eberl G, Ware CF, Elewaut D (2015) Commensal microbiota influence systemic autoimmune responses. EMBO J, 34, 466–474.

x

Foreword

Wells CD (1812) Observations on the dropsy that succeeds scarlet fever. Trans Soc Imp Med Cir Knowledge, 3, 167–186. Wesemann DR, Portuguese AJ, Meyers RM, Gallagher MP, Cluff-Jones K, Magee JM, Panchakshari RA, Rodig SJ, Kepler TB, Alt FW (2013) Microbial colonization influences early B-lineage development in the gut lamina propria. Nature, 501, 112–115. Wong JM, de Souza R, Kendall CW, Emam A, Jenkins DJ (2006) Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol, 40, 235–243. NYU Grossman School of Medicine New York, NY, USA January 31, 2022

Gregg J. Silverman

Preface

The book “Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases” is focused on how microbial pathogens can subvert the immune system into responding against self so resulting in the development of autoimmune disease against specific organs or tissues. Importantly, the understanding that the book provides, with respect to the role of microorganisms in autoimmunity, can aid in the design of therapeutic strategies. Volume 1 of the book “Liver, Skin, Thyroid, Rheumatic and Myopathic Diseases” consists of six sections. The first part overviews the concept of autoimmunity as trigged by infectious agents, including newly investigated mechanisms. Particularly, the relationship between the gut microbiota and autoimmune disease is discussed. Subsequent parts cover the role of different microbes and the gut microbiota in causing autoimmune liver, skin, thyroid, rheumatic and myopathic diseases. Moreover, their role in the management and/or prevention of the abovementioned disorders is also put forward. We, the editorial team, strongly believe that the contents of the individual chapters will provide recent and updated information as well as new insights into the interrelation of microbes and autoimmunity. As such, the book will be useful in education and as a scientific tool for academics, clinicians, scientists, researchers, and health professionals in various disciplines including microbiology, medical microbiology, immunology, biotechnology, and medicine. As the editors, we would like to express our sincere gratitude to all authors for their excellent contributions. We are also indebted to the publishers for their efforts to publish the book in a timely fashion. Surat, Gujarat, India Surat, Gujarat, India Sheffield, UK Tel Hashomer, Israel

Mitesh Kumar Dwivedi Natarajan Amaresan Elizabeth Helen Kemp Yehuda Shoenfeld

xi

Contents

Part I

Overview of Infectious Microorganisms & Microbiota in Inducing Autoimmunity

1

The Concept of Infection-Triggered Autoimmunity . . . . . . . . . . . . . Fabrizio Guarneri

2

The Interaction of Gut Microbiota with Immune System and Their Effects on Immune Cell Development and Function . . . . . . . Priyanka Sarkar

3

The Link Between Gut Microbiota and Autoimmune Diseases . . . . Divya Goyal, Mangaldeep Dey, and Rakesh Kumar Singh

4

The Factors Influencing Gut Microbiota in Autoimmune Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Syed Afroz Ali, Samir Ranjan Panda, Mangaldeep Dey, Ashok Kumar Datusalia, V. G. M. Naidu, and Rakesh Kumar Singh

Part II 5

3

21 33

69

Microorganisms in Pathogenesis & Management of Autoimmune Liver Diseases

Microorganisms in Pathogenesis and Management of Autoimmune Hepatitis (AIH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tanuj Upadhyay and Shvetank Bhatt

93

6

Microorganisms in Pathogenesis and Management of Primary Biliary Cholangitis (with Focus on Molecular Mimicry) . . . . . . . . . 121 Eirini I. Rigopoulou, Andreas L. Koutsoumpas, and Dimitrios P. Bogdanos

7

Microorganisms in the Pathogenesis and Management of Primary Biliary Cholangitis (with Focus on SARS-CoV-2 & Gut Microbiota) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 Matei-Alexandru Cozma and Camelia-Cristina Diaconu

xiii

xiv

Contents

Part III

Microorganisms in Pathogenesis & Management of Skin Autoimmune Diseases

8

Microorganisms in Pathogenesis and Management of Psoriasis . . . . 175 Luis F. Santamaria-Babí

9

Microorganisms in Pathogenesis and Management of Vitiligo . . . . . 189 Prashant S. Giri, Ankit Bharti, E. Helen Kemp, and Mitesh Kumar Dwivedi

10

Microorganisms in Pathogenesis and Management of Scleroderma (Systemic Sclerosis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Rossella Talotta

11

Microorganisms in Pathogenesis and Management of Atopic Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Paolo Custurone, Luca Di Bartolomeo, and Fabrizio Guarneri

12

Microorganisms in Pathogenesis and Management of Pemphigus Vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 Matina Zorba, Aikaterini Patsatsi, and Dimitrios Andreadis

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 Faith Ai Ping Zeng and Dedee F. Murrell

Part IV

Microorganisms in Pathogenesis & Management of Autoimmune Thyroid Diseases

14

Microorganisms in Pathogenesis and Management of Graves’ Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333 Silvia Martina Ferrari, Fabrizio Guarneri, Poupak Fallahi, Alessandro Antonelli, and Salvatore Benvenga

15

Microorganisms in Pathogenesis and Management of Hashimoto Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 Y. Cuan-Baltazar and E. Soto-Vega

Part V 16

Microorganisms in Pathogenesis & Management of Autoimmune Rheumatic Diseases

Microorganisms in Pathogenesis and Management of Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 Baskar Balakrishnan and Veena Taneja

Contents

xv

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419 Zhussipbek Mukhatayev, Aigul Sharip, Ayaulym Nurgozhina, Darya Chunikhina, Dimitri Poddighe, Bayan Ainabekova, Almagul Kushugulova, and Jeannette Kunz

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459 Aigul Sharip, Zhussipbek Mukhatayev, Darya Chunikhina, Madina Baglanova, Dimitri Poddighe, Bayan Ainabekova, Almagul Kushugulova, and Jeannette Kunz

19

Microorganisms in Pathogenesis and Management of Psoriasis Arthritis (PsA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489 Dobrică Elena-Codruța, Banciu Laura Mădălina, Voiculescu Vlad Mihai, and Găman Amelia Maria

20

Microorganisms in Pathogenesis and Management of Systemic Lupus Erythematosus (SLE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 Ping Yi, Ming Zhao, and Qianjin Lu

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553 Luca Di Bartolomeo, Paolo Custurone, and Fabrizio Guarneri

22

Autoimmune Diseases Associated with Chikungunya Infection . . . . 585 Jozélio Freire de Carvalho, Mitesh Kumar Dwivedi, Luisa Rodrigues Cordeiro, Thelma Larocca Skare, and Yehuda Shoenfeld

Part VI

Microorganisms in Pathogenesis & Management of Idiopathic Inflammatory Myopathies

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM) and Polymyositis (PM) . . . . . . . . . . . . . . . . 611 Maria Giovanna Danieli, Alberto Paladini, Luca Passantino, and Eleonora Longhi

24

Microorganisms in Pathogenesis and Management of Necrotising Autoimmune Myopathy (NAM) and Inclusion Body Myositis (IBM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639 Maria Giovanna Danieli, Eleonora Antonelli, Cristina Mezzanotte, Mario Andrea Piga, and Eleonora Longhi

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657

About the Editors

Mitesh Kumar Dwivedi is an assistant professor of microbiology at C. G. Bhakta Institute of Biotechnology, Uka Tarsadia University. He has published 57 research papers in reputed journals, written 33 book chapters, and is the editor of 7 books. He has an h-index of 23 with 1729 citations for his research papers. He has more than 14 years of experience in research and teaching in various allied fields of microbiology and immunology. He has contributed significantly in the field of vitiligo—a skin autoimmune depigmenting disorder. His current research interests include investigation of immunogenetic, autoimmune, and therapeutic aspects of vitiligo, rheumatoid arthritis, sickle cell disease and role of probiotics in ameliorating the autoimmune diseases. He has been serving as an editorial board member and reviewer of many international journals. He has been honored with many international and national awards for his excellent research performance [DST-SERB Core Research Grant (2022), Research Excellence Award (2022), Best Researcher Award (2020), INSA Visiting Scientist Award (2019), DST-SERB Early Career Research Award (2018), Young Scientist Awards (2011, 2013, and 2018)] and secured all India rank “32” in CSIR-NET National examination (2011; Life Sciences). He has successfully completed research projects from national funding agencies such as SERBDST, GUJCOST, UTU, and Neosciences & Research Solutions Pvt. Ltd. and guided students for their doctoral and master’s degrees.

xvii

xviii

About the Editors

N. Amaresan is an assistant professor at C.G. Bhakta Institute of Biotechnology, Uka Tarsadia University, Gujarat. He has received his undergraduate, postgraduate, and doctorate degree in microbiology. Dr. N. Amaresan has over fifteen years of experience in teaching and research in various allied fields of microbiology mainly microbial ecology, plant–microbe interactions, and others. He has been awarded young scientist awards by Association of Microbiologists of India, National Academy of Biological Sciences and recipient of visiting scientist fellowship from National Academy of India. He has published more than 100 research articles, books, and book chapters of national and international reputes. He has handled various projects sponsored by DBT, DST, GEMI, etc., and guided students for their doctoral and master’s degrees. E. Helen Kemp completed her PhD in microbiology at the University of Warwick and the Centre for Applied Microbiology and Research, Salisbury, in 1988. Since 1989, she has worked at the University of Sheffield as a research fellow in the Medical School. She has longstanding interests in the autoimmune and genetic aspects of the depigmenting disease vitiligo, characterizing autoimmune responses against the calcium-sensing receptor in patients with parathyroid autoimmunity, and the etiology of autoimmune thyroid disease. She has published more than 70 research papers in these areas of research and has contributed to books and review articles in the field of autoimmunity. Yehuda Shoenfeld is the founder and previous head of the Zabludowicz Center for Autoimmune Diseases, at the Sheba Medical Center, which is affiliated to the Sackler Faculty of Medicine in Tel-Aviv University, in Israel. Professor Shoenfeld was also the Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases at the Tel-Aviv University. Professor Shoenfeld’s clinical and scientific works focus on autoimmune and rheumatic diseases, and he has published more than 2250 papers in reputed journals. His articles have had over 130,000 citations. His Scopus h-index is 123. He has written more than 350 chapters in books and has authored and edited 35 books, some of which

About the Editors

xix

became cornerstones in science and clinical practice. Professor Shoenfeld is on the editorial boards of 43 journals in the field of rheumatology and autoimmunity and is the founder and the editor of four high impact factor journals related to autoimmunity, science, and medicine. Professor Shoenfeld received the EULAR prize in 2005, in Vienna, Austria: “The infectious aetiology of anti-phospholipid syndrome,” and received a gold medal from the Slovak Society of Physicians for his contribution to Israel–Slovakia collaboration (March 2006). He is also an honorary member of the Hungarian Association of Rheumatology and the Royal Society of Physicians (UK). In UC Davis, USA, Professor Shoenfeld received the Nelson’s Prize for Humanity and Science for 2008. In 2009 he was honored as Doctoris Honoris Causa, from Debrecen University (Hungary) and Hasselt University in Belgium (2018) and from 2009 he is honorary member of the Slovenian National Academy of Sciences. He was recently awarded a Life Contribution Prize in Internal Medicine in Israel, 2012, as well as the ACR Master Award in 2013. In 2018, he was elected to the Israeli Academy of Sciences, and in 2021 he was nominated as a President of the Ariel University in Israel. Professor Shoenfeld has educated a long list of students with >55 becoming heads of departments and institutes.

Part I Overview of Infectious Microorganisms & Microbiota in Inducing Autoimmunity

1

The Concept of Infection-Triggered Autoimmunity Fabrizio Guarneri

Abstract

Hypothesized on an epidemiological basis soon after the discovery of autoimmunity, microbial triggering of autoimmune diseases is a complex and, despite the great efforts performed, not yet fully elucidated topic of current interest in basic and clinical research. While the causal link between some autoimmune diseases and specific infections has been demonstrated and explained, such association is more controversial in other cases, reflecting our incomplete knowledge of the multiple interactions occurring between microbes and the human immune system, as well as of the mechanisms that may transform a homeostatic and defensive system into a cause of disease and self-destruction. This chapter presents a general overview on the molecular basis of autoimmunity, the natural systems aimed at preventing this undesirable phenomenon, and the mechanisms by which microbial infections, in predisposed individuals and in specific circumstances, may alter the physiological equilibrium of the immune system, leading to autoimmune diseases: molecular mimicry, bystander activation of autoreactive cells, epitope spreading and polyclonal activation, and others, currently less known, which could prove interesting in the next future. Keywords

Autoimmunity · Autoimmune diseases · Microbes · Infections · Molecular mimicry · Bystander activation · Epitope spreading · Polyclonal activation · Superantigens

F. Guarneri (*) Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_1

3

4

1.1

F. Guarneri

Introduction

The idea that some infectious agents may trigger autoimmune diseases in genetically predisposed individuals and under certain conditions dates back to the beginning of the twentieth century, very soon after the theoretical definition and first experimental demonstrations of autoimmunity. In 1901, Paul Ehrlich proposed the possible existence of antibodies directed against self-antigens, a concept that was really revolutionary in that historical period (Plotz 2014). This hypothesis was experimentally confirmed few years later by Donath and Landsteiner: They observed that the serum of a patient who had developed hemoglobinuria after exposure of limbs to cold temperature contained autoantibodies which could specifically recognize erythrocytes from the same patient and fix complement after rewarming, ultimately leading to cell destruction (Donath and Landsteiner 1906). A link between autoimmunity and microbial infection was found shortly thereafter by Wasserman, who demonstrated that sera from patients affected by syphilis reacted not only against Treponema pallidum-infected tissues, but also against normal tissues (Plotz 2014), suggesting that the infection had somehow caused the onset of autoimmunity. Subsequent epidemiological studies further showed the significantly high frequency of association between some autoimmune diseases and infections, and the progress in immunology, particularly from the second half of the century, shed more light on the mechanisms of autoimmunity and confirmed the possible causal role of all kinds of microbes, including not only bacteria, but also viruses, fungi, and parasites (Martinelli et al. 2015). Experimental data suggested that immune response is a delicate and much more complex equilibrium than previously thought, whose evolution is influenced by genetic, individual, behavioral, environmental, and microenvironmental factors. Acting to take advantage of the biological resources of the host organism and/or for self-preservation, microbes may directly or indirectly alter this equilibrium in several ways, with results that are currently almost unpredictable. This complexity has several consequences that make investigation on microbial triggering of autoimmunity particularly difficult. First, contrary to speculations initially formulated on theoretical basis, there is no univocal or biunivocal association between specific microbes and specific autoimmune diseases: In other words, depending on the context of the interaction with the host, a given microorganism may be the trigger of multiple diseases, and a given disease may be triggered by different microorganisms (Getts et al. 2014, 2020; Martinelli et al. 2015). Second, the risk of developing an autoimmune disease after an infection is subject to large interindividual and even intraindividual variability (Getts et al. 2014, 2020; Martinelli et al. 2015). Third, but not least, microbes may—and, actually, do— alter the course of physiological host immune response by acting on multiple targets and pathways (Getts et al. 2014, 2020; Martinelli et al. 2015). Although the picture of immune response against infections (and its possible spontaneous and/or induced dysfunctions) is yet to be fully elucidated, some wellestablished elements and pathways are useful to understand, at least in part, infection-triggered autoimmunity. The first line of defense is the innate immune response, activated through the recognition of pathogen-associated molecular

1

The Concept of Infection-Triggered Autoimmunity

5

patterns by the family of human molecules defined as pattern recognition receptors (PRRs). The PRR family includes several members, such as toll-like receptors (TLRs), a subset of C-type lectin receptors (CLR), nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), and (RIG-I)-like helicases (Getts et al. 2014, 2020; Ishii et al. 2008). Activation of PRR-related pathways leads in turn to activation of several immune cell lines and biosynthesis and release of type I interferons, chemokines, cytokines, and costimulatory molecules. Other than exerting an aspecific antimicrobial role, these elements stimulate the clonal expansion of T and B lymphocytes, which are selected on the basis of their specificity for the peptides exposed, within MHC molecules, on the membrane of antigenpresenting cells (APCs) after internal processing of captured microbial antigens (Getts et al. 2014, 2020; Ishii et al. 2008). Tight regulation of all steps of this process is crucial: Events must occur with a precise timing, inflammation must be amplificated enough to provide an adequate clearance of infection but, at the same time, limited with both aspecific and antigenspecific mechanisms to avoid excessive damage to host cells and tissues, and the immune response must be selective enough to target the invading microorganism but not so highly selective as to be bypassed by small antigenic variations in the same microorganism (Getts et al. 2014, 2020; Ishii et al. 2008; Martinelli et al. 2015; Rose 2015). Alone or, more often, in combination, genetic polymorphisms/defects of one or more of the multiple factors involved in the host response to microbes, events of life (even not medically relevant), general condition of the organism at the time of infection, local condition at the point of infection, and microbial characteristics may impair the balancement of immune response, leading to autoimmunity (or, in a more recent view, causing excessive enhancement of self-reactive cells normally present in healthy organisms) and, in some cases, to the onset of overt autoimmune diseases (Blank et al. 2007; Floreani et al. 2016; Martinelli et al. 2015; Rose 2015).

1.2

Molecular Basis of Autoimmunity

The molecular basis of immunological autoreactivity can be understood through the analysis of the mechanism of antigen recognition and presentation. As outlined in the introduction of this chapter, after capture and enzymatic digestion of an antigen, fragments of it are exposed on the surface of APCs, within an MHC molecule. For the activation of an immune response, the MHC–peptide complex must be recognized by a specific T-cell receptor (TCR) or B-cell receptor (BCR) molecule. This recognition depends on the complementarity of the electrostatic, biochemical, and three-dimensional structure characteristics of the two molecular surfaces that come into contact (Roche and Cresswell 2016). Various combinations of different MHC and peptides may generate similar molecular surfaces, and the recognition mechanism has a certain degree of flexibility, because the presence of some amino acids in specific positions of the peptide (“anchor residues”) is sufficient for its binding to a given MHC molecule. As a consequence, some microbial peptides may

6

F. Guarneri

be undistinguishable by this system, opening the way for autoimmunity (Mason 1998). From an evolutionary point of view, the reasons for the existence of a nonperfectly selective defense mechanism may appear unclear, particularly when considering the high frequency of autoimmune diseases (according to some authors, about 5% of general population in industrialized countries) and their significant negative effects, which may include death in some cases. The explanation comes from the consideration that the human T-cell repertoire includes about 108 different clones, while the number of possible antigenic peptides is in the order of magnitude of 1012–1015, depending on their length. If each T-cell clone would be absolutely specific, i.e., able to recognize a single antigenic peptide, autoimmunity could be avoided, but only a number of antigens ranging between 1 out of 10,000 and 1 out of 10,000,000 could be identified, and the defensive function would be highly ineffective. In this model, total protection could be achieved only with a remarkably large increase of the portion of genetic code devoted to the immune system, and additional problems would arise: Small antigenic mutations would allow a microbe to easily avoid the specific immunity acquired by the host in a previous infection, and with the elimination of autoreactive T-cell clones from the available repertoire, necessary to avoid autoreactivity, microbes that mimic host antigens would become immunologically “invisible.” In the actual configuration of the immune system, each T-cell clone recognizes many slightly different antigenic peptides, thus allowing for recognition of a microbial species even after mutations, unless they involve some critical positions of the peptide, and often also of different microbial species of the same family, because of conserved molecular structures. So, the flexibility in the recognition of MHC–peptide complexes by TCR is a necessary condition for an effective immune surveillance, and antigenic cross-reactivity, also between self and non-selfmolecules, is at the same time an advantage and the biological “price” to be paid for it (Mason 1998). However, the above considerations generate another question: If each T-cell clone is able to recognize a number of different peptides ranging from 10,000 to 10,000,000, autoimmune diseases should be much more frequent than reported in epidemiological literature. Indeed, several mechanisms exist to inhibit the activation of lymphocyte clones with a high risk of autoreactivity and to limit the risk of autoimmunity (Anderson and Chan 2004; Anderton et al. 2001; Anderton and Wraith 2002; Hildeman et al. 2002; Ryan et al. 2007; Torina et al. 2018; Xing and Hogquist 2012).

1.3

Mechanisms of Prevention of Autoimmune Reactions

1.3.1

Central and Peripheral Deletion of Autoreactive T-Cell Clones

Deletion of autoreactive T-cell clones in the thymus was postulated as a protective mechanism against autoimmunity. Indeed, studies demonstrated that only highly dangerous clones are deleted, and those below a certain threshold of autoreactivity remain in the available repertoire (Ryan et al. 2007; Xing and Hogquist 2012).

1

The Concept of Infection-Triggered Autoimmunity

7

In addition to negative selection in the thymus, elimination of autoreactive T-cell clones among mature T cells of peripheral blood was observed in the course of an immune reaction. Specific T lymphocytes may also be deleted because of contact with MHC–peptide complexes presented by dendritic cells in “steady state,” i.e., devoid of the costimulatory molecules that are exposed on their surface, because of contact with pathogen-associated molecular patterns, during an infection. In this case, death of lymphocytes occurs as a consequence of the lack of expression of antiapoptotic proteins like Bcl-2, Bcl-xL, and NF-kB (Anderton et al. 2001; Anderton and Wraith 2002; Hildeman et al. 2002; Ryan et al. 2007; Xing and Hogquist 2012). Inefficient or incomplete deletion—central or peripheral—of autoreactive T-cell clones is linked to an increase of autoimmunity. Failure of negative selection may be due to inefficient recognition/presentation of self-molecules in secondary organs by immature APCs. Alterations of the apoptotic process may cause the persistence of autoreactive lymphocytes in the T-cell repertoire, but the mechanism is still unclear. For many researchers, this is simply due to missed apoptosis of the autoreactive lymphocytes, but another theory postulates that as a consequence of altered apoptosis, the release of autoantigens is not efficient enough to allow capture and presentation by tolerogenic APCs, thus preventing negative selection (Anderson and Chan 2004; Ryan et al. 2007; Xing and Hogquist 2012). The mere presence of autoreactive T lymphocytes in the organism is not sufficient to cause autoimmune diseases, as these cells need to be activated. APCs play a fundamental role in the induction of immunity (and autoimmunity). As outlined in the introduction of this chapter, TLRs and other PRRs directly and indirectly modulate specific immune response: When they are not stimulated, T regulatory (Treg) cells are active and prevent autoimmunity, while their stimulation induces specific cellular and/or humoral immune reaction (which in some cases becomes autoimmune) and inhibits Treg function through IL-6 (Blank et al. 2007; Floreani et al. 2016; Getts et al. 2014, 2020; Ishii et al. 2008; Rose 2015). The role of natural killer T (NKT) cells in autoimmune diseases is certainly important but not yet completely defined. Experimental evidence shows that a decrease of NKT cells favors the development of autoimmunity, while induction of their increase may positively influence the course of some autoimmune diseases, as observed in murine models of diabetes. However, NKT cells cannot be simplistically considered as suppressors of the immune response, as they play a demonstrated role in the promotion of antitumor immunity (Torina et al. 2018). Another step for the development of an autoimmune disease is the expansion of the activated autoreactive T-cell clone, which requires modulation of the mechanisms which control lymphocyte proliferation. Lymphocyte homeostasis is maintained thanks to the balancement of cytokines. Several studies evaluated the effects of modified levels of each cytokine, but the overall picture is not completely clear because of the multiple mediators involved, with frequent functional overlaps and/or interactions. Some studies also underlined the importance of the SOCS (Suppressors of Cytokine Signaling) proteins, negative regulators of cytokine signaling, which represent an interesting field of research, also from a therapeutic point

8

F. Guarneri

of view. Last but not least, possible alterations of the apoptotic process might also play a role (Vella et al. 1995; Yoshimura et al. 2007). Reactivation of anergic T cells may also contribute to the increase of activated autoreactive T lymphocytes. In this model, failure of peripheral deletion of autoreactive clones would create a pool of anergic autoreactive lymphocytes, which could be reactivated by several factors at any time (Schwartz 2003).

1.3.2

Anergy/Adaptation

The term “anergy” was originally used to describe the lack of IL-2 production by properly stimulated (with specific antigen and costimulatory molecules) T cells, if those cells had been previously stimulated through TCR only, without costimulation. However, successive studies showed that this is not a good model of the development of tolerance in vivo (defined as “adaptive anergy”), which induces total unresponsiveness of inhibited lymphocytes (no proliferation, no production of IL-2, or effector cytokines) and depends on antigen persistence (inhibited functions may be fully recovered if the lymphocytes are experimentally transferred in a host which does not possess the antigen targeted by that cell clone) (Grossman and Paul 2001; Kuklina 2013; Sakaguchi 2005; Schwartz 2003; Zheng et al. 2008). On the basis of experimental data, Grossman and Paul proposed the theory of “adjustable activation threshold,” which postulates that T cells may calibrate the threshold of their maximum activation in relation to the environmental antigenic stimuli perceived (Grossman and Paul 2001). This mechanism was initially demonstrated at a peripheral level, in steady-state conditions, and subsequently observed also in experimental conditions similar to those found during infections. There is also evidence that thymocytes may undergo desensitization, rather than apoptosis, during their development, in response to a relatively strong antigenic signal (Grossman and Paul 2001; Kuklina 2013; Sakaguchi 2005; Schwartz 2003; Zheng et al. 2008).

1.3.3

Immune Regulation

The action of Treg cells, CD4+CD25+ lymphocytes, is a factor that limits the expansion of activated autoreactive T lymphocytes. As in the case of NKT cells, experimental models show that elimination of Treg cells accelerates the progression of autoimmune diseases, while their increase has a protective effect. Indeed, in subjects affected by autoimmune diseases, the function of Treg cells is usually decreased (Giganti et al. 2021; Pasare and Medzhitov 2003; Sakaguchi et al. 2020; Zhang et al. 2021; Zohouri et al. 2021). The model proposed postulates that developing thymocytes whose affinity for MHC–self-peptide complexes is high, but not enough to activate the mechanisms of clonal deletion, tend to differentiate as Treg cells. Because of the aforementioned high affinity, these cells have a significant advantage over other autoreactive cells in the selection process which determines the type of immune response, and this explains their ability to prevent autoimmune

1

The Concept of Infection-Triggered Autoimmunity

9

diseases (Giganti et al. 2021; Pasare and Medzhitov 2003; Sakaguchi et al. 2020; Zhang et al. 2021; Zohouri et al. 2021). Moreover, Treg cells may limit immunologic priming during the inflammatory process (Giganti et al. 2021; Pasare and Medzhitov 2003; Sakaguchi et al. 2020; Zhang et al. 2021; Zohouri et al. 2021).

1.4

Mechanisms of Microbial Triggering of Autoimmunity

Several mechanisms have been postulated, and experimentally demonstrated in different contexts, to explain infection triggered autoimmunity and autoimmune diseases. These mechanisms are not to be considered as mutually exclusive and, indeed, two or more of them may sequentially or simultaneously occur in the pathogenetic processes (Getts et al. 2014, 2020; Martinelli et al. 2015). The most credited and better defined are molecular mimicry, bystander activation of autoreactive cells, epitope spreading, and polyclonal activation (Blank et al. 2007; Floreani et al. 2016; Getts et al. 2014, 2020; Martinelli et al. 2015).

1.4.1

Selection and Deception: Mimicry and Molecular Mimicry

1.4.1.1 Mimicry Similarity of specific characters of different living organisms is a well-known and common phenomenon in nature, and the degree of similarity was considered since the origins of biology as an index of the phylogenetic distance between species, useful also for classification purposes. However, the finding of identical or very similar characters in biologically, and often also geographically, distant species remained for a long time an apparently unexplainable contradiction of the above principle. A significant change in our understanding of this peculiarity and, more important, of the underlying reasons and mechanisms, began in 1862, when Henry Walter Bates published the results of his studies on some animal species of the Amazon valley (Bates 1862). In particular, he reported that some lepidoptera, although belonging to different families (Pieridae and Nymphalidae), showed an unexpected similarity of their wings. Bates observed that Nymphalidae are not edible for some predator species, which learn through experience to identify (and avoid) them on the basis of the typical color pattern of the wings. The chance of survival for Pieridae, which would be edible for the same predators, is remarkably increased thanks to the similarity of their wings with those of Nymphalidae, resulting from a process of natural selection over time. The term “mimicry” was used for the first time by Bates to describe this phenomenon, and successive researchers defined as “Batesian mimicry” all cases where a species, to defend itself from a predator, resembles characteristics of another species which is noxious for that predator (Anderson and de Jager 2020). The development of similar morphologic and/or behavioral characteristics (defensive systems, thermal regulation, etc.) in different species when exposed to specific environmental conditions had been already described earlier. However, the

10

F. Guarneri

work published by Bates introduced a profound conceptual revolution: While the interaction between organisms and environment was until then considered only of a physical and/or biochemical type, the new discovery suggested that some relationships between different species (prey–predator) were based on information transmitted through a visual code. Moreover, data demonstrated that some species deceptively used this code to convey misleading information, as a system of adaptation to the environment. Subsequent studies showed that the communication code is not only visual, but may also be acoustic, olfactory, behavioral; however, apart from some details, the original definition of mimicry given about 160 years ago is substantially still valid (Anderson and de Jager 2020). An apparent contradiction to the “theory of mimicry“ emerged some years later, when Bates found that a similar color pattern was shared by some unrelated species of butterflies, all nonedible for the same predators: In this case, mimicry did not give any advantage, in terms of survival, to one of the species involved. The solution to the “Bates paradox” was found by Fritz Müller (1878), who suggested that the “standardization” of the visual signal allowed to split between more than one species the number of individuals sacrificed for the learning of predators. In other terms, when a predator eats a prey and learns that it is nonedible, all similar prey species gain an advantage; moreover, victims of this learning process are equally divided between all similar prey species, rather than only one (Müller 1878). This type of mimicry is termed “Mullerian mimicry.” However, some authors argue that this mechanism cannot be strictly defined “mimicry,” because the information transmitted is not deceiving, and it is not possible to distinguish a model and a mimicking species. Another type of mimicry is termed “Emsleyan” (from M.G. Emsley, who firstly proposed it) or “Mertensian” (from the German herpetologist R. Mertens). In this case, initially demonstrated in the Micrurus tener snake, a prey, which can cause the death of its predator, shows the characters of a less noxious species (Emsley 1966). This apparently gives no evolutionary advantage, because the death of the predator prevents learning, but studies demonstrated that it leads to the selection of predators that have an instinctive and genetically transmitted tendency to avoid preys characterized by specific chromatic patterns, and also that predators may learn to avoid some preys or behaviors from the observation of negative effects on other individuals of their own kind (Jouventin et al. 1977). A fourth type of mimicry is termed “aggressive mimicry,” and is used by predators that resemble characteristics of other species to deceive and capture preys. A typical example of aggressive mimicry is that of some insects which can resemble plant elements (flowers, leaves) (Anderson and de Jager 2020). Some authors also consider a fifth type of mimicry, defined “automimicry,” which is indeed a particular case of Batesian mimicry. In this case, an individual of a species resembles a characteristic of a different type of individual of the same species (Speed et al. 2006). Examples are frequent in many families of bees and wasps, where male subjects, which do not have defensive systems against predators, deceptively show color patterns typical of females of the same species, equipped with a sting and for this reason avoided by predators.

1

The Concept of Infection-Triggered Autoimmunity

11

1.4.1.2 Molecular Mimicry The great progress of knowledge and technology in biology and laboratory techniques led, in relatively recent times, to discover that also at a molecular level mimicry plays a significant role in the interactions between organisms. Indeed, the phenomenon of “molecular mimicry” is widely present in nature and probably even more frequent than its “macroscopic” counterpart, and while sharing general rules with it, shows some distinctive and important peculiarities (Rojas et al. 2018). Limiting the discussion simply to the field of medical interest for the sake of brevity, the role played by molecular mimicry in the interaction between the human body and pathogenic microorganisms cannot be classified in one of the aforementioned types: Use of mimicry by pathogens to attack the host may be considered an example of “aggressive mimicry,” but in this case, the mimicked “model” is the prey. Moreover, at the same time, a series of mechanisms are activated by the host as a reaction to destroy the attacking microorganism, which in turn uses molecular mimicry to defend itself, like a prey in the scheme of Batesian mimicry. Another peculiarity is that, from a biological point of view, the interest of pathogens is not to kill the host organism, but to exploit its resources for as long as possible: This is particularly true in the case of viruses, which entirely rely on the biosynthetic structures of infected cell for replication and propagation. In the light of the above considerations, molecular mimicry appears as a powerful way for microorganisms to hijack to their own advantage the metabolic pathways of the host, but it must be finely regulated to fit into the complex and delicate network of molecular signals without excessively damaging it. Generally, there are no characteristics in nature which confer an “absolute” advantage to a species over another. The rare exceptions to this rule usually imply the concomitant occurrence of abrupt environmental changes, and cause the extinction of the disadvantaged species. In the vast majority of cases, each adaptation mechanism has its own level of efficacy, usually defined “fitness,” which is variable and depends on the synergy of multiple variables, but typically never reaches zero nor the highest possible values. Mimicry, at a macroscopic as well as at a molecular scale, is no exception to this rule: In a specific complex of (micro)environmental conditions, the ratio between predators and preys tends to be constant, suggesting the development of mechanisms able to contrast the advantage gained by some species through exploitation of molecular mimicry. Similarly, the human organism is able, in ways not yet completely understood, to identify and effectively counteract pathogens despite their use of molecular mimicry for invasion and self-protection against the host immune system. However, the human defensive mechanism against molecular mimicry is not absolutely effective and precise, intrinsically and because of the interference of pathogens, and consequently it may sometimes happen that an immune reaction raised against a “non-self”-molecule mistakenly turns against an antigenically similar self-molecule and ultimately causes an autoimmune disease (Cusick et al. 2012; Rojas et al. 2018). The mechanisms by which molecular mimicry between microbial and human molecules may interfere with normal biologic functions of the human organism, and become part of pathogenic processes, may be divided in two groups.

12

F. Guarneri

Emulation of Human Regulatory Molecules, with Consequent Improper Stimulation and/or Inhibition of Homeostatic Mechanisms Several microbes are able to produce proteins similar to the human ones involved in the regulation of fundamental processes like control of apoptosis and cell proliferation, induction, maintaining and inhibition of inflammation, regulation of immune response, and Th1/Th2 balance. A typical example is that of human herpesvirus 8 (HHV8), notoriously linked to Kaposi’s sarcoma: It was experimentally demonstrated that this virus extensively exploits molecular mimicry to interact with internal cell mechanisms at multiple levels (Sturzl et al. 1999). The genetic loci ORFK12 and ORFK72 (ORF ¼ Open Reading Frame) of HHV8 are responsible for the synthesis of vFLIP, a viral analog of the protein that inhibits FLICE (Fas-associated death domain-like interleukin 1 beta-converting enzyme), and v-cyc-D, a viral analog of human cyclin D, respectively. The products of these genes mimic the action of human proteins involved, in different ways, in apoptosis: Namely, FLIP (FLICE-Inhibiting Protein) prevents cell apoptosis mediated by tumor necrosis factor (TNF)-alpha and Fas-ligand, while cyclin D, through activation of the cyclin dependent kinases (CDKs) 4 and 6, induces phosphorylation and inactivation of pRb, the product of the RB1 gene, whose role in case of DNA damage is to temporarily stop the G1 phase of the cell cycle and prevent transition in the S phase. HHV8 also produces a homolog of Bcl-2, which can block Bax-induced apoptosis, and of the interferon regulating factor (IRF), a transcription factor which regulates response to interferons. Molecular mimicry is also exploited by the virus to influence the immune system, because the viral homologs of human interleukin (IL)-6 and macrophage inflammatory proteins (MIP) I, II, and III cause the switch from a Th1to a Th2-type response. Taken together, the actions performed by these viral proteins explain the oncogenicity of HHV8, as they alter the control of cell proliferation, inhibit apoptosis, and prevent proper reaction of the immune system against infected/damaged cells (Sturzl et al. 1999). Induction of Autoimmunity The strict epidemiologic and chronologic association between some infections and diseases with certain or suspect autoimmune pathogenesis is well known: Examples are diabetes (Xie et al. 2014), autoimmune thyroid diseases (Benvenga and Guarneri 2016), multiple sclerosis (Cossu et al. 2018), systemic lupus erythematosus (IllescasMontes et al. 2019), scleroderma (Gourh et al. 2020), and lichen sclerosus (Guarneri et al. 2017). Molecular mimicry may give a plausible explanation of this association: Because of the similarity between microbial and self-antigens, the defensive immune response of the host may, in some cases, turn against components of its own body. The first mention of the term “molecular mimicry” dates back to the end of January 1976, in an article published on The Lancet by Shapiro et al. (1976), who proposed this mechanism as a possible explanation for the association between HLA-B27 and inflammatory arthropathies. Although the idea of molecular mimicry was interesting, its demonstration remained impossible for a long time, because of the technical limits of laboratory methods of that period, and only three more articles on this topic were published in the 1970s. The technological progress occurred in the

1

The Concept of Infection-Triggered Autoimmunity

13

1980s led to the first experimental evidences and a consequent increase of the interest of researchers, as confirmed by the 90 papers published in that decade. Among these, fundamental is the paper by Fujinami and Oldstone (1989), who fully enunciated the theory of molecular mimicry as trigger of autoimmune diseases. The complete maturation of research in this field occurred in the 1990s, thanks to the combination of availability of better systems for the analysis of biologic macromolecules, exponential development of the calculation power of computers with almost proportional reduction of their cost, and worldwide expansion of informatic databases and networks with simultaneous simplification of access and use. In brief, it was experimentally demonstrated in animal models, and confirmed by observation of patients, that in genetically predisposed subjects and in particular circumstances, similarity between a microbial antigen and a human autoantigen may turn a physiological immune reaction against infection into an autoimmune reaction (Rojas et al. 2018). In combination with traditional laboratory techniques, bioinformatics allowed large-scale, fast, and low-cost analysis of the molecules involved, showing that in some cases, there is a strict similarity, or even identity, between large portions or epitopes of microbial and human antigens, while in other cases, the flexibility of the antigen recognition mechanism is responsible for cross-reactivity between molecules with a rather limited amino acid homology. However, this is not sufficient to elicit an autoimmune disease: Additional signals, given by infection and currently known only in part, are necessary. Indeed, transgenic animals expressing a microbial antigen responsible for an autoimmune disease do not develop the corresponding disease spontaneously, but only when infected with the microbe which bears that antigen (Evans et al. 1996; Oldstone et al. 1991). Also, animals stimulated with a combination of a peptide which mimics an autoantigen and Freund’s adjuvant show intense proliferation of specific T cells but do not develop the corresponding autoimmune disease, which instead occurs when the infective pathogen is added (Carrizosa et al. 1998; Croxford et al. 2006). When proper conditions are met, even autoreactive T cells with a low affinity for the autoantigen are able to induce autoimmune diseases: This was confirmed in experiments where expression of a microbial antigen responsible for an autoimmune disease was induced in the thymus, thus inducing negative selection of T cells highly specific for that antigen, but the disease occurred anyway after infection (von Herrath et al. 1994). Finally, the frequency of infection-induced autoimmune diseases is not equal for all microbes whose molecules share similarity with human autoantigens, and not all cases of infection caused by a given microbe determine the onset of an autoimmune disease. These data suggest that other cofactors play a role in determining the fate of the interaction between immune system and microbes: Pathogens may hijack immune response, again via molecular mimicry or in other ways, thus increasing or decreasing the probability of an autoimmune response; number, avidity, and affinity of autoreactive T cells may largely vary between individuals, and even in the same individual under different circumstances; innate inflammatory signals must

14

F. Guarneri

be activated to the right extent and for an adequate time (Blank et al. 2007; Cusick et al. 2012; Getts et al. 2014; Martinelli et al. 2015; Rojas et al. 2018).

1.4.1.3 Bystander Activation of Autoreactive Lymphocytes The mechanism of bystander activation was described for the first time by Tough and collaborators in 1996. In this model, signals produced during a specific immune reaction and determining an inflammatory milieu (microbial particles, cytokines, and chemokines) may cause TCR- or BCR-independent activation of other nonantigenspecific T or B cells (Tough et al. 1996). In physiological conditions, bystander activation is involved in “maintenance operations” of the human organism, such as B-cell development and homeostasis and clearance or particles resulting from apoptosis. In some infections, bystander activation is essential for the host to bypass and/or counteract the effects of some microbial substances which would inhibit and/or hijack the immune response (Boyman 2010; Pacheco et al. 2019). However, this mechanism may become a cause of autoimmune disease when autoreactive lymphocytes are activated. Evidence exists of the involvement of bystander activation in the pathogenesis of many frequent autoimmune diseases, type 1 diabetes, rheumatoid arthritis, autoimmune thyroid disease, multiple sclerosis, systemic lupus erythematosus, and autoimmune hepatitis (Boyman 2010; Pacheco et al. 2019). 1.4.1.4 Epitope Spreading Immune response requires interaction of the immune system with solvent-exposed epitopes of antigens. However, antigens typically have several epitopes, some of which are located in normally inaccessible parts of the molecule, and become solvent-exposed only after conformational changes or structural alteration of the molecule itself. The development of immune reactions against these “hidden” or “cryptic” epitopes, different from dominant epitopes and not cross-reactive with them, is defined “epitope spreading.” The phenomenon is defined “intramolecular spreading” when the immune response against a molecule spreads toward other epitopes of the same molecule, “intermolecular spreading” when it involves epitopes belonging to different molecules (Cornaby et al. 2015; Powell and Black 2001). The term “epitope spreading” is used in a broader sense in discussions on the pathogenesis of autoimmune diseases: In this case, it also includes the development of immune response against autoantigens which are located in compartments normally not accessible to the immune system, and become “immunologically visible” only as a consequence of tissue or cell damage during a chronic autoimmune or infectious process (Powell and Black 2001). Like molecular mimicry and bystander activation, epitope spreading is not an error, but a normal process of the immune response, which has beneficial effects when correctly operating. In detail, it is particularly useful in antimicrobial and antitumor response, because it allows to hit multiple molecular targets and provides a stronger, more complete, and timely clearance. However, as outlined above, this mechanism becomes dangerous when autoantigens are involved. The case of normally “sequestered” autoantigens is peculiar: As they are always “hidden,” negative

1

The Concept of Infection-Triggered Autoimmunity

15

clonal selection of lymphocytes specific for these molecules is not possible; consequently, although being part of the self, from the point of view of the immune system, they are new/unknown antigens, and lymphocyte clones with high specificity and affinity against them may exist. Examples of autoimmune diseases whose known pathogenetic mechanisms include epitope spreading are bullous pemphigoid, systemic lupus erythematosus, and paraneoplastic pemphigus (Cornaby et al. 2015; Powell and Black 2001).

1.4.1.5 Polyclonal Activation Some microbes may produce superantigens, molecules able to directly interact with MHC-II and TCR and generate antigen-independent and nonantigen-specific activation of a large number (up to 20%) of the T cells of the host, with consequent massive release of proinflammatory substances (Deacy et al. 2021; Llewelyn and Cohen 2002). In detail, one of the domains of a superantigen initially binds to an MHC-II molecule, preferentially those encoded by HLA-DQ genes. Superantigens most frequently bind to the alpha chain of MHC molecules, although binding to beta chain has been documented in some cases. When binding to both chains, superantigens cause cross-linking of MHC molecules and induce not only cytokines, but also expression of costimulatory molecules on the surface of APCs (Deacy et al. 2021). Subsequently, another domain of the superantigen binds to a TCR, namely to the variable region of the beta chain (Vβ). This elicits an immune response which is similar to that of classical antigen presentation, but is not antigen-specific and involves a large number of clones, because each Vβ is shared by multiple TCRs, and, moreover, some superantigens may bind to multiple Vβs (Alouf and MüllerAlouf 2003; Deacy et al. 2021; Li et al. 2015; Spaulding et al. 2013). In the acute phase of this uncoordinated immune response, a massive inflammatory reaction occurs, which can even lead to multiorgan failure or death. After this phase, mistakenly activated self-reactive lymphocytes may lead to autoimmune diseases (Alouf and Müller-Alouf 2003; Deacy et al. 2021). Prolonged microbial infections, like those caused by some viruses, are another possible cause of polyclonal activation of immune cells: Because of the continuous antigenic stimulation, loss of tolerance toward self-molecules may eventually occur, with mechanisms not yet fully elucidated (Getts et al. 2014; Fujinami et al. 2006).

1.5

New and Emerging Mechanisms of Microbial Induction of Autoimmune Diseases

In addition to the most studied and verified ones, some other mechanisms have been proposed and demonstrated in specific cases of autoimmune diseases; their importance remains to be fully explored and could significantly increase with the progress of knowledge in this field.

16

F. Guarneri

One of the possible consequences of the hijacking of the normal functions of the human immune system, performed by microbes to avoid recognition and killing, is the selection and activation of autoreactive lymphocytes (Getts et al. 2014; King et al. 2007). It has also been shown that some viruses are able to immortalize autoreactive cells or increase their resistance to death, and even drive their differentiation (Nanbo et al. 2002; Pender 2003; Thorley-Lawson and Gross 2004). Finally, microbial products may cause lipid raft aggregation on the membrane of lymphocytes and, through this mechanism, enhance immune signaling (Deng and Tsokos 2008; James and Robertson 2012).

1.6

Conclusions

Understanding the mechanisms that lead to the development of autoimmune diseases has always been a fundamental goal of basic and clinical research, not only for the great scientific interest of the topic, but also for the possible implications in prevention and treatment. Microbial infections certainly cannot be considered the universal explanation for autoimmune diseases, but their decisive triggering role has been experimentally confirmed in several cases and is suspected, with different strength of evidence, in many others. Indeed, the “relative weight” of infections in the pathogenesis of autoimmune diseases appears far from being completely defined. What we currently know could be the so-called “tip of the iceberg,” because the interaction between microbes and humans often produces mild, aspecific symptoms or is totally asymptomatic, making it difficult to define a connection with an autoimmune disease that may even occur after a long time and in a distant body site, as a consequence of that interaction or of a chain of events triggered by it. Moreover, infections might represent only a part of the much wider picture of the dynamic equilibrium between the human body and the extremely large number of commensal microbes living on and inside it (a topic that, for its complexity, will be discussed separately in this book), and of the interactions of this holobiont (functional unit of human host and commensal microbes) with the environment. Ultimately, 120 years after the intuition of autoimmunity by Paul Ehrlich and more than 100 years after the observations made by Wasserman on the crossreactivity between microbial and human antigens, this argument does not appear to have aged at all; rather, what has been discovered so far appears to be just the beginning of a long and fascinating journey, potentially capable of substantially changing our way of thinking in this field.

References Alouf JE, Müller-Alouf H (2003) Staphylococcal and streptococcal superantigens: molecular, biological and clinical aspects. Int J Med Microbiol 292:429–440

1

The Concept of Infection-Triggered Autoimmunity

17

Anderson CC, Chan WF (2004) Mechanisms and models of peripheral CD4 T cell self-tolerance. Front Biosci 9:2947–2963 Anderson B, de Jager ML (2020) Natural selection in mimicry. Biol Rev Camb Philos Soc 95:291– 304 Anderton SM, Wraith DC (2002) Selection and fine-tuning of the autoimmune T-cell repertoire. Nat Rev Immunol 2:487–498 Anderton SM, Radu CG, Lowrey PA et al (2001) Negative selection during the peripheral immune response to antigen. J Exp Med 193:1–11 Bates HW (1862) Contributions to an insect fauna of the Amazon valley. Lepidoptera: Heliconidae. Trans Linnean Soc 23:495–566 Benvenga S, Guarneri F (2016) Molecular mimicry and autoimmune thyroid disease. Rev Endocr Metab Disord 17:485–498 Blank M, Barzilai O, Shoenfeld Y (2007) Molecular mimicry and auto-immunity. Clin Rev Allergy Immunol 32:111–118 Boyman O (2010) Bystander activation of CD4+ T cells. Eur J Immunol 40:936–939 Carrizosa AM, Nicholson LB, Farzan M et al (1998) Expansion by self antigen is necessary for the induction of experimental autoimmune encephalomyelitis by T cells primed with a crossreactive environmental antigen. J Immunol 161:3307–3314 Cornaby C, Gibbons L, Mayhew V, Sloan CS, Welling A, Poole BD (2015) B cell epitope spreading: mechanisms and contribution to autoimmune diseases. Immunol Lett 163:56–68 Cossu D, Yokoyama K, Hattori N (2018) Bacteria-host interactions in multiple sclerosis. Front Microbiol 9:2966 Croxford JL, Ercolini AM, Degutes M et al (2006) Structural requirements for initiation of crossreactivity and CNS autoimmunity with a PLP139-151 mimic peptide derived from murine hepatitis virus. Eur J Immunol 36:2671–2680 Cusick MF, Libbey JE, Fujinami RS (2012) Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol 42:102–111 Deacy AM, Gan SK, Derrick JP (2021) Superantigen recognition and interactions: functions, mechanisms and applications. Front Immunol 12:731845 Deng GM, Tsokos GC (2008) Cholera toxin B accelerates disease progression in lupus-prone mice by promoting lipid raft aggregation. J Immunol 181:4019–4026 Donath J, Landsteiner K (1906) Ueber paroxysmale hamoglobinurie. Z Klin Med 58:173–189 Emsley MG (1966) The mimetic significance of Erythrolamprus aesculapii ocellatus Peters from Tobago. Evolution 20:663–664 Evans CF, Horwitz MS, Hobbs MV et al (1996) Viral infection of transgenic mice expressing a viral protein in oligodendrocytes leads to chronic central nervous system autoimmune disease. J Exp Med 184:2371–2384 Floreani A, Leung PS, Gershwin ME (2016) Environmental basis of autoimmunity. Clin Rev Allergy Immunol 50:287–300 Fujinami RS, Oldstone MB (1989) Molecular mimicry as a mechanism for virus-induced autoimmunity. Immunol Res 8:3–15 Fujinami RS, von Herrath MG, Christen U et al (2006) Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev 19:80–94 Getts DR, Getts MT, King NJC et al (2014) Infectious triggers of T cell autoimmunity. In: Rose NR, Mackay IR (eds) The autoimmune diseases, 5th edn. Academic Press, London, pp 263–274 Getts DR, Spiteri A, King NJC et al (2020) Microbial infection as a trigger of T cell autoimmunity. In: Rose NR, Mackay IR (eds) The autoimmune diseases, 6th edn. Academic Press, London, pp 363–374 Giganti G, Atif M, Mohseni Y et al (2021) Treg cell therapy: how cell heterogeneity can make the difference. Eur J Immunol 51:39–55 Gourh P, Safran SA, Alexander T et al (2020) HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry. Proc Natl Acad Sci U S A 117:552–562

18

F. Guarneri

Grossman Z, Paul WE (2001) Autoreactivity, dynamic tuning and selectivity. Curr Opin Immunol 13:687–698 Guarneri F, Giuffrida R, Di Bari F et al (2017) Thyroid autoimmunity and lichen. Front Endocrinol (Lausanne) 8:146 Hildeman DA, Zhu Y, Mitchell TC et al (2002) Molecular mechanisms of activated T cell death in vivo. Curr Opin Immunol 14:354–359 Illescas-Montes R, Corona-Castro CC, Melguizo-Rodríguez L et al (2019) Infectious processes and systemic lupus erythematosus. Immunology 158:153–160 Ishii KJ, Koyama S, Nakagawa A et al (2008) Host innate immune receptors and beyond: making sense of microbial infections. Cell Host Microbe 3:352–363 James JA, Robertson JM (2012) Lupus and Epstein-Barr. Curr Opin Rheumatol 24:383–388 Jouventin P, Pasteur G, Cambefort JP (1977) Observational learning of baboons and avoidance of mimics: exploratory tests evolution. Evolution 31:214–218 King NJ, Getts DR, Getts MT et al (2007) Immunopathology of flavivirus infections. Immunol Cell Biol 85:33–42 Kuklina EM (2013) Molecular mechanisms of T-cell anergy. Biochemistry (Mosc) 78:144–156 Li J, Yang J, Lu YW et al (2015) Possible role of staphylococcal enterotoxin B in the pathogenesis of autoimmune diseases. Viral Immunol 28:354–359 Llewelyn M, Cohen J (2002) Superantigens: microbial agents that corrupt immunity. Lancet Infect Dis 2:156–162 Martinelli M, Agmon-Levin N, Amital H et al (2015) Infections and autoimmune diseases: an interplay of pathogenic and protective links. In: Shoenfeld Y, Agmon-Levin N, Rose NR (eds) Infection and autoimmunity, 2nd edn. Academic Press, London, pp 13–23 Mason D (1998) A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol Today 19:395–404 Müller F (1878) Ueber die vortheile der mimicry bei schmetterlingen. Zool Anz 1:54–55 Nanbo A, Inoue K, Adachi-Takasawa K et al (2002) Epstein-Barr virus RNA confers resistance to interferon-alpha induced apoptosis in Burkitt’s lymphoma. EMBO J 21:954–965 Oldstone MB, Nerenberg M, Southern P et al (1991) Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65:319– 331 Pacheco Y, Acosta-Ampudia Y, Monsalve DM et al (2019) Bystander activation and autoimmunity. J Autoimmun 103:102301 Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033–1036 Pender MP (2003) Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol 24:584–588 Plotz PH (2014) Autoimmunity: the history of an idea. Arthritis Rheumatol 66:2915–2920. https:// doi.org/https://doi.org/10.1002/art.38796 Powell AM, Black MM (2001) Epitope spreading: protection from pathogens, but propagation of autoimmunity? Clin Exp Dermatol 26:427–433 Roche PA, Cresswell P (2016) Antigen processing and presentation mechanisms in myeloid cells. Microbiol Spectr 4. https://doi.org/10.1128/microbiolspec.MCHD-0008-2015 Rojas M, Restrepo-Jiménez P, Monsalve DM et al (2018) Molecular mimicry and autoimmunity. J Autoimmun 95:100–123 Rose NR (2015) Introduction. In: Shoenfeld Y, Agmon-Levin N, Rose NR (eds) Infection and autoimmunity, 2nd edn. Academic Press, London, pp 1–12 Ryan KR, Patel SD, Stephens LA et al (2007) Death, adaptation and regulation: the three pillars of immune tolerance restrict the risk of autoimmune disease caused by molecular mimicry. J Autoimmun 29:262–271 Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+ CD4+ regulatory T cells in immunological tolerance to self and nonself. Nat Immunol 6:345–352

1

The Concept of Infection-Triggered Autoimmunity

19

Sakaguchi S, Mikami N, Wing JB et al (2020) Regulatory T cells and human disease. Annu Rev Immunol 38:541–566 Schwartz RH (2003) T cell anergy. Annu Rev Immunol 21:305–334 Shapiro RF, Wiesner KB, Bryan BL et al (1976) HLA-B27 and modified bone formation. Lancet 1: 230–231 Spaulding AR, Salgado-Pabón W, Pl K et al (2013) Staphylococcal and streptococcal superantigen exotoxins. Clin Microbiol Rev 26:422–447 Speed MP, Ruxton GD, Broom M (2006) Automimicry and the evolution of discrete prey defences. Biol J Linn Soc 87:393–402 Sturzl M, Hohenadl C, Zietz C et al (1999) Expression of K13/v-FLIP gene of human herpesvirus 8 and apoptosis in Kaposi's sarcoma spindle cells. J Natl Cancer Inst 91:1725–1733 Thorley-Lawson DA, Gross A (2004) Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 350:1328–1337 Torina A, Guggino G, La Manna MP et al (2018) The Janus face of NKT cell function in autoimmunity and infectious diseases. Int J Mol Sci 19:440 Tough DF, Borrow P, Sprent J (1996) Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 272:1947–1950 Vella AT, McCormack JE, Linsley PS et al (1995) Lipopolysaccharide interferes with the induction of peripheral T cell death. Immunity 2:261–270 von Herrath MG, Dockter J, Oldstone MB (1994) How virus induces a rapid or slow onset insulindependent diabetes mellitus in a transgenic model. Immunity 1:231–242 Xie Z, Chang C, Zhou Z (2014) Molecular mechanisms in autoimmune type 1 diabetes: a critical review. Clin Rev Allergy Immunol 47:174–192 Xing Y, Hogquist KA (2012) T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol 4:a006957 Yoshimura A, Naka T, Kubo M (2007) SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 7:454–465 Zhang R, Miao J, Zhu P (2021) Regulatory T cell heterogeneity and therapy in autoimmune diseases. Autoimmun Rev 20:102715 Zheng Y, Zha Y, Gajewski TF (2008) Molecular regulation of T-cell anergy. EMBO Rep 9:50–55 Zohouri M, Mehdipour F, Razmkhah M et al (2021) CD4(+)CD25()FoxP3(+) T cells: a distinct subset or a heterogeneous population? Int Rev Immunol 40:307–316

2

The Interaction of Gut Microbiota with Immune System and Their Effects on Immune Cell Development and Function Priyanka Sarkar

Abstract

The quest of revealing colonization of unicellular organisms in a multicellular organism, creating complex networks and regulating the host immunity and dayto-day activities is indeed the flaming concern for this decade. Undoubtedly, the inquisitive scientists have long been thronged with wonders of prokaryotic association in human health. Since the era of Socrates, to unfold the gut microbial mysterious associations in the host survival, has been the food for the researchers. In this purview, the key gut microbial role in host immunity development and maintenance will be discussed in this chapter. Keywords

Immune system · Gut microbiome · Immune modulation · Adaptive and innate immunity

2.1

Introduction

The immune system of an individual is accountable for protecting and defending the host from invading pathogens. Other than this, the immune system also plays a noteworthy role in identifying and destroying tumour cells; along with this, it is also the responsibility of the immune system to discriminate self-cells from non-self-cells for avoiding the disastrous immune responses against the host tissue. The immune system is made up of an innate immune system and an adaptive immune system

P. Sarkar (*) Wellcome/DBT (Indian Alliance) Lab, Asian Healthcare foundation, Asian Institute of Gastroenterology, Hyderabad, Telangana, India # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_2

21

22

P. Sarkar

(Abbas et al. 2019). The innate immune system is liable for defending the body from non-specific pathogens that enter into the body by using killer cells and phagocytes. On the other hand, the adaptive immune system targets the pathogen that was encountered by the body previously. This is the reason due to which it is referred to as the acquired or specific immune system. The adaptive immune system involves lymphocytes and is characterized by the functional properties of both B and T lymphocytes. This immune response is directed by antigen-specific surface receptors (Simon et al. 2015). In the next section, we will emphasize on why we are not dead yet, briefing the development and activation of our immune cascades.

2.2

Development and Activation of the Immune System

The immune system in the newborn is highly competent and has the ability to save the infant from contagions and handle responses to immunization. However, it significantly varies from the immune system of adults as, at the time of birth, the adaptive and innate immune system is not as functional as that in adults. Moreover, at the time of birth, the immune system of the infants is not exposed to a wide range of antigens. Furthermore, for preventing immunological reactions between the mother and foetus throughout the pregnancy, the immune system in the newborn does not favour the production of pro-inflammatory cytokines (Levy 2007). Moreover, in the case of the infants’, diverse elements of the first line of defence are weakened; as well as, the components of the second line of defence (such as granulocytes including neutrophils and eosinophils) are less in number. Additionally, the components of the second line of defence display abridged expression of L-selectin, impaired transmigration along with chemotaxis (Smith et al. 1992). However, the immune system keeps on strengthening as the child grows, and thus, adults have well-developed immune systems. In the maturation process of the immune system, microbes play a noteworthy role, which has been hypothesized by the ‘hygiene hypothesis’ (Strachan 1989). In support of the hygiene hypothesis, studies have divulged that modification in the microbial exposure pattern leads to an upsurge in the occurrence of atopic disorders. Furthermore, the study carried out recently revealed that an increase in allergic diseases in adulthood indicates a reduction in infection during the childhood stage (Singh and Ranjan Das 2010). Furthermore, in line with the above discussion, the study led by Brandtzaeg (2010) stated that gut microbiota composition along with exposure to both food-borne and orofaecal microbe act as the homeostatic influencers by augmenting the SIgA-mediated intestinal surface barrier. Additionally, it also encourages oral tolerance via a shift from crucial Th2 cell activity in the newborn stage to a more balanced cytokine profile in the later stage. Other than this, as per an alternative mechanism, a reduction in the activity of the regulatory T cells (Tregs) can be observed due to reduced microbial burden. This mechanism has been referred to as the ‘extended hygiene hypothesis’ (Romagnani 2007; Yazdanbakhsh et al. 2002). This hypothesis lays significant emphasis on the induction of Treg cells

2

The Interaction of Gut Microbiota with Immune System and Their Effects. . .

23

as a crucial part of carrying out microbe-driven immunological homeostasis. Furthermore, in foetal mucocutaneous lymph node syndrome (MLNs), a large number of naturally arising Treg cells with repressive properties are present. This, in turn, helps in keeping a check on the autoreactive effector T cells such that inflammation and tissue damage could be avoided.

2.3

Role of Gut Microbiota in Shaping the Immune System

The human body harbours more than 1014 bacterial cells as compared to 1013 human cells. However, significant attention has been received by the gut microbiota which predominantly is dominated by microbial groups like Bacteroides, Clostridium, Eubacterium, Veillonella, Ruminococcus, Bifidobacterium, Fusobacterium, Lactobacillus, Peptostreptococcus, and Peptococcus (Moore and Holdeman 1974; Xu and Gordon 2003). Gut microbiota and its composition play a crucial role in the maturation of the human immune system as they are the key source of microbedriven immune regulation. Thus, any change or alteration in the gut microbial composition will also change the outcome of the immune development as well as predilection to immune-related disorders in the later phase of life. For instance, the study led by He et al. (2001) revealed that infants facing allergies have been found to be less frequently colonized by Bifidobacteria. Furthermore, gut microbiota not only regulate the local intestinal immune system but also have a significant influence upon the systemic immune responses.

2.3.1

Microbiota and Innate Immune Homeostasis

In the innate immune system, one of the vital components is GALTs, which act as the first line of defence that non-specifically recognize the pathogen. As per most of the studies, the structural development of GALT profoundly depends upon the gut microbiota. In addition to this, the development of the gut secondary lymphoid organs such as ILFs (Isolated lymphoid follicles), Peyer’s patches, and mLNs depends not only upon the lymphoid tissue inducer but also on its crosstalk with the colonized gut microbiota (Pozzilli et al. 1993; Mebius et al. 1997; Adachi et al. 1997). As per one of the studies on germ-free (GF) mice, it was found that the absence of the commensal flora affected the size of the Peyer’s patches. Moreover, it also led to a reduction in the germinal centres (Clarke et al. 2010). Therefore, gut microbiota plays a crucial role in the structural development of the GALT. Moreover, the antigen-presenting cells (APCs) which have been coevolved with the microbiota protect the body against infection without disrupting immune tolerance to the usual gut bacteria. Moreover, the influence of microbiota on the regulations of the neutrophils has also been validated. One of the studies revealed that recognition of peptidoglycan by the cytosolic receptor-nucleotide oligomerization domain 1 (NOD1) from gut microbiota played a crucial role in enhancing the bone marrow neutrophil’s killing activity. Henceforth, the development, as well as

24

P. Sarkar

the functioning of the innate system, vastly depends upon the gut microbiota composition of the body. Additionally, reports have suggested that the presence of the microbiota-derived ligands has been found to influence the differentiation as well as the function of the myeloid and lymphoid lineage cells through pattern recognition receptors (PRRs) (Gorjifard and Goldszmid 2016; Weaver et al. 2019; McCoy et al. 2019). Just as innate immune memory has been observed as the attribute of the myeloid cells like monocytes or macrophages, innate lymphoid cells (ILCs; bone marrow progenitors and NK cells) are mediated by the transcriptional changes. These changes are found to occur either in the genes or on the specific locus and epigenetic rewiring of these innate cells at the time of the primary exposure (Gourbal et al. 2018). Thereafter, it has been found that the secondary response to a consecutive infection is rapid, upsurge and non-specific. Similar phenomenon also exists in the bone marrow progenitors, indicating the prevalence of systemic influence of the gut microbiota (Mitroulis et al. 2018). Moreover, the study led by Pahari et al. (2017) has divulged that training of the PRRs expressing the innate cells with the either gut microbial or non-microbial ligands is necessary for providing protective mechanism during the secondary infection or during pathogenic exposures, independent of the adaptive immunity. In alignment to the above findings, Ribes et al. (2014) revealed that protection can be conferred in sepsis as well as meningitis model by the administration of unmethylated CpG oligodeoxynucleotides before infection. Furthermore, microbial components like peptidoglycans that are expressed on diverse bacteria lead to generation of innate memory in case of Toxoplasma infection (Krahenbuhl et al. 1981). Along with this, the studies have revealed that the occurrence of the activated NK-cell memory during second stimulation (Ribes et al. 2014; Romee et al. 2012) and prevalence of dendritic cells (DCs) increase IFN signalling pathway activation besides specific histone (H3K4me3 and H3K27me3) modifications (Hole et al. 2019). All these availabilities are the outcome of the existence of commensals in the gut who play a crucial role in the production of the immunomodulatory metabolites (Hole et al. 2019; Levy et al. 2016; Tremaroli and Bäckhed 2012). Additionally, studies have further provided the evidences related to the rewiring of the innate cells owing to diet-induced microbial changes in the gut. For instance, the Western diet has been found to enhance the innate immune responses by inducing epigenetic and transcriptional reprogramming of the myeloid progenitors through the NLRP3 inflammasome and IL-1R signalling (Christ et al. 2018). Apart from the diet, stress leads host cell to secrete small molecules or causes cellular damage that, in turn, activates PRRs (Ramirez et al. 2015; Salam et al. 2018; Seong and Matzinger 2004). Moreover, stressors have been found to trigger the release of MAMPs (Microbe-Associated Molecular Patterns) in the blood circulation which is triggered by the gut microbes. Further, there is also emerging evidence that gut microbiota also affect the innate memory phenotype at the peripheral tissues or at distant mucosal sites. In this context, Yao et al. (2018) reported the presence of immunological memory phenotype as well as protective functions in response to respiratory virus infection in the alveolar macrophages. Further, studies have also revealed about the prevalence of the crosstalk between gut microbiota and ILCs,

2

The Interaction of Gut Microbiota with Immune System and Their Effects. . .

25

where the commensal microbes aid in the conditioning and development of the cells (Minton 2019; Miani et al. 2018).

2.3.2

Microbiota and Adaptive Immune Homeostasis

In the mucosa, both T cells and B cells in the immune system have position-specific phenotypes as well as functions that are affected by the microbiota. In the case of CD4+ T cells, gut microbiota play a key role in their development both within as well as outside the intestine. A research study has shown that a substantial diminution in the quantity of LP CD4+ cells has taken place in the GF mice (Macpherson et al. 2002). Moreover, spleens and mesenteric lymph nodes of GM animals have also been found to display defects due to the absence of the lymphocyte zones. Furthermore, bacterial species have also been found to be associated with the development of certain specific subtypes of the T cell. For instance, the development of the systemic Th1 cells is facilitated by Bacteroides fragilis through its polysaccharide A (PSA) molecules (Mazmanian et al. 2005). Other than this, induction of LP Th17 cells is facilitated by segmented filamentous bacteria (SFB) (Gaboriau-Routhiau et al. 2009). Similarly, Clostridia, especially cluster IV and XIVa, were found to promote the induction of colonic Tregs (Crabbe et al. 1968). Further, the role of microbes in stimulating CD8+ T cells has also been documented. One such study revealed that microbial dysbiosis contributes to the susceptibility of colon tumour by hyper-stimulating the CD8+ T cells. This, in turn, promotes chronic inflammation as well as T-cell exhaustion leading to the reduction in the anti-tumour immunity (Amy et al. 2020). Another study suggested the role of commensal bacterium in regulating the function of IgA. Mucosal IgA, which is secreted across the epithelium, initially, binds with the polymeric immunoglobulin receptors and then with the microbes. In the absence of IgA, Bacteroides thetaiotaomicron is found to express high levels of the gene products that play a crucial role in the metabolism of the nitric oxide and also elicits pro-inflammatory signals in the host cells (Peterson et al. 2007). Furthermore, analysis of the repertoire of T-cell receptors (TCR) and other transcription factors revealed that gut Treg cells that are available before weaning have thymus origin as Treg-specific transcription factor Helios and surface marker Neuropilin-1 are expressed by them (Thornton et al. 2010; Weiss et al. 2012; Yadav et al. 2012). On the contrary, microbiota-induced Treg cells express low level of Helios (Nutsch et al. 2016). Thus, this indicates that a group of Treg cells are influenced by the presence of the gut microbiota. On the other hand, B cells are also significantly influenced by the presence of bacterial cells. B cells, which are mostly found in the Peyer’s patches, are also influenced by the existence of the gut microbiota. In the GF animals, the number, as well as the cellularity of the Peyer’s patches, was found to be low due to which the levels of IgA along with plasma cells were also found to be reduced (Crabbe et al. 1968). Similarly, the spleen extracted from the GF mice also displayed a smaller number of germinal centres. On the contrary, an elevation in the allergy-associated Ig isotype, IgE, was found in the vicinity of the intestine as well as systemically in

26

P. Sarkar

the serum of GF rats (Durkin et al. 1989). Thus, dysbiosis or imbalance in the gut microbiota triggers diverse immune disorders via the activity of the T cells which are both near to and distant from the site of initiation (Honda and Littman 2016). Similar evidences provided by Zhao and Elson (2018) suggested that gut microbial exposure plays a vital role in leading to continuous diversification of B-cell repertoire and in the production of the T-cell-dependent and -independent antibodies, especially IgA. Thus, microbial dysbiosis will have a negative impact on gut microbial homeostasis and this, in turn, will increase the susceptibility of such individuals to diverse immune disorders.

2.4

Host–Microflora Crosstalk on the Mucosal Surface

A precise understanding of the microbial environment is required by the defence system of the host to differentiate commensals from the pathogens. Three major types of immune cells and epithelium barrier provide primary line of defence against the pathogens and other adverse conditions (Fig. 2.1). Primarily, the enterocytes of the surface serve as the afferent sensors of danger in the colonic environment by secreting cytokines and chemokines that alert and direct both the innate and adaptive immune responses to the infected area (Shanahan 2005). Secondly, the environment and transport of luminal antigens to the sub-adjacent dendritic cells (DCs) and other APCs are sampled by the M cells that overlie lymphoid follicles exerting the

Fig. 2.1 Microbes–host crosstalk for maintaining homeostasis, defence against pathogens and cellcycle regulation (adopted and modified from Rooks and Garrett 2016; Sarkar 2019)

2

The Interaction of Gut Microbiota with Immune System and Their Effects. . .

27

protection against pivotal infection. Lastly, the intestinal contents are sampled by the intestinal DCs themselves, which have a vital immune-sensory role, either entering or extending dendrites between surface entrecotes without disrupting the tight junctions (Rimoldi et al. 2005). The immune responses to the commensal bacteria are induced locally at the mesenteric lymph node from dendritic cells, which is able to limit the concentration of the commensal gut flora (Macpherson and Uhr 2004).Thus, the mesenteric lymph node acts as a gatekeeper, by preventing the access of commensal gut bacteria to the internal milieu. On the other hand, the two major host pattern recognition receptor (PRR) systems Toll-like receptors (TLRs) family and the nucleotide-binding oligomerization domain/caspase (NOD/CARD) engage in the discrimination of pathogenic and commensal bacteria (Cario 2005). In response to specific microbial-associated molecular patterns, these have a vital role in the activation of immune cells. Peptidoglycan and lipoteichoic acids activate TLR2 and TLR4 by lipopolysaccharide and TLR5 by flagellin, along with NOD1/CARD4 and NOD2/ CARD15 function as intracellular receptors. Surface enterocytes and DCs help in the expression of TLRs and NOD proteins, which is a crucial factor for bacterial–host communication (Abreu et al. 2005). Decreased enterocyte proliferation and cytoprotective factors have been observed in TLR-deficient mice. TLR signals mediated by commensal bacteria and their metabolites are essential factors in repair of host intestinal barrier (Fukata et al. 2005; Rakoff-Nahoum et al. 2004). Interestingly, many host pattern recognition receptor ligands are expressed by commensal gut bacteria, yet the healthy gut does not evoke inflammatory responses to these bacteria. Conversely, some commensal bacteria can also exert protective effects by attenuating pro-inflammatory responses induced by various enteropathogenic bacteria (Gewirtz et al. 2001; Schmaußer et al. 2005; Otte et al. 2004).

2.5

Peaceful Co-existence of the Immune System with the Good Bacteria

The human gut is the residence of many beneficial bugs which play the key role in supporting functions like digestion of the food and in strengthening the immune responses (Pickard et al. 2017). Despite being a foreign entity, these bacteria are not attacked by the human system in the healthy state. Conversely, in severe chronic diseases like cancer, inflammatory bowel disease (IBD) and others, the immune system attacks the beneficial bacteria. This, in turn, results in chronic inflammation and contributes to the progression of the disease (Hepworth et al. 2013). Recently, researchers have discovered an important and noteworthy mechanism in which the innate lymphoid cells (ILCs) limit the reaction by the inflammatory T cells to the commensal bacteria in the mice gut. Thus, the functional loss of the ILCs directs the immune system to attack the commensal bacteria. In this regard, deletion of the protein called RORγt, required for one class of ILCs, in mice resulted in exacerbated T-cell responses against commensal bacteria and systemic inflammation. On the contrary, depletion of ILC effector cytokines like IL-22 and IL-17 did

28

P. Sarkar

not cause an immune reaction to commensal bacteria. Thus, it can be divulged that ILCs use a different regulatory pathway for eliciting the immune response of the T cells against the commensal bacteria. Thus, it is a promising research area, and its exploration could reveal new therapeutic pathways for the treatment of chronic diseases like IBD, cancer and others.

2.6

Immune Modulation by Microbial Metabolites

SCFAs aka short-chain fatty acids, e.g., butyric, propionic and acetic acid, are produced by colonic bacteriome, bind with G protein-coupled receptors (GPCRs), residing on the epithelial cell surfaces. Transport or diffusion of SCFAs into host cells results in their metabolism and/or inhibition of histone deacetylase (HDAC) activity. The SCFAs are generally responsible for epithelial barrier integrity and immune tolerance, promoting gut homeostasis through unique mechanisms. They can enhance the production of mucus goblet cells, inhibit the nuclear factor-κB (NF-κB), followed by activation of inflammasomes and subsequent production of interleukins, etc. SCFAs also enhance the colonic regulatory T (Treg) cells, which includes its expression of forkhead box P3 (FOXP3) and subsequent production of anti-inflammatory cytokines (TGF-β, IL-10, etc.). SCFAs can also reduce inflammation (directly or indirectly) by acting on local or resident antigen-presenting cells, respectively (Tao et al. 2007; Rooks and Garrett 2016). Additionally, specific bacterial species have been shown to direct influence the adaptive immune cells’ differentiations. The attachment of segmented filamentous bacteria (SFB) to the intestinal epithelium elevates the function of antigen-specific T helper 17 (TH17) cells via interleukin-23 (IL-23), IL-22 and serum amyloid A (SAA) proteins which further promote IgA synthesis (Maslowski et al. 2009; Voltolini et al. 2012; Vieira et al. 2015; Erny et al. 2015). Another example in this context is Bacteroides fragilis which influences the balance between TH1 and TH2 cells and directs Treg cell development through polysaccharide A (PSA) (Singh et al. 2014). Selected strains of Clostridia also induce the Treg cells (Ghorbani et al. 2015). The microbiome also affects the intestinal plasma cells accumulation which in turn produces as well as degrades IgA (Willemsen et al. 2003). Additionally, at high nanomolar concentrations, S. aureus derived formyl peptides; phenol-soluble modulins (PSMs) stimulate massive neutrophil influx to infection sites by binding to FPR2. Induced neutrophil activation leads to an oxidative burst. PSMs affect the adaptive immune system by inducing a tolerogenic phenotype in DCs and inhibiting the differentiation of TH1 cells. S. aureus can also use PSMs to escape from phagolysosomes, lyse host cells and disperse biofilms, and can also kill competing bacteria HBP (a monosaccharide) produced by Neisseria gonorrhoeae-enhanced innate and adaptive immune responses by phosphorylation-dependent oligomerization of TRAF-interacting protein with FHA domain-containing protein A (TIFA). Activation of TIFA will further activate the TRAF6 leading to TRAF6 ubiquitin (Ub)-dependent activation of nuclear factor-κB (NF-κB), inducing further the

2

The Interaction of Gut Microbiota with Immune System and Their Effects. . .

29

expression of pro-inflammatory immune genes (e.g. IFNγ, interferon-γ; P, phosphate; TCR, T-cell receptor) (Gaudet et al. 2015).

2.7

Conclusion

With all the evidences pouring in, we now recognize the immense role of host microbiome in maintaining the host immunity, though we need more mechanistic evidences to illustrate the strain-specific mechanism of the microbiota in host immune crosstalk. Sometimes, the load matters in activation of the immune responses, while in other times, the diversity holds the key in immune activation. Hopefully, with accumulating researches, we will able to decode the specific role of each microbiota and will be able to use the knowledge in improving the quality of life of the host. Acknowledgements I am truly grateful to Dr. Rupjyoti Talukdar (AIG), Dr. Harigopal Boyapatti (AIG), Dr. Mohan Chandra Kalita (G.U.) and Dr. Mojibur R. Khan (IASST) for guiding me in my postdoctoral and PhD research works. I am also thankful to Asian Healthcare Foundation, Asian Institute of Gastroenterology, for providing me the research infrastructural facility.

References Abbas AK, Lichtman A, Pillai S (2019) Basic immunology: functions and disorders of the immune system, 6th edn. Sae-E-Book. Elsevier India Abreu MT, Fukata M, Arditi M (2005) TLR signaling in the gut in health and disease. J Immunol 174(8):4453–60 Adachi S, Yoshida H, Kataoka H, Nishikawa S (1997) Three distinctive steps in Peyer's patch formation of murine embryo. Int Immunol 9:507–514. https://doi.org/10.1093/intimm/9.4.507 Amy IY, Zhao L, Eaton KA, Ho S, Chen J, Poe S, Becker J, Gonzalez A, McKinstry D, Hasso M, Mendoza-Castrejon J (2020) Gut microbiota modulate CD8 T cell responses to influence colitisassociated tumorigenesis. Cell Rep 31(1):107471 Brandtzaeg P (2010) Food allergy: separating the science from the mythology. Nat Rev Gastroenterol Hepatol 7:380–400. erratum: 478 Cario E (2005) Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2. Gut 54(8):1182–1193 Christ A, Günther P, Lauterbach MA, Duewell P, Biswas D, Pelka K, Scholz CJ, Oosting M, Haendler K, Baßler K, Klee K. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell 2018;172(1–2):162–75 Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN (2010) Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med 16(2): 228–231 Crabbe PA, Bazin H, Eyssen H, Heremans JF (1968) The normal microbial flora as a major stimulus for proliferation of plasma cells synthesizing IgA in the gut. Int Arch Allergy Immunol 34(4): 362–375 Durkin HG, Chice SM, Gaetjens E, Bazin H, Tarcsay L, Dukor P (1989) Origin and fate of IgE-bearing lymphocytes. II. Modulation of IgE isotype expression on Peyer's patch cells by feeding with certain bacteria and bacterial cell wall components or by thymectomy. J Immunol 143(6):1777–1783

30

P. Sarkar

Erny D, de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, Schwierzeck V (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18(7):965–977 Fukata M, Michelsen KS, Eri R, Thomas LS, Hu B, Lukasek K, Nast CC, Lechago J, Xu R, Naiki Y, Soliman A (2005) Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J PhysiolGastrointest Liver Physiol 288(5):G1055–G1065 Gaboriau-Routhiau V, Rakotobe S, Lécuyer E, Mulder I, Lan A, Bridonneau C, Rochet V, Pisi A, De Paepe M, Brandi G, Eberl G (2009) The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31(4):677–689 Gaudet RG, Sintsova A, Buckwalter CM, Leung N, Cochrane A, Li J, Cox AD, Moffat J, GrayOwen SD (2015) Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity. Science 348(6240):1251–1255 Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL (2001) Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol 167(4):1882–1885 Ghorbani P, Santhakumar P, Hu Q, Djiadeu P, Wolever TM, Palaniyar N, Grasemann H (2015) Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth. Eur Respir J 46(4):1033–1045 Gorjifard S, Goldszmid RS (2016) Microbiota—myeloid cell crosstalk beyond the gut. J Leukoc Biol 100(5):865–879 Gourbal B, Pinaud S, Beckers GJ, Van Der Meer JW, Conrath U, Netea MG (2018) Innate immune memory: an evolutionary perspective. Immunol Rev 283(1):21–40 He F, Ouwehand AC, Isolauri E, Hashimoto H, Benno Y, Salminen S (2001) Comparison of mucosal adhesion and species identification of bifidobacteria isolated from healthy and allergic infants. FEMS Immunol Med Microbiol 30:43–47 Hepworth MR, Monticelli LA, Fung TC, Ziegler CG, Grunberg S, Sinha R, Mantegazza AR, Ma HL, Crawford A, Angelosanto JM, Wherry EJ (2013) Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 498(7452):113–117 Hole CR, Wager CM, Castro-Lopez N, Campuzano A, Cai H, Wozniak KL, Wang Y, Wormley FL (2019) Induction of memory-like dendritic cell responses in vivo. Nat Commun 10(1):1–3 Honda K, Littman DR (2016) The microbiota in adaptive immune homeostasis and disease. Nature 535(7610):75–84 Krahenbuhl JL, Sharma SD, Ferraresi RW, Remington JS (1981) Effects of muramyl dipeptide treatment on resistance to infection with Toxoplasma gondii in mice. Infect Immun 31(2): 716–722 Levy O (2007) Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 7:379–390 Levy M, Thaiss CA, Elinav E (2016) Metabolites: messengers between the microbiota and the immune system. Genes Dev 30(14):1589–1597 Macpherson AJ, Uhr T (2004) Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303(5664):1662–1665 Macpherson AJ, Martinic MM, Harris N (2002) The functions of mucosal T cells in containing the indigenous commensal flora of the intestine. Cell Mol Life Sci 59(12):2088–2096 Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, Xavier RJ (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461(7268):1282–1286 Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL (2005) An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122(1):107–118 McCoy KD, Burkhard R, Geuking MB (2019) The microbiome and immune memory formation. Immunol Cell Biol 97(7):625–635

2

The Interaction of Gut Microbiota with Immune System and Their Effects. . .

31

Mebius RE, Rennert P, Weissman IL (1997) Developing lymph nodes collect CD4+ CD3 LTβ+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity 7(4):493–504 Miani M, Le Naour J, Waeckel-Enée E, Chand Verma S, Straube M, Emond P, Ryffel B, Van Endert P, Sokol H, Diana J (2018) Gut microbiota-stimulated innate lymphoid cells support β-defensin 14 expression in pancreatic endocrine cells, preventing autoimmune diabetes. Cell Metab 28(4):557–572 Minton K (2019) ILC3s take control in small intestine. Nat Rev Immunol 19(6):353 Mitroulis I, Ruppova K, Wang B, Chen LS, Grzybek M, Grinenko T, Eugster A, Troullinaki M, Palladini A, Kourtzelis I, Chatzigeorgiou A (2018) Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172(1–2):147–161 Moore WE, Holdeman LV (1974) Human fecal flora: the normalflora of 20 Japanese-Hawaiians. Appl Microbiol 27:961–979 Nutsch K, Chai JN, Ai TL, Russler-Germain E, Feehley T, Nagler CR, Hsieh CS (2016) Rapid and efficient generation of regulatory T cells to commensal antigens in the periphery. Cell Rep 17(1):206–220 Otte JM, Cario E, Podolsky DK (2004) Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology 126(4):1054–1070 Pahari S, Kaur G, Aqdas M, Negi S, Chatterjee D, Bashir H, Singh S, Agrewala JN (2017) Bolstering immunity through pattern recognition receptors: a unique approach to control tuberculosis. Front Immunol 8:906 Peterson DA, McNulty NP, Guruge JL, Gordon JI (2007) IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2(5):328–339 Pickard JM, Zeng MY, Caruso R, Núñez G (2017) Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease. Immunol Rev 279(1):70–89 Pozzilli P, Signore A, Williams AJ, Beales PE (1993) NOD mouse colonies around the world-recent facts and figures. Immunol Today 14(5):193–196 Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118(2): 229–241 Ramirez K, Shea DT, McKim DB, Reader BF, Sheridan JF (2015) Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav Immun 46:212–220 Ribes S, Meister T, Ott M, Redlich S, Janova H, Hanisch UK, Nessler S, Nau R (2014) Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection. J Neuroinflammation 11(1):1–1 Rimoldi M, Chieppa M, Salucci V, Avogadri F, Sonzogni A, Sampietro GM, Nespoli A, Viale G, Allavena P, Rescigno M (2005) Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat Immunol 6(5):507–514 Romagnani S (2007) Coming back to a missing immune deviation as the main explanatory mechanism for the hygiene hypothesis. J Allergy Clin Immunol 119:1511–1513 Romee R, Schneider SE, Leong JW, Chase JM, Keppel CR, Sullivan RP, Cooper MA, Fehniger TA (2012) Cytokine activation induces human memory-like NK cells. Blood 120(24):4751–4760 Rooks MG, Garrett WS (2016) Gut microbiota, metabolites and host immunity. Nat Rev Immunol 16(6):341–352 Salam AP, Borsini A, Zunszain PA (2018) Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders. Mol Psychiatry 23(2):170–176 Sarkar P. (2019) Effect of alcoholism on human gut microbiota and comparison with that of colorectal cancer patients. http://hdl.handle.net/10603/267678 Schmaußer B, Andrulis M, Endrich S, Müller-Hermelink HK, Eck M (2005) Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori. Int J Med Microbiol 295(3):179–185

32

P. Sarkar

Seong SY, Matzinger P (2004) Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol 4(6):469–478 Shanahan F (2005) Physiological basis for novel drug therapies used to treat the inflammatory bowel diseases I. Pathophysiological basis and prospects for probiotic therapy in inflammatory bowel disease. Am J Physiol-Gastrointest Liver Physiol 288(3):G417–G421 Simon AK, Hollander GA, McMichael A (2015) Evolution of the immune system in humans from infancy to old age. Proc R Soc B Biol Sci 282(1821):20143085 Singh M, Ranjan Das R (2010) Probiotics for allergic respiratory diseases – putting it into perspective. Pediatr Allergy Immunol 21:e368–e376 Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH, Lee JR (2014) Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40(1):128–139 Smith JB, Kunjummen RD, Kishimoto TK, Anderson DC (1992) Expression and regulation of L-selectin on eosinophils from human adults and neonates. Pediatr Res 32:465–471 Strachan DP (1989) Hay fever, hygiene, and household size. Br Med J 299:1259–1260 Tao R, De Zoeten EF, Özkaynak E, Chen C, Wang L, Porrett PM, Li B, Turka LA, Olson EN, Greene MI, Wells AD (2007) Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 13(11):1299–1307 Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, Shevach EM (2010) Expression of Helios, an Ikaros transcription factor family member, differentiates thymicderived from peripherally induced Foxp3+ T regulatory cells. J Immunol 184(7):3433–3441 Tremaroli V, Bäckhed F (2012) Functional interactions between the gut microbiota and host metabolism. Nature 489(7415):242–249 Vieira AT, Macia L, Galvão I, Martins FS, Canesso MC, Amaral FA, Garcia CC, Maslowski KM, De Leon E, Shim D, Nicoli JR (2015) A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout. Arthritis Rheumatol 67(6):1646–1656 Voltolini C, Battersby S, Etherington SL, Petraglia F, Norman JE, Jabbour HN (2012) A novel antiinflammatory role for the short-chain fatty acids in human labor. Endocrinology 153(1): 395–403 Weaver LK, Minichino D, Biswas C, Chu N, Lee JJ, Bittinger K, Albeituni S, Nichols KE, Behrens EM (2019) Microbiota-dependent signals are required to sustain TLR-mediated immune responses. JCI Insight 4(1) Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA, Parkhurst CN, Xiong H, Dolpady J, Frey AB, Ruocco MG, Yang Y (2012) Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med 209(10):1723–1742 Willemsen LE, Koetsier MA, Van Deventer SJ, Van Tol EA (2003) Short chain fatty acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E1 and E2 production by intestinal myofibroblasts. Gut 52(10):1442–1447 Xu J, Gordon JI (2003) Inaugural article: honor thy symbionts. Proc Natl Acad Sci U S A 100: 10452–10459 Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, Anthony BA, Sverdrup FM, Head R, Kuster DJ, Ruminski P (2012) Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 209(10): 1713–1722 Yao Y, Jeyanathan M, Haddadi S, Barra NG, Vaseghi-Shanjani M, Damjanovic D, Lai R, Afkhami S, Chen Y, Dvorkin-Gheva A, Robbins CS (2018) Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 175(6): 1634–1650 Yazdanbakhsh M, Kremsner PG, Van Ree R (2002) Allergy, parasites, and the hygiene hypothesis. Science 296:490–494 Zhao Q, Elson CO (2018) Adaptive immune education by gut microbiota antigens. Immunology 154(1):28–37

3

The Link Between Gut Microbiota and Autoimmune Diseases Divya Goyal, Mangaldeep Dey, and Rakesh Kumar Singh

Abstract

Gut microbes comprise of millions of microbes together called gut microbiota. Their vast diversity plays an important role in maintenance of immune homeostasis. Gut microbes released several molecules against the antigenic pathogen and stabilize the self-tolerance of the immune system. Disturbance in the microbial community could be the major cause of loss of self-tolerance and thus results in autoimmunity. Literatures highlighted the number of diseases which are linked with the gut microbiota and its modulation. The various diseases are chronic obstructive pulmonary disease (COPD), ulcerative colitis, autism, type-1 diabetes, etc. Here, we present evidence mechanism links between gut microbiota dysbiosis and autoimmune diseases to understand the future treatment approaches based on gut microbiota for the autoimmune disease. Keywords

Gut homeostasis · Autoimmune diseases · Gut dysbiosis · Immune tolerance · Autoimmunity

All authors have contributed equally in the preparation of this manuscript. D. Goyal · M. Dey · R. K. Singh (*) Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow, Uttar Pradesh, India e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_3

33

34

3.1

D. Goyal et al.

Introduction

Trillions of microbes are colonized all over the body including skin, throat, and the gut. These commensal microbes of the gut are called as gut microbiota (Kosiewicz et al. 2011; Hoffmann et al. 2016). They are mainly present in the small intestine; moreover, a high number of anaerobic bacteria reside in the proximal colon of the large intestine. Not only bacteria, but viruses, archaea, and fungi that live in the digestive tract of humans and animals make the gut microbiome. It encodes approximately 3.3 million genes which are 100-folds compared to the human genome; hence, it is also considered as human second genome (Hoffmann et al. 2016). As the gut microbiome encodes for vast genetic information, it also has vital role in maintaining the health of human being. The gut microbiota is comprised of six phyla among which two are majorly present such as Firmicutes and Bacteroidetes, and the rest includes Actinobacteria, Verrucomicrobia, Proteobacteria, and Euryarchaeota (Fujio-Vejar et al. 2017). There are various physiological functions performed by the microorganisms under these phylas, such as metabolism of nutrients, metabolism of xenobiotics, metabolism of amino acids such as tryptophan, fermentation of complex polysaccharides, and production of short chain fatty acids such as butyrate, that are helpful in providing the energy to the epithelial cells lined in the gut as well as production of trophic factors and regulatory T cells (Treg cells) (Goyal et al. 2020). Apart from these functions, the microbes also have bad impact on the human system when their balance gets disturbed. The dysbiosis, i.e., the production of pathogenic bacteria over to normal microflora, results into harmful insults and metabolites which causes the activation of immune system of the gut (Al-Nasiry et al. 2020). There are various causative factors due to which the dysbiosis occurs. These factors include the changes in lifestyle patterns such as time and type of meal, sleeping patterns, and hygienic conditions; self-administration or overuse of medications like antibiotics, iron salts, etc.; age, like older ones and infants have less community of bacteria comparatively and mode of delivery such as in case of caesarean delivery, the infant has less number of microorganisms as it has not exposed through vagina (a place where thousands of microbes resides) of mother (Hasan and Yang 2019). The gut is the most proficient organ in the human body that exposes first to any harmful antigen. When any kind of insult enters the gastrointestinal tract, it tries to cross the intestinal epithelial barrier, and invasion in lamina propria ultimately reaches into the mesenteric lymph nodes. However, the process of invasion is not that much simple as gut immune system get activates and fights against that pathogen. Literatures suggested that gut has several molecules or cells such as mucin, antimicrobial peptides, immunoglobulin A (IgA), antigen-presenting cells (dendritic cells, macrophages), and T and B cells through which it destroys the pathogenic antigen by maintaining the self-tolerance to its own immune cells. However, sometimes the self-tolerance system of the immune system gets disturbed which contributes to the autoimmunity (Wu and Wu 2012). However, the aim of the chapter is to explain the role of gut microbiota in development and regulating the immune system of the gut; how the eubiosis and

3

The Link Between Gut Microbiota and Autoimmune Diseases

35

dysbiosis shape the gut-immune homeostasis; mechanisms of self-tolerance to the immune system; how the self-tolerance and the immune-tolerance affect and lead to autoimmunity; and the direct contribution of microbiota with the different organs and systemic autoimmune diseases.

3.2

Immune Homeostasis of the Gut and Influence of Microbiota

When environmental agents enter the body, they first attack the gastrointestinal tract (GIT). Therefore, the immune system of the gut should always remain in a dynamic state. Various kinds of glycoproteins and peptides act as first line of defense against the entered insult.

3.2.1

First Line of Defense: Influence of Gut Microbiota

Mucins are the glycosylated proteins which are of two types such as transmembrane and gel-forming mucins (Paone and Cani 2020). Transmembrane mucins such as MUC1, 12, 15, and 17 are released by enterocytes. Gel-forming mucins such as MUC2 and MUC6 are secreted by the goblet cells. These mucins act as diffusion barrier and provide the appropriate amount of mucus in the small and large intestine (Cone 2009). However, recent research suggested that mucin is also involved in host–microbiota interactions. For instance, some microbes released LPS (lipopolysaccharides) in the lumen, and there they activate the release of gel-forming mucins (Paone and Cani 2020). One study showed the effect of LPS on cultured murine biliary epithelial cells (BECs) and found four to five times enhanced expression of MUC2 than the control (BECs) (Zen et al. 2002). Another evidence is that meprin β enzyme, which is induced by bacteria, has less organized and dense mucus. Meprin β enzyme is responsible for the proteolytic cleavage of MUC2 glycoprotein, and its inactivation causes distinct phenotype of mucus than the mucus of wild-type mice (Schütte et al. 2014). Studies revealed that some bacteria have the potential to shape the transmembrane mucins by inducing the expression of host fucosyltransferase which adds fructose group at its α 1, 2 positions (Derrien et al. 2010). After the induction of glycosylation process, bacteria get attach to the sites of mucin and take nutrition from them (Landry et al. 2006). It has been suggested that short chain fatty acids (SCFAs) produced after the fermentation of complex carbohydrates by the bacteria also stimulate the mRNA expression of MUC2 (Burger-van Paassen et al. 2009). The LS174T cells, a human goblet cell line when exposed to different concentrations of butyrate, showed the 2.5-fold increase in MUC2 mRNA level expression compared to the untreated cells at the concentration of 1 mM (Hatayama et al. 2007). Hence, the evidences suggested that gut microbiota and their products have a crucial role in maintaining the composition and density of mucus.

36

D. Goyal et al.

Antimicrobial peptides are short-chain defense peptides which are released by the Paneth cells and the enterocytes (Seo et al. 2012). These peptides possess the bactericidal activity. There are three types of peptides which are synthesized by host cells such as defensins, Reg III α/β/γ, and cathelicidins (Kościuczuk et al. 2012). They work by disrupting the bacterial membrane and preventing the pathogen colonization; thus, they modulate the immune system of gut (Gordon et al. 2005). Apart from this, studies revealed that gut microbes also regulate these peptides and thereby modulate the immune homeostasis of the gut (Garcia-Gutierrez et al. 2019; Zong et al. 2020). The mRNA expression of DEFA5 (alpha-defensin-5) gene was quantified by qRT-PCR in the small and large intestine epithelium of conventional (CV) and germ-free (GF) mice. The results showed that DEFA5 mRNA expression was significantly high in small intestine of CV mice compared to GF mice (Sugi et al. 2017). Some antimicrobial peptides are also released by bacteria to destroy the pathogenic insult (Simons et al. 2020). The bacteriocin is the most commonly known antimicrobial compound and is mainly secreted by lactic acid bacteria (Meade et al. 2020). This bacteriocin shows its bactericidal action by breaking the DNA strands and misleading the protein structure. One study reported that bacteriocin produced by Enterococcus faecalis KT11 showed antimicrobial activity against some foodborne pathogens and vancomycin/methicillin-resistant bacteria.

3.2.2

Innate Immunity and Influence of Gut Microbiota

The toll-like receptors are the transmembrane proteins present on the gut innate immune cells such as intestinal epithelium cells, antigen-presenting cells such as dendritic cells, and macrophages of lamina propria (Cheng et al. 2019; Burgueño and Abreu 2020). These toll-like receptors when exposed to any pathogenic ligand activate the MyD88-dependent pathway and activate downstream NF-қB signaling pathway and further release of cytokine- and chemokine-mediated inflammation (Hold et al. 2011). This acute reaction is sufficient to destroy the pathogen and thus maintains the immune homeostasis (Lazar et al. 2018). On the other hand, the microbiota of the gut also affect this TLR-mediated signaling. The gut microbesderived products act as the ligand for the TLR, resulting into maintenance and modulation of the immune system of the gut (Pagliari et al. 2015). It has been suggested that in case of dysbiosis, the composition of microbe-derived products gets changed and converted into harmful insults, which when bind to the TLRs result in either loss of immunity tolerance or dysregulation of homeostasis (Santaolalla and Abreu 2012; Goyal et al. 2020). One study showed that peptidoglycan and lipoteichoic acid, which are derived from Staphylococcus aureus, induced the cell activation process by TLR2-mediated NF-қB pathway in HEK293 cell line (human embryonic kidney cell line) (Schwandner et al. 1999). Another study suggested that bacterial products in the state of gut eubiosis showed bactericidal properties and thus restore the innate immunity. A. Melissa et al. showed that bacterial flagellins have the potential to act against Vancomycin-resistant enterococcus infection in mice. The flagellin stimulates the

3

The Link Between Gut Microbiota and Autoimmune Diseases

37

RegIIIγ in intestinal epithelial cell after binding to the TLR-5 (Kinnebrew et al. 2010). Nod-like receptors (NLR) and RIG-like receptors (RIL), apart from the TLRs, NLRs, and RILs, are also classified as pattern recognition receptors. NLRs recognize the pathogen-associated molecular pattern (PAMPs) and microbe-associated molecular pattern (MAMPs) and thus regulate the host innate immune responses. NLRs are mostly present in cytosol of the intestine and act as a barrier for the intestinal inflammation. The retinoic acid-inducible gene-I-like receptors (RIG-I) are helicases that present in cytosol and mainly sense the viruses. Nod1 and Nod2 are the family members of NLRs that activate the NF-κB and MAP kinase signaling and control the various inflammatory processes. The Nod2 presence in intestine is restricted to the intestinal epithelial cells, Paneth cells, macrophages, and dendritic cells, while Nod 1 is present constitutively. These receptors respond to the bacterial antigens by releasing proinflammatory cytokines, but overproduction of these cytokines causes the stimulation of innate immune cells and their loss of tolerance. A recent study suggested that Nod1 and Nod2 receptors recognize γ-D-glutamylmesodiaminopimelic acid (iE-DAP) and muramyl peptide from gram-positive and gram-negative bacteria. Their activation resulted in activation of scaffolding kinase receptor-interacting protein (RIP2) to activate further NF-κB and MAPK pathways associated with inflammatory responses. The mutations in Nod protein are associated with the inflammatory diseases. Study showed that frameshift variant and two missense variants of Nod2 encode a member of Apaf-1/Ced-4 superfamily resulting in leucine-rich repeats domain of protein. This Nod2 gene variant confers the Crohn’s disease by overactivating NF-қB in monocytes. The SCFAs such as butyrate act on GPR43 to produce the energy which also attenuates the NLR such as pyrin domain-containing protein 3 (NLRP3) and leucinerich repeat (LRR), reducing both inflammasome activity and subsequent secretion of IL-18.

3.2.3

Adaptive Immunity (T Cells)

Beneath the epithelial cells of intestine, the lamina propria have high density of T cells among which CD4+ T cells account for 60–70% (Kato et al. 2014). These cells are the key components of immune homeostasis. These T cells interact with other innate immune cells such as dendritic cells (DCs) and macrophages through the costimulatory molecules such as CD40, CD80, and MHC-II (Major Histocompatibility Complex-II) to process the bacterial pathogen (Kato et al. 2014). Further, these T cells have different subsets to modulate the inflammatory response depending upon their purpose of activation. The different subsets include Th1, Th2, Th17, and Tregs (Smith and Garrett 2011). Each subset of T cells further releases different types of proinflammatory cytokines and chemokines depending upon the expression of their transcription factors. A commensal bacterium plays an important role in development of CD4+ T cells (Zhang et al. 2015). A study conducted in GF mice showed the decrease in density of CD4+ T cells in lamina propria. A recent study

38

D. Goyal et al.

showed that administration of flagellins from segmented filamentous bacteria in C57BL/6 mice led to significant increase in the expression of genes (RORγT) associated with IL-17 pathway (Th-17) cells (Wang et al. 2019c). Another recent study has shown that treatment of Bifidobacterium animalis and human origin Lactobacillus plantarum in female C57BL/6 mice resulted in decreased expression of ROR-γT (Th17) and T-bet (Th1) and significantly increased expression of FOXp3 + (Treg) and GATA3 (Th2). This reflects the alteration of CD4+ T-cell subset and further ameliorated the neuroinflammation in EAE model of multiple sclerosis (Salehipour et al. 2017).

3.2.4

Adaptive Immunity (B Cells)

The B cells are the another type of adaptive immune cells which are called T-celldependent or -independent plasma cells (Zhao and Elson 2018). They are mostly found in the Peyer’s patches and secrete IgA. When these antibodies present the antigen to the T cells, they differentiate to Treg cell via releasing IL-10 and IL-21 cytokines as inflammatory cytokine (Wang et al. 2019b). It has been evidenced that gut microbes also regulate by IgA secreted from the plasma cells and maintain the immune homeostasis against the bacterial antigen (Zhang et al. 2015). One study reported that IgA has the potential to induce some bacteria and thus causes the downregulation of the expressed proinflammatory epitopes (Peterson et al. 2007). In contrast, IgA production is facilitated by the gut microbes is not clear yet. The mechanism of production of IgA by the commensal microorganisms is not clearly defined. However, current literatures suggested that the activation-induced cytidine deaminase (AID) is the key enzyme to regulate the class switch recombination, i.e., from IgM+ B cells to IgA+ plasma cells. One study reported that Bacteroids that are gram-negative bacilli showed higher expression of AID enzyme when the Peyer’s patches cells were cocultured with the Bacteroids (Yanagibashi et al. 2009). Furthermore, the composition of microbiota also has an impact on production of IgA. In continuation of the above study, it has also been concluded that Lactobacillus, the most predominant microorganism, produces lesser IgA production than Bacteroids as the level of expression of AID enzyme was also less in these microorganisms (Yanagibashi et al. 2009). Thus, these studies suggested that maintenance and modulation of gut-immune system are influenced by the gut microbiota, and the weak defense system is found in germ-free mice toward the bacterial antigen.

3.3

Immune Tolerance and Its Mechanisms

Immune tolerance is a phenomenon in which immune cells of the body such as B and T cells develop the resistance against the self-antigens (Pan et al. 2008). Due to this, these cells will not be having the further potential to activate against the self-antigen and, hence, can bypass the autoimmunity (Crispe 2014). The tolerance is broadly

3

The Link Between Gut Microbiota and Autoimmune Diseases

39

categorized into two types on the basis of the origin of immune cells: central and peripheral tolerance (Lu and Finn 2008).

3.3.1

Central Tolerance (B- and T-Cell Tolerance)

The maturation of T cells occurs in spleen and thymus. Each of the lymphocyte expresses antigen-specific receptor, and when it interacts with Ag, signal processing takes place, causing proliferation of immune cells and further differentiation into memory and effector T cells (Weiner 1997). Each B and T cell has infinite number of lymphocyte having specific antigen receptor on its surface. Along with this, autoreactive lymphocytes are also present over there. But every time non-autoreactive should be matured to recognize the nonself Ag. Otherwise, autoreactive lymphocyte will start to damage the own tissues after its activation. The T-cell receptor (TCR) presented over the surface of T cell recognizes the peptide Ag-MHC-I (displayed by thymic cells or nucleated cells) and MHC-II (displayed by DCs and macrophages) complexes (Pelanda and Piccirillo 2008). The immature T lymphocyte also interacts with self-peptide Ag–MHC complexes. Further, it undergoes three mechanisms of tolerance through which its activation could be prohibited. (i) If immature T cell fails to recognize the self-peptide–MHC molecule due to less affinity, T cell or lack of interaction that would prevent spontaneous apoptosis and thereafter will die in thymus. This process is called as “nonselection” (Pelanda and Torres 2012). (ii) If T cell will recognize the self-peptide–Ag-MHC molecule, the survival signal will reach up to nucleus of immature T cells that will grow further, and process is called “positive selection.” These cells require the presence of self-antigen in the thymus. But it is reported that not all antigens occur in thymus and thus requires the migration of T cells to peripheral lymphoid organ for the prevention of activation and maturation (Pelanda and Torres 2012). (iii) If immature T cell/B cell binds with the higher affinity with peptide Ag-MHC molecule, it undergoes the activation of AIRE (autoimmune regulatory gene) gene expressed in medulla of the thymus, present on chromosome number 21q22.3. This functional AIRE gene is responsible for deletion of self-reactive T cells by the mechanism of apoptosis. Studies reported that mutation in the AIRE gene causes the development of autoimmune syndrome such as autoimmune polyendocrinopathy (Goverman 2011). Furthermore, receptor editing is the phenomenon in which the antigen receptor of autoreactive immature B cell gets modified. Because they have the ability to rearrange their immunoglobulin gene in light chain loci (Retter and Nemazee 1998). So, self-reactive light chains either get deleted or if not then after every possible recombination in light chain the cell undergoes apoptosis (Halverson et al. 2004).

40

3.3.2

D. Goyal et al.

Peripheral Tolerance

The activated T cell and B cell migrated from thymus and bone marrow enters to peripheral lymphoid organs such as spleen and lymph nodes to prevent their maturation and finally eliminate them (Arnold et al. 1993). Various kinds of mechanisms exist for the development of peripheral tolerance such as clonal deletion, anergy, immune deviation, immune privilege, immunosuppressive cytokines and regulatory T cell (Soyer et al. 2013). Clonal deletion and anergy are the two main mechanisms which prevent the autoreactive T-cell antigen.

3.3.2.1 Clonal Deletion In normal condition, self-antigens are expressed but no danger signals exist. This self-antigen is taken up by antigen-presenting cells such as DC’s, processed and then display of antigen-MHC on its surface occurs (Kroemer and Martínez 1992). This antigen is displayed to naïve T cell in lymph node. An autoreactive T cell whose TCR is specific for self-antigen displayed by DCs, will lead to the interaction between these cells. The T cell received first signal for its activation but in absence of danger signals, DCs cells do not express the costimulatory molecule (B7: CD28). Hence, second costimulatory signal will not generate and T cell will undergo apoptosis. The process by which autoreactive T-lymphocyte eliminated by programmed cell death is called as “peripheral clonal deletion” (Benson and Whitacre 1997).

3.3.2.2 Anergy When the T cell receives its first signal for activation after binding to the specific antigen-MHC molecule, and fails to produce the second costimulatory signal; the T cell then enters into the apoptotic phase (Ramsdell and Fowlkes 1990). Studies suggested the cell death caused by Fas-Fas ligand binding as “activation-induced cell death.” But sometimes the week signal gets generate in the T cell for survival but they remained inactive, so that they cannot differentiate into effector T cells and ultimately the cells would not be able to respond to their specific antigen (Kroemer and Martínez 1992). Considerable evidences suggested that if any how the autoreactive lymphocyte gets activated, then several other peripheral tolerance mechanisms occur such as immune deviation: conversion of harmful immune response to less harmful immune responses; immune privilege: the T cells are subjected to anatomical regions which are less exposed to immune response such as brain and eyes (Choi 2012); and immunosuppressive cytokines: these are the anti-inflammatory mediators which are released in response to any kind of inflammation include IL-10 and TGF-β. Regulatory T cells (Tregs) are the helper T cells which are regulated by the transcription factor FOXP3+ and responsible for the control of activated T cells and thus prevent their proliferation (Palomares et al. 2014; Choi 2012). These Tregs can suppress the activated T cells through IL-10 and TGF-β.

3

The Link Between Gut Microbiota and Autoimmune Diseases

3.4

41

Gut Microbiota-Dependent Breakdown of Tolerance Contributes to Autoimmune Diseases

Autoimmune diseases are not the result of a single factor; literatures reported that there are number of factors responsible for loss of tolerance which ultimately contributes to the development of autoimmune diseases. The factors majorly include defects in apoptosis (programmed cell death) process, molecular mimicry, breakdown of anergy, suppression of Treg cells and up regulation of helper T cells, bystander-activation, etc. (Ohashi and DeFranco 2002; Pieterse and van der Vlag 2014). Recent emerging evidences have suggested that along with genetic and environmental factors, gut microbiome also plays a crucial role in breakdown of tolerance. Gut bacteria and their metabolites such as long and short chain fatty acids and other membrane components such as lipopolysaccharides have a crucial role in immunomodulation. Studies have suggested that defective apoptosis plays a vital role in production of peptide antigen (Eguchi 2001). Exposure of cell to various stimuli such as any infectious agent or viral particle, and severe DNA damage triggers the cell for apoptosis process in intrinsic way, thereby causes the upregulation of proapoptotic genes and results in mitochondrial perforations (Elumalai et al. 2012). Further, the released cytochrome C form the apoptosome in association with APaf-1 (Apoptosis Protease containing factor-1) and procaspase-9, ultimately activating the caspase-3 resulting into DNA fragmentation and thus apoptosis (Loreto et al. 2014). This type of cell death is also called mitochondrial mediated PCD pathway or nonreceptormediated pathway. On the other hand, the extrinsic pathway involves the receptormediated signaling process after binding of the ligand on its specific receptor such as FAS-R, TNF-R, and TRAIL-R. This activates the death domain FADD induced by death inducing signaling cascade (DISC) (Nair et al. 2014). Further, procaspase-8 in association with FADD activates caspase-8 which disperses and further activation of caspase-3 causes the activation of NF-ҚB pathways followed by proteolytic cleavage of cytosol and nuclear proteins and activation of DNase that cleaves the chromatin (Ricci and El-Deiry 2007). However, the gut metabolites also have a big impact in the regulation of apoptotic-mechanisms (Kho and Lal 2018). One study revealed that the SCFA such as butyric acid involves the transcriptional stimulation of the Bax gene via activation of the JNK/AK1 pathway and thus trigger the apoptosis in the colon cancer cells (Mandal et al. 2001). The dysbiosis in the gut may hinder the mechanism of apoptosis and thus production of autoantigens triggers the autoimmunity. Studies reported that PI3K and Akt pathway promotes the survival of the DCs. This pathway is activated by bacterial CpG DNA (the unmethylated motif in bacterial DNA) and thus, promotes the survival. Further, the study revealed that this CpG DNA inhibits the apoptosis by upregulating apoptotic proteins cIAP (cellular inhibitor of apoptotic proteins) and downregulating the apoptotic signaling molecule, Caspase-3 (Park et al. 2002). Molecular mimicry is another concept which was first explained by Raymond T. Damian in 1964. This process has seen in breaking the tolerance of the immune system. It is a result of autoimmunity disorder develops when the antibodies of

42

D. Goyal et al.

microorganism epitope binds to the autoantigen (Cusick et al. 2012). Various evidences suggested that the development of autoimmune diseases mediated by the mechanism of gut microbiota-dependent molecular mimicry (Franceschi et al. 2019; Sprouse et al. 2019). Various proteins derived from the gut bacteria such as the amyloid protein and ubiquitin protein have the potential to trigger the autoimmune diseases. One recent literature suggested that bacterial amyloid such as curli protein released by Escherichia coli, staphylococcus aureus, etc. resembles to the human brain amyloid and serum amyloid A (sAA). The curli protein is utilized by bacteria for the formation of biofilm around them to prevent the bacterial community from the immune system. Human and bacterial amyloids are recognized by the same receptor called “TLR2/TLR1” heterocomplex (Nicastro and Tükel 2019). The similarity of both type of amyloids trigger the immune system to recognize these molecules and thus initiate the autoimmune response. Ubiquitin (ubb), a highly conserved protein found in eukaryotes as well as Bacteroides fragilis (Bf) having 60% similarity. Stewart et al. reported that the structural similarity in both the proteins result in cross-reacting epitopes. The individuals exposed to Bfubb resulted in generation of IgG antibodies compared to healthy volunteer (Stewart et al. 2018). A recent report highlighted the concept of eukaryotic-like proteins that are released by bacteria and are similar to the eukaryotic protein of the human (Mondino et al. 2020). Several genera are responsible for the production of eukaryotic-like protein but Legionella is the only one which has the highest number and widest variety of eukaryotic-like proteins (Lurie-Weinberger et al. 2010). Some of the bacterial eukaryotic-like-proteins function in the metabolism of the host cell to scavenge the nutrition for its replication. For instance, L. pneumophila sphingosine 1-phosphate lyase (LpSpl/LegS2) which structurally and functionally mimics eukaryotic sphingosine 1-phosphate lyases (Rolando et al. 2016). During, infection, LpSpl reduces host cell protein and prevents the autophagy by increasing its survival and could lead to damage in alveolar lung macrophages. The Treg cells are required to maintain the immune tolerance and it is suggested that the suppression of Treg cells is gut microbiota-dependent (Abbas et al. 2004). Literatures indicate that decreased number and frequency of the Treg cells results in breakdown of tolerance (Mellanby et al. 2009). DCs are also necessary for the maintenance of immune tolerance (Audiger et al. 2017). Currently, it has been found that TRAF6 is a signaling molecule require for the development of DCs. Defects in TRAF6 molecule lead to the defective induction of intestinal Treg cells and disruption of tolerance by mediated Th2 immune responses (King et al. 2006). The recent evidence suggested that TRAF6 suppression causes significant lower frequency and number of FOXP3+ cells in the intestinal propria (Han et al. 2017). To delineate the effect of gut microbiota on immune homeostasis, researchers administered the antibiotics to the mice wild type and TRAF6 deficient mice. The study found that mice treated with antibiotics have high number and frequency of FOXP3+ cells compared to the untreated mice. This shows that the defective Treg cell population in TRAF6 deficient mice depends on the presence of microbiota (Han et al. 2013).

3

The Link Between Gut Microbiota and Autoimmune Diseases

43

Furthermore, Th2 cell-mediated immune responses in the absence of TRAF6 gene cause the loss in mucosal tolerance which is also well established with the presence of microbiota. In continuation, the evidence suggested that Th2 cell cytokines such as IL-4, IL-13, and IL-5 levels in the ileum of the TRAF6 deficient mice were significantly higher than the wild-type mice. Further to investigate the effect of gut microbiota, the mice were treated with antibiotics and found that the levels of Th2 cytokines was significantly decreased in the antibiotic treated mice compared to the untreated mice (Han et al. 2013). This shows that TRAF6 deficient mice exhibit defective induction of Th2 cell cytokines which also affected by the presence of gut microbiota. Moreover, the checkpoint mechanism is also discussed in the reports to state that they prevent the autoimmunity (Paluch et al. 2018). During chronic infection, these checkpoint molecules also get expressed on the surface of T cell such as CTLA4 (cytotoxic T-lymphocyte antigen 4), PD-1 and interacts with CD80 and PD-L present on APCs respectively results in anergy (Suárez et al. 2020). Emerging evidence suggested that microbes and its metabolite also influence the activity of CTLA4 and PD-1 and has implications in inflammatory diseases (Miller and Carson 2020). Previous study reported that B. fragilis plays an immunoregulatory role in the CTLA-4 pathway by production of polysaccharide A, which is hypothesized to upregulate the production of IL-10 and downregulate the IL-17 to decrease the inflammation (Mazmanian et al. 2008). Bacterial translocation is the emerging process of tolerance breakdown and contributes to autoimmunity (Suárez et al. 2020). Mirza Ali et al. hypothesized that low-grade microbial associated molecular patterns can translocate to the brain and could be the result of autoimmune disease. For instance, LPS in low concentration induces a persistent activation of proinflammatory mediators such as TNF-α and IL-6 and hence, precipitate multiple sclerosis (Mirza and Mao-Draayer 2017). In another context, acute respiratory distress syndrome (ARDS) is a multifactorial disease and microbial translocation is one of the common causes of it in the state of dysbiosis. A study reported that microbiome of the lung is enriched with the gut microbiome, especially with Bacteroides spp. in the murine model of sepsis and ARDS established in humans (Dickson et al. 2016).

3.5

Link Between Gut Microbiota and Autoimmune Diseases

3.5.1

Connection Between Gut Microbiota and COPD

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation, and obstruction of lung airflow which causes the symptoms of difficulty in breathing and cough (Quaderi and Hurst 2018). Globally, it has become the third leading cause of morbidity and mortality. In particular, there are various evidences suggested the mechanism of COPD such as cigarette smoking, occupational pollution, dysbiosis in the lung microbiome and some genetic factors (Wang et al. 2017; Shukla et al. 2017). But the exact mechanism underlying the

44

D. Goyal et al.

pathogenesis of disease is not much clear. Recent evidences suggesting that the gut dysbiosis also have great impact on the lung-immune homeostasis (Mendez et al. 2019; Xu et al. 2020b). The gut dysbiosis occurs after the exposure of myriad compounds of smoke, particulate matter, antibiotics and western diet (Vaughan et al. 2019; Papoutsopoulou et al. 2020). A study reported that dysbiosis in the gut induced after administration of antibiotics (Abx) is able to induce the allergic-airway inflammation by the mechanism of macrophage polarization toward M2 type. Further they have suggested that the Candida species in the gut is able to release the prostaglandin E2 in systemic circulation which further induced the macrophage polarization (Kim et al. 2014). Therefore, maintenance of gut eubiosis is essential to control these fungal growth-associated with these autoimmune diseases (Li et al. 2020a). These studies suggest the association between gut microbiota and COPD. Currently the more focus is drawn on smoking-induced COPD. Various studies suggested the mechanism of smoke induce COPD (Song et al. 2021; Khalloufi et al. 2018). But the exact pathogenesis is not much clear. However, there is very little research on the smoking-induced gut dysbiosis which is further linked to the COPD. Here, we have demonstrated the link as shown in Fig. 3.1. Studies reported that smoking decreased the population of Bifidobacterium, Lactoccoci, Ruminococcus, Enterobacteriaceae, and segmented filamentous bacteria (SFB) in the cecal microflora (Huang and Shi 2019; Sublette et al. 2020). One study suggested that cigarette smoke induces proinflammatory cytokine release such as IL-8 and TNF-α by activation of NFҚB and posttranslational modification of histone deacetylase in macrophages (Yang et al. 2006). In contrast, one study suggested that stimulation of THP-1 cells with cigarette smoke extract in the presence and absence of Lactobacillus rhamnosus (L. rhamnosus) and Bifidobacterium breve (B. breve) attenuated the inflammation by modulating the expression of various inflammatory mediators such CXCL8 and IL-1β, released by macrophages in COPD (Mortaz et al. 2015). However, its direct effect in COPD has not been established yet. Another study suggested that subcutaneous injection of Klebsiella treatment attenuated the smokeinduced lung-inflammation by reducing the quantity of airway bronchoalveolar lavage (BAL) lymphocytes and macrophages. They demonstrated that Klebsiella attenuated the cigarette smoke induced increased Th1 cytokines such as CXCL5, CXCL10, CXCL9, IFN-γ, and IL-6 in BAL and serum (Bazett et al. 2017) (Fig. 3.2; Table 3.1).

3.5.2

Connection Between Gut Microbiota and Ulcerative Colitis

Ulcerative colitis (UC), is a well-known chronic-inflammatory disease which affects mainly the distal part of the colon (Feuerstein and Cheifetz 2014); whereas, Crohn’s disease which is another inflammatory bowel disease (IBD) affects the whole GIT. Studies suggested that the global prevalence of IBD projected up to 30 million people up to 2025 (Porter et al. 2020). Various drugs have been approved by FDA for the treatment of ulcerative colitis such as, anti-inflammatory (corticosteroids, and sulfasalazine) as well as immunomodulators (Azathioprine and 6-mercaptopurine,

The Link Between Gut Microbiota and Autoimmune Diseases

Fig. 3.1 Illustration of gut dysbiosis-induced chronic obstructive pulmonary disease

3 45

46

D. Goyal et al.

HEALTHY PERSON

ANTIBIOTICS Lactobacillus Clostridium Oscillospira Faecalibacterium Parabacteroides Bacteroides Pervotella

PARTICULATE MATTER

Firmicutes (70.6%) Proteobacteria (14.5%) Bacteroidetes (10.3%) WESTERAN Actinobacteria (2.1%) DIET Verrucomicrobia & Fusobacteria (0.6%) Lactobacillus johnsonii Lactobacillus gasseri Pervotella Ruminococcus torques

UPREGULATION

Escherichia coli Bacteroides

AND DOWREGULATION

Lactobacillus reuteri Oscillospira

OF GUT MICROBES

Enterococcus faecalis

SMOKING Aggregatibacter Bilophila wadsworthia Parabacteroides Bifidobacteria Clostridium Lachnospiraceae

Paraprevotella Alcaligenaceae Bacteroides

Fig. 3.2 Illustration of upregulation and downregulation of microbes toward exposure of different conditions such as antibiotics, particulate matter, smoking, and Western diet Table 3.1 Probiotics-based attenuation of chronic-obstructive pulmonary disease Gut dysbiosis autoimmune diseases COPD COPD

COPD

COPD

Probiotic therapy Parabacteroides goldsteinii Lactobacillus rhamnosus Bifidobacterium breve, Lactobacillus rhamnosus Klebsiella

Species Mus musculus C57Bl/6 Mus musculus IBD patients

Model Cigarette smokeinduced COPD Cigarette smokeinduced COPD Cigarette smokeinduced COPD

C57Bl/6 Mus musculus

Air and cigarette smoke-induced COPD

Reference Lai et al. (2022) Carvalho et al. (2020) Aimbire et al. (2019) Bazett et al. (2017)

methotrexate, cyclosporine) (Meier and Sturm 2011). However, these drugs do not exert direct effects on the inflammatory profile of the colon. Hence, there is a need to evolve new therapeutic agents which can ameliorate the mucosal colonic

3

The Link Between Gut Microbiota and Autoimmune Diseases

47

inflammation. Recent evidence suggested that probiotics and fecal microbiota transplantation have the efficient role in maintaining the immune homeostasis and mucosal inflammation of the colon (Shen et al. 2018). This suggested the role of gut microbiota in modulation of immune responses of the colon. The disturbance in the gut microbiota is the characteristic cause of IBD (Nishida et al. 2018). The dysbiosis in the gut microbes and its metabolites can reduce the expression of tight junction proteins, i.e., α-defensin 5 protein. In support of this, one study suggested that α-defensin 5 protein in intestinal epithelial cells is regulated by lactic acid and other molecules found in cecum and responsible for mediating intestinal immunity. This tight junction protein is also able to cause the mutation in the NOD2 receptor coding gene which ultimately results in intestinal barrier impairment and allow the entry of the pathogenic bacteria from colonic lumen to lamina propria of the colon (Wehkamp et al. 2004). One research study reported that, dysbiosis in the gut produce excessive amount of ATP that stimulates the subset of lamina propria CD70high CD11clow which express the TH17 prone molecules such as IL-6, IL-23 and TGF-β (Atarashi et al. 2008). The activated TH17 cells further release the IL-17 which contributes to the autoimmunity-mediated colitis. Studies have been suggested that host–bacteria interaction is necessary for maintaining the immune system of the GIT (Parker et al. 2018). However, dysbiosis in the gut produce altered metabolites that interact with the colonic epithelial cells in a dysregulated manner which causes the loss of immune tolerance. Meanwhile, the host antigen starts to react with its own immune cells and the production of autoantibodies in the GIT mucosa. The two autoantibodies, perinuclear antineutrophil cytoplasmic antibody (pANC) and tropomyosin have been found in the patients suffering from the UC (Taniguchi et al. 2001; Lee et al. 2010). Some bacteria such as Fusobacteria (Firmicutes of the gut) have the potential to regulate the expression of peroxisomeproliferator-activated receptor gamma (PPAR-γ) which is responsible for the activation of NFҚB pathway responsible for the transcription of proinflammatory genes (Hasan et al. 2019). However, suppression of PPAR-γ activity due to the bacterial pathogen may be the result of upregulation of NFҚB pathway which transcribes the proinflammatory genes such as TNFA, IL6, and IFNG. Another study reported that SCFA-producing bacteria such as Faecalibacterium prausnitzii, Clostridium leptum, and Eubacterium hallii regulate the expression of Treg cells in the colonic lamina propria against the gut pathogen. Moreover, one research suggested that SCFAs promote the IL-10 production in Th1 cells through the activation of STAT3 and mTOR pathway in the normal as well as IBD conditions (Sun et al. 2018). Thus, it is considered as a therapeutic agent for treatment of IBD. The disturbance in the SCFAs producers lead to the high concentration of butyrate which activates the T-bet in T cells resulting in IFN-γ-producing Treg cells (Kespohl et al. 2017). Further, downregulation of FOXP3+ Treg cells is responsible for the decreased release of anti-inflammatory molecules such as TGF-β and IL-10. Study showed that Bifido capsule containing the mixture of Bifidobaterium, Enterococcus, and Lactobacillus treated the experimental colitis by increasing CD4+CD25+FOXP3+T cell and regulated the balance of Th1 and Th2 cytokines in the colonic mucosa of mice. The DCs, macrophages and monocytes are the antigen presenting cells (APCs)

48

D. Goyal et al.

Fig. 3.3 Illustration of the gut dysbiosis-induced ulcerative colitis

which have the potential to maintain the innate immune response of the colon (Gaudino and Kumar 2019). The sampling of harmful bacterial antigen by the DCs further present to CD4+ T cells which aberrantly release the IL-4 and stimulate the expression of STAT6 and GATA3 (Gaudino and Kumar 2019). The expression of these genes is responsible for stimulation of Th2 cells-mediated colitis. The Th2 cells release IL-4 and IL-13 in the bottom of epithelium cells and results into increase in barrier permeability and disruptions in tight junctions and further recruitment of NKT cells and innate lymphoid cells (Heller et al. 2002). These cells are responsible for the further release of IL-13 and exacerbation of the colitis as shown in Fig. 3.3. A study investigated the potential role of probiotic- Lactobacillus plantarum YS4 in the attenuation of oxazolone-induced UC (Yi et al. 2020). Another study suggested that addition of prebiotics to the combination of probiotic increase the number and activity of probiotic as well as its lifespan. A randomized-controlled study reported that symbiotic combination of probiotics and prebiotics results in mild-to-moderate effect in UC (Altun et al. 2019). On the other hand, various probiotic formulations have been tested on different models of UC and few of them are listed in the Table 3.2.

3

The Link Between Gut Microbiota and Autoimmune Diseases

49

Table 3.2 Probiotics-based attenuation of the ulcerative colitis Gut dysbiosis autoimmune diseases UC

UC

Probiotic therapy Lactobacillus rhamnosus Lactobacillus plantarum Lactobacillus acidophilus Enterococcus faecium VSL#3

Species Human

Model IBD patients

C57BL/ 6 mice BALB/ c mice, human

DSS-induced colitis

UC

Bifidobacterium longum VSL#3

UC

Lactobacillus casei

Human

2,4,6trinitrobenzene sulfonic acid (TNBS)-induced murine colitis IBD patients

UC

Saccharomyces boulardii

C57BL/ 6 mice

Azoxymethane/DSS colitis

UC

Lactobacillus plantarum YS4

UC

Enterococcus faecium, Lactobacillus plantarum, Streptococcus thermophilus, Bifidobacterium lactis, Lactobacillus acidophilus, Bifidobacterium longum fructooligosaccharide

BALB/ c mice Human

Oxazolone-induced colitis IBD patients

3.5.3

Reference Bjarnason and Sission (2019) Liu et al. (2019) Chen et al. (2019)

Vejdani et al. (2017) Wang et al. (2019a) Yi et al. (2020) Altun et al. (2019)

Connection Between Gut Microbiota and Autism Spectrum Disorder

Autism spectrum disorder (ASD) is an autoimmune as well as complex neurodevelopmental disorder which is characterized by repetitive stereotyped behavior, deficits in social interaction and communication (Abou-Donia 2020). Prefrontal cortex and striatum, the two major portions of brain are responsible for the social behavior, cognition and decision-making abilities. However, any synaptic dysfunctions and aberrant trajectories in these particular areas results in autistic-like behavior. Studies suggested that the occurrence of autism is more prevalent in boys compared to the girls (Strang et al. 2020; Lai and Szatmari 2020). It is linked with the several genetic factors; however, literatures suggested that along with the genetic factors, nongenetic factors are also responsible for autism (Oldenburg et al. 2020; Yoon et al. 2020). The nongenetic factors involve the immune dysregulation, autoantibodies in systemic circulation and gut–brain axis (Sabit et al. 2021). Current evidences suggested that gut–brain axis is the main leading cause of ASD (Serra

50

D. Goyal et al.

et al. 2020; Sabit et al. 2021). It has been reported that autistic children have more gastrointestinal symptoms such as diarrhea, constipation and gas retention (Leader et al. 2020). Hence, modulation of gut microbiota could be a potential therapy for the autistic-patients. Disbalance in the intestinal microbes and its metabolites leads to alteration in the neuronal and glial proteins, causing cognitive impairment as well as behavioral abnormalities (Saurman et al. 2020; Madra et al. 2020). For instance, neuroactive compounds present in the gut are responsible for the modulation of behavior (Mohanta et al. 2020). In support of this, one major study reported that gut microbiota from ASD patients is sufficient to promote altered behavior in GF mice by increased repetitive behavior, decreased locomotion and communication deficits (Morais et al. 2020). Recent studies have given insights on alteration in plasma metabolites associated with ASD patients compared to the typically developing mice. For instance, tryptophan derivatives, such as indolepropionate is responsible for mucosal homeostasis by releasing IL-10 and is neuroprotective antioxidant (Alexeev et al. 2016). To support this, one study suggested that nicotinamide riboside was lower in ASD patients which is positively correlated with indolepropionate (Kang et al. 2020). This study also reported that the levels of medium-chain fatty acid such as caprylate and heptanoate are closely correlated with ASD group and found its elevated levels. Study reported that the levels of above metabolites can be attenuated to the normal levels after the microbiota transfer therapy (MTT). The p-cresol sulfate induces oxidative stress and dopamine metabolism and has been implicated in etiology of ASD (Pascucci et al. 2020). Study reported that p-cresol sulfate isolated from fecal metabolite was higher in the ASD patient and after the MTT, the Desulfovibrio was increased associated with decreased in p-cresol sulfate (Kang et al. 2020). The concentration of SCFAs was found to be increased in children with ASD. Propionic acid mainly produced by Clostridia and Desulfovibrio which crosses the blood–brain barrier (BBB) and produces autistic-like behavior (Wang et al. 2012). A recent study has reported that Diacylglycerol lipase β involved in endocannabinoid system and axonal growth was significantly decreased in ASD-colonized mice (Sharon et al. 2019). This study suggested that altered metabolite profiles or amino acids in the colon is associated with ASD as they maintain the neuronal function and behavior. Moreover, this study suggested that 5-aminovaleric acid and taurine are the weak agonists of γ-amino butyric acid and decrease in the ASD mice compared to the TD mice. It has been reported that 5-aminovaleric acid and taurine is positively associated with the increase in social behavior and decrease in repetitive behavior respectively. Another weak glycine receptor agonist, i.e., 3-aminoisobutyric acid was increased in ASD mice (Sharon et al. 2019). Recent literatures highlighted that autism could be due to the various genetic defects which are regulated by the gut microbiota. A whole genome sequencing and transcriptome analysis showed that EphB6 is a gene which is regulated by the gut microbiota and associated with the autistic-like features. One recent study justified that gut microbiota regulate autism like behavior by mediating the vitamin B6 homeostasis (Li et al. 2019). It has been concluded from the study that vitamin B6 plays a major role in maintaining the level of dopamine in prefrontal cortex (Tang

3

The Link Between Gut Microbiota and Autoimmune Diseases

51

and Wei 2004). Further study revealed that upregulation of Mucispirillum genus (involved with Vitamin B6 synthesis) after treating fecal microbiota from wild type mice to EphB6-deficient mice (Li et al. 2020b). Diet is also an important environmental factor that contributes to the gut microbial dysbiosis (Carding et al. 2015). Studies suggested that maternal diet is an important tool which leads to the modulation of the infant gut microbiome (Maher et al. 2020; Ferretti et al. 2018). Further the altered microbiome of the infant represented the hyperactivity, impairment in social behavior and increased in repetitive behavior. To support this notion, one study suggested that the exposure of high salt diet in the parental female diet leads to the transfer of altered microbiome in the offspring. The sequencing analysis revealed the decrease in the genus Lactobacillus and increase proportion of the Akkermansia which expected to be hamper the expression of GABA-receptors and tryptophan system in the medial prefrontal cortex region of the brain (Afroz et al. 2021). Kong et al. published that Lactobacillus helveticus was more beneficial in regulating the serotonin (5-HT) metabolism and balancing the excitatory and inhibitory neurotransmitter release (Kong et al. 2021). Further analysis of gut microbiota showed high abundance of Turicibacter and low levels of SCFAs which are associated with the 5-HT levels autistic-like behavior which is ameliorated after the treatment with Lactobacillus helveticus (Kong et al. 2021). Recent literatures have suggested for altered numbers of SCFA-producing bacteria in children with neurodevelopmental disorder, indicating a role of SCFA in synthesis of neuronal proteins in brain (Silva et al. 2020; Morris et al. 2017). A study was conducted including 36 children with neurodevelopmental disorder. Sequencing of selected rDNA amplicons revealed that there is less frequent number of SCFA-producing bacteria such as Faecalibacterium prausnitzii, Butyricicoccus pullicaecorum, and Eubacterium rectale. Moreover, there was increased incidence of harmful bacteria such as Desulfotomaculum guttoideum, Intestinibacter bartlettii, and Romboutsia ilealis that are closely related to Clostridia clusters (Bojović et al. 2020). This study also suggested that the frequency of commensal bacteria such as Enterococcus faecalis, Enterococcus gallinarum, Streptococcus pasteurianus, Lactobacillus rhamnosus, and Bifidobacteria sp. was found to be lower in patients (Bojović et al. 2020). Another recent research highlighted that the administration of probiotics (including strains of Bifidobacterium and Lactobacillus) with fructo-oligosaccharide (FOS) in autistic children alleviated the lower abundance of commensal bacteria B. longum and higher levels of clostridim and ruminococcus, low levels of SCFAs and zonulin (marker of intestinal and BBB permeability). Furthermore, the elevated plasma levels of serotonin and tryptophan metabolism disorder associated with the clostridium was ameliorated after the administration of the probiotic and FOS therapy (Wang et al. 2020). One recent placebo controlled-pilot trial study investigated the effect of VISBIOME (a combination of seven bacterial strains) in 3 to 12 years of children and reported that the probiotic modulates the autistic-like features by modulating the GIT symptoms (Santocchi et al. 2020) (Fig. 3.4).

52

D. Goyal et al.

Fig. 3.4 Gut microbiota dysbiosis-induced autism spectrum disorder and ADAM (a disintegrin and metalloprotease)

3.5.4

Connection Between Gut Microbiota and Type-1 Diabetes

Type-1 diabetes is the autoimmune disorder characterized by increased autoantibodies against β cell in the pancreas resulting in loss of β cells and increased blood glucose level (Lernmark and Larsson 2013). The autoantibodies develop in response to the any kind of dietary antigen and exposure of antibiotics (Snethlage et al. 2021). The detrimental exposure of various environmental factors modulates the tolerogenic cells into the autoimmune cells of the pancreas (Paun and Danska 2016). However, recent literature suggested that modulated gut bacterial antigens and gut metabolites activate the aberrant innate and adaptive immune response in the intestine which is similar to the pancreas immune system and the presence of similar adhesion molecules (Zheng et al. 2020). The dysbiosis in the gut could be an underlying cause of the Type 1 Diabetes. Evidence suggested that gut microbial

3

The Link Between Gut Microbiota and Autoimmune Diseases

53

dysbiosis causes the increase in gut permeability which leads to the development of anti-islet cell antibodies that further suppress the β cells of pancreas and thus increases glucose in blood, i.e., hyperglycemia (Bibbò et al. 2017). To justify this, a prospective cohort study reported that children with multiple islet autoantibodies had gut dysbiosis and decreased abundance of prevotella and Butyricimonas genera. Small-intestinal permeability was also found to be higher in the diabetic children (Harbison et al. 2019). The SCFAs are the fermented products of the dietary fibers that maintain the intestinal immune system and mucosal homeostasis. The various SCFAs promote the anti-inflammatory activity by upregulating Treg cells and by attenuating the effect of various proinflammatory cytokines such as IFN-γ (Vinolo et al. 2011). A recent study suggested that defective differentiation of FOXP3+ Treg cells in the extra-thymic region develops the self-reactive T cells in the gut which migrate to the pancreatic lymph nodes from the intestinal mucosa (Badami et al. 2011). The diet is an important factor which determines the composition and diversity of gut microbiota (Jiang et al. 2018; Alou et al. 2016). Recent studies suggested that the changes in diet such as fatty diet modulates the intestinal immune system and increases the gut permeability of the intestine leading to the disturbance in immune homeostasis of the gut as well as autoantibodies in islet cells (Tanaka et al. 2020; Jain and Walker 2015). The extra virgin olive oil containing polyunsaturated fatty acid inhibits the formation of TMAO which is responsible for the development of type 1 DM (Janeiro et al. 2018). The TMAO is a metabolic product of phosphatidylcholine and L-carnitine produced after the dysbiosis in the gut (Koeth et al. 2014). Hence, the studies suggested that the Mediterranean diet is able to produce the anti-inflammatory molecules and improves the decreased levels of Bacteroides and Firmicutes which also regulate the tryptophan metabolites and omega-3 fatty acids (Calabrese et al. 2021). Recent studies have also shown the association between difference in microbial diversity and occurrence of Type 1 DM. It was reported that the decrease abundance of Prevotella, Bifidobacterium and Lactobacillus in Type 1 DM patients leads to less production of butyrate and decreased anti-inflammatory and immunomodulatory activity, thereby resulting in loss of intestinal barrier integrity (Brown et al. 2012). However, the administration of L. johnsonii N6.2 has been shown to mitigate the development of Type-1 diabetes by downregulating the oxidative stress response proteins such as catalase and proinflammatory cytokine such as IFN-γ. It was also reported to upregulate the tight junction protein claudin (Valladares et al. 2010). There are various factors involved with the development of gut microbiota such as pattern of birth, exposure of breastfeeding, exposure of complementary food (Matsuyama et al. 2019). The pattern of birth either to cesarean and vaginal determines the composition and diversity of the microbiota. Children who born by the vaginal delivery are exposed to all bacteria of the maternal vagina that reshapes the infant’s microbiota and hence less risk is associated with the development of Type 1 DM (Rutayisire et al. 2016). Cesarean delivery is associated with the less diversity of microbes and altered microbial composition (Rutayisire et al. 2016). Literature suggested that the infants who are fed by the maternal milk for the long term duration are less prone for the development of the disease. The maternal milk

54

D. Goyal et al.

contains the very commensal bacteria and hormones such as insulin and leptin that regulates glucose homeostasis in the blood (Power and Schulkin 2013). However, the exposure of cow milk and formula-milk at early age causes the lack of insulin and beneficial microbes associated with the development of Type-1 DM (Saboo et al. 2016). Research suggested that maternal milk contains the high amount of Bifidobacterium and γ-proteobacteria which is associated with the insulin and mucosal homeostasis (Larmonier et al. 2013). After 6 months of age, the complementary foods should be given to the infant for the development of immune system (Grimshaw et al. 2013). A recent study suggested that the infant feeding habits is able to develop the β-cell autoimmunity against insulin and glutamic acid decarboxylase. A perspective cohort study of children established that feeding of various food-items and formula-based milk products in the early stage causes the development of Type 1 DM. It was shown that the young children with HLA-conferred susceptible gene developed advanced β-cell autoimmunity with the presence of these antibodies insulin antibodies, autoantibodies to GADA in the plasma (Virtanen et al. 2006). Studies reported that the diabetic people have the potential of reducing pancreatic β cell mass and pathogenesis of insulitis and insulin autoantibody (Campbell-Thompson et al. 2016). However, recent research suggested that the administration of the combination of probiotic IRT5 (immune regulation and tolerance 5) in NOD mice had attenuated the insulitis condition and the levels of serum insulin autoantibody. The study further suggested the increased β cell mass and upregulation of tight junction proteins and downregulation of IFN-γ (Kim et al. 2020). Recent developing strategies are suggesting that focusing on prevention of loss in pancreatic β cell could be a potential therapy for type-1 diabetes (Eizirik et al. 2009). Gut secretes the incretin hormone such as glucagon like peptide-1 which is secreted by enteroendocrine cells was reported to regulate the growth of β cell and increase the release of insulin to maintain the glucose homeostasis (Hirasawa et al. 2005). However, the recent research suggested that SCFAs are able to induce the secretion of GLP-1 by acting on G-protein-coupled receptors (GPCRs) of enteroendocrine cells. Hence, the administration of probiotic can alleviate the secretion of GLP-1 (Psichas et al. 2015). One research suggested that the administration of two probiotic strains could stimulate the enteroendocrine cells to secrete GLP-1 thereby, preventing the development of Type 1 Diabetes. The probiotic strains Lactobacillus kefiranofaciens M and Lactobacillus kefiri K were reported to prevent the onset of Type 1 Diabetes by stimulating the production of GLP-1, regulating the immunemodulatory reaction and modifying the microbiota (upregulating the Lactic acid bacteria and Bifidobacteria ratio and downregulating the C. perfringen) (Wei et al. 2015). This study also suggested that administration of probiotic downregulated the secretion of proinflammatory cytokines (IL-6 and TNF-α) in the pancreas and upregulation of anti-inflammatory cytokine such as IL-10 (Wei et al. 2015) (Fig. 3.5).

3

The Link Between Gut Microbiota and Autoimmune Diseases

55

Fig. 3.5 Gut microbiota-induced type-1 diabetes mellitus

3.5.5

Connection Between Gut Microbiota and Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory, chronic, demyelinating, and degenerative disease that affects the central nervous system (Schepici et al. 2019). Approximately 2.5 million people are affected worldwide with MS and the disease is found to be more prevalent in females than males (Harbo et al. 2013; Dendrou et al. 2015). The main pathological hallmark of MS is the development of inflammatory plaques, focal demyelination in both white and gray matter of the brain and spinal cord. The plaques are formed by inflammatory process that causes the demyelination and destruction of neuronal supporting cells and neuronal loss. The demyelination is caused by an alteration of the BBB that allows infiltration of wide range of immune cells to the CNS. The lymphocytes that recognize the myelin antigen (CD4+ or CD8+ T cells) cross the BBB, triggers the inflammatory cascades that causes demyelinating lesions (Frohman et al. 2006). Genetic and environmental factors play a key role in the development of MS (Miyake and Yamamura, 2019; Oksenberg 2013). One of the main environmental factors, i.e., the gut microbiota appears to play an important role in the pathogenesis of MS. The gut microbiota is involved in modulation of the host’s immune system, alters the integrity and functionality of the BBB, triggers autoimmune demyelination, and interacts directly with the different cell types present in the CNS (Calvo-Barreiro et al. 2018). One study compared the microbiota of healthy subjects and patients with MS (Cosorich et al. 2017). The 16 s ribosomal RNA sequencing analysis revealed that the microbiota isolated from

56

D. Goyal et al.

small intestine exhibited a decrease in phylum Bacteroidetes in patients with MS and increase in Firmicutes (Cosorich et al. 2017). Additionally, the study also reported an increase in Streptococcus mitis (S. mitis) and Streptococcus oralis and decrease in Prevotella. The Prevotella produces the anti-inflammatory metabolite such as propionate. A decreased level of Prevotella in patients with MS is linked higher activity of Th17 cells which is involved in the cell-mediated tissue damage of autoimmunity (Schwiertz et al. 2010; Engen et al. 2014).

3.5.6

Connection Between Gut Microbiota and Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus (SLE) is a multiple systemic autoimmune disease involving multiple organs throughout the body (Mok and Lau 2003). The disease is characterized by severe inflammation in target organs, leading to tissue damage. The damaged cell products picked up by autoantibodies from immune complexes and activate APCs, which induce inflammatory T cells and proinflammatory cytokines, creating a continuous cycle of inflammation (Luo et al. 2018). In recent years, there has been a lot of reports on the relationship between SLE and intestinal flora (Guo et al. 2020; Hevia et al. 2014). The gut microbiota is comprised of the main two phyla, Bacteroidetes and Firmicutes, and the rest composed of bacteria such as Proteobacteria, Actinobacteria, and Fusobacteria. Among these Firmicutes/Bacteroidetes ratio disbalance indicates for gut dysbiosis. In SLE, elevated Bacteroidetes levels and a reduced Firmicutes/Bacteroidetes ratio have been observed (Moon et al. 2020). The gut flora of SLE patients showed significantly lower Firmicutes/Bacteroidetes ratio and exhibited a depletion of Lachnospiraceae and Ruminococcaceae and an enrichment of Bacteroidaceae and Prevotellaceae families (Hevia et al. 2014). In another study, the SLE patients exhibited the decreased levels of Firmicutes, enrichment of Bacteroidetes, Actinobacteria, and Proteobacteria, and significant increase of the family Prevotellaceae (He et al. 2016; Wei et al. 2019).

3.5.7

Connection Between Gut Microbiota and Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA) is a chronic autoimmune disease, caused by abnormal immune activation, and immune tolerance which results into synovial inflammation, and bone damage in multiple joints (Xu et al. 2020a). Recent studies have found that over 100 genetic susceptibility loci are involved in RA (Okada et al. 2014). It was recently shown that an immunoglobulin A (IgA) anticitrullinated protein antibody (ACPA) is detectable before the onset of arthritis which suggests that RA originates at mucosal sites, such as the oral cavity and the gut (Nielen et al. 2004; Rantapää-Dahlqvist et al. 2003). Porphyromonas gingivalis, a major pathogenic bacterium of periodontal diseases, may correlate with the development of RA because this

3

The Link Between Gut Microbiota and Autoimmune Diseases

57

bacterium is the only known pathogen that expresses a peptidyl arginine deiminase and may be related to ACPA (Lappin et al. 2013; Hendler et al. 2010). Previous studies found that the composition of the intestinal microbiota is altered in patients with onset RA. Commensal segmented filamentous bacteria (SFB) induce Th17 cells in the intestine and trigger arthritis inflammation in mice (Wu et al. 2010; Ivanov et al. 2009).

3.5.8

Connection Between Gut Microbiota and Sjögren’s Syndrome (SS)

Sjögren’s syndrome (SS) is a chronic autoimmune disease which is associated with lymphocytic infiltration in exocrine glands and various other organs. The symptoms of SS include musculoskeletal pain, dry mouth, and dry eyes (Moon et al. 2020; Foulks et al. 2015). Among these symptoms, dry eye is one of the most discomforting symptoms in SS patients (Akpek et al. 2015). There are only few reports regarding the dysbiosis of the gut in SS (Akpek et al. 2015; De Paiva et al. 2016). Emerging evidences indicate that gut dysbiosis contributes to the pathophysiology or exacerbation of autoimmune diseases, including SS through the imbalance of the immune system (Mandl et al. 2017). One study found the gut dysbiosis in SS and reported the reduced numbers of Bacteroides, Parabacteroides, Faecalibacterium, Prevotella, whereas increased numbers of Pseudobutyrivibrio, Escherichia/Shigella, Blautia, and Streptococcus (De Paiva et al. 2016).

3.6

Conclusion

The impact of commensal bacteria on health and illness via immune function modulation has emerged as a scientific and clinically important topic. The development of a culture-independent and detailed method to characterize gut microbial communities has been revolutionized due to the recent advances in “next-generation” sequencing. It is now clear that the gut microbiota has a significant impact on the immune system of the host and can influence autoimmune illnesses both inside and outside the gut. Environmental variables, in addition to genetic factors, play an essential role in developing the microbiota. These issues should be approached with caution, as improper practices such as antibiotic usage may raise the risk of autoimmune illness through microbiota-mediated immunomodulation. Increasing gut microbiota-related approaches may contribute novel directions for the treatment of autoimmune diseases. The modulation of gut microbiota via probiotics, prebiotics and fecal microbiota transplantation showed effective results for the treatment of autoimmune diseases. There are various factors responsible for the condition of gut dysbiosis such as smoking, particulate matter, antibiotics and western diet. Interestingly, administration of various probiotic based therapies has been successful in establishing the gut homeostasis. However, it is not yet clear whether the gut dysbiosis is the cause or the consequence of autoimmune disease. Moreover, there

58

D. Goyal et al.

are certain limitations in targeting the gut dysbiosis, as each individual have different shape of resident microbes. Along with this, it is not yet clear that which particular microbes are responsible for the specific autoimmune disease; hence more research is needed in this area.

References Abbas AK, Lohr J, Knoechel B, Nagabhushanam V (2004) T cell tolerance and autoimmunity. Autoimmun Rev 3:471–475 Abou-Donia MB (2020) Autism—a potential autoimmune disease neurodegeneration-induced autoantibodies against neural proteins. J Cell Immunol 2(2):47–54 Afroz KF, Reyes N, Young K, Parikh K, Misra V, Alviña K (2021) Altered gut microbiome and autism like behavior are associated with parental high salt diet in male mice. Sci Rep 11:1–14 Aimbire, F., Carvalho, J. L., Fialho, A. K., Miranda, M., Albertini, R. & Keller, A. 2019. Role of probiotics Bfidobacterium breve and Lactobacillus rhmanosus on lung inflammation and airway remodeling in an experimental model of chronic obstructive pulmonary disease. Eur Respiratory Soc. Akpek EK, Mathews P, Hahn S, Hessen M, Kim J, Grader-Beck T, Birnbaum J, Baer AN (2015) Ocular and systemic morbidity in a longitudinal cohort of Sjögren’s syndrome. Ophthalmology 122:56–61 Alexeev EE, Lanis JM, Schwisow KD, Kominsky DJ, Colgan SP (2016) Microbiota-Derived Tryptophan Metabolites Activate Aryl Hydrocarbon Receptor and Induce IL-10 Receptor Expression in Intestinal Epithelia. FASEB J 30:57.2-57.2 Al-nasiry, S., Ambrosino, E., Schlaepfer, M., Morré, S. A., Wieten, L., Voncken, J. W., Spinelli, M., Mueller, M. & Kramer, B. W. 2020. The Interplay Between Reproductive Tract Microbiota and Immunological System in Human Reproduction Alou MT, Lagier J-C, Raoult D (2016) Diet influence on the gut microbiota and dysbiosis related to nutritional disorders. Human Microbiome Journal 1:3–11 Altun HK, Yıldız EA, Akın M (2019) Effects of synbiotic therapy in mild-to-moderately active ulcerative colitis: a randomized placebo-controlled study. Turk J Gastroenterol 30:313 Arnold B, Schönrich G, Hämmerling GJ (1993) Multiple levels of peripheral tolerance. Immunol Today 14:12–14 Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H, Ishii N, Evans R, Honda K (2008) ATP drives lamina propria TH 17 cell differentiation. Nature 455: 808–812 Audiger C, Rahman MJ, Yun TJ, Tarbell KV, Lesage S (2017) The importance of dendritic cells in maintaining immune tolerance. J Immunol 198:2223–2231 Badami E, Sorini C, Coccia M, Usuelli V, Molteni L, Bolla AM, Scavini M, Mariani A, King C, Bosi E (2011) Defective differentiation of regulatory FoxP3+ T cells by small-intestinal dendritic cells in patients with type 1 diabetes. Diabetes 60:2120–2124 Bazett M, Biala A, Huff RD, Zeglinksi MR, Hansbro PM, Bosiljcic M, Gunn H, Kalyan S, Hirota JA (2017) Attenuating immune pathology using a microbial-based intervention in a mouse model of cigarette smoke-induced lung inflammation. Respir Res 18:1–11 Benson J, Whitacre C (1997) The role of clonal deletion and anergy in oral tolerance. Res Immunol 148:533–541 Bibbò S, Dore MP, Pes GM, Delitala G, Delitala AP (2017) Is there a role for gut microbiota in type 1 diabetes pathogenesis? Ann Med 49:11–22 Bjarnason I, Sission G (2019) A randomised, double-blind, placebo-controlled trial of a multi-strain probiotic in patients with asymptomatic ulcerative colitis and Crohn’s disease. Inflammopharmacology 27:465–473

3

The Link Between Gut Microbiota and Autoimmune Diseases

59

Bojović K, Soković Bajić S, Vojnović Milutinović D, Tomić M, Golić N, Tolinački M (2020) Gut microbiota dysbiosis associated with altered production of short chain fatty acids in children with neurodevelopmental disorders. Front Cell Infect Microbiol 10:223 Brown K, Decoffe D, Molcan E, Gibson DL (2012) Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients 4:1095–1119 Burger-Van Paassen N, Vincent A, Puiman PJ, Van Der Sluis M, Bouma J, Boehm G, Van Goudoever JB, Van Seuningen I, Renes IB (2009) The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelial protection. Biochem J 420:211– 219 Burgueño JF, Abreu MT (2020) Epithelial Toll-like receptors and their role in gut homeostasis and disease. Nat Rev Gastroenterol Hepatol 17:263–278 Calabrese CM, Valentini A, Calabrese G (2021) Gut microbiota and Type 1 diabetes mellitus: the effect of mediterranean diet. Front Nutr 7:329 Calvo-Barreiro L, Eixarch H, Montalban X, Espejo C (2018) Combined therapies to treat complex diseases: the role of the gut microbiota in multiple sclerosis. Autoimmun Rev 17:165–174 Campbell-Thompson M, Fu A, Kaddis JS, Wasserfall C, Schatz DA, Pugliese A, Atkinson MA (2016) Insulitis and β-cell mass in the natural history of type 1 diabetes. Diabetes 65:719–731 Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ (2015) Dysbiosis of the gut microbiota in disease. Microbial Ecol Health Dis 26:26191 Carvalho JL, Miranda M, Fialho AK, Castro-Faria-Neto H, Anatriello E, Keller AC, Aimbire F (2020) Oral feeding with probiotic Lactobacillus rhamnosus attenuates cigarette smoke-induced COPD in C57Bl/6 mice: relevance to inflammatory markers in human bronchial epithelial cells. PLoS One 15:e0225560 Chen X, Fu Y, Wang L, Qian W, Zheng F, Hou X (2019) Bifidobacterium longum and VSL# 3® amelioration of TNBS-induced colitis associated with reduced HMGB1 and epithelial barrier impairment. Dev Comp Immunol 92:77–86 Cheng H-Y, Ning M-X, Chen D-K, Ma W-T (2019) Interactions between the gut microbiota and the host innate immune response against pathogens. Front Immunol 10:607 Choi IS (2012) Immune tolerance by induced regulatory T cells in asthma. Allergy Asthma Immunol Res 4:113 Cone RA (2009) Barrier properties of mucus. Adv Drug Deliv Rev 61:75–85 Cosorich I, Dalla-Costa G, Sorini C, Ferrarese R, Messina MJ, Dolpady J, Radice E, Mariani A, Testoni PA, Canducci F (2017) High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv 3:e1700492 Crispe IN (2014) Immune tolerance in liver disease. Hepatology 60:2109–2117 Cusick MF, Libbey JE, Fujinami RS (2012) Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol 42:102–111 De Paiva CS, Jones DB, Stern ME, Bian F, Moore QL, Corbiere S, Streckfus CF, Hutchinson DS, Ajami NJ, Petrosino JF (2016) Altered mucosal microbiome diversity and disease severity in Sjögren syndrome. Sci Rep 6:1–11 Dendrou CA, Fugger L, Friese MA (2015) Immunopathology of multiple sclerosis. Nat Rev Immunol 15:545–558 Derrien M, Van Passel MW, Van De Bovenkamp JH, Schipper R, De Vos W, Dekker J (2010) Mucin-bacterial interactions in the human oral cavity and digestive tract. Gut Microbes 1:254– 268 Dickson RP, Singer BH, Newstead MW, Falkowski NR, Erb-Downward JR, Standiford TJ, Huffnagle GB (2016) Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nat Microbiol 1:1–9 Eguchi K (2001) Apoptosis in autoimmune diseases. Internal Med 40:275–284 Eizirik DL, Colli ML, Ortis F (2009) The role of inflammation in insulitis and β-cell loss in type 1 diabetes. Nat Rev Endocrinol 5:219

60

D. Goyal et al.

Elumalai P, Gunadharini D, Senthilkumar K, Banudevi S, Arunkumar R, Benson C, Sharmila G, Arunakaran J (2012) Induction of apoptosis in human breast cancer cells by nimbolide through extrinsic and intrinsic pathway. Toxicol Lett 215:131–142 Engen SA, Rukke HV, Becattini S, Jarrossay D, Blix IJ, Petersen FC, Sallusto F, Schenck K (2014) The oral commensal Streptococcus mitis shows a mixed memory Th cell signature that is similar to and cross-reactive with Streptococcus pneumoniae. PLoS One 9:e104306 Ferretti P, Pasolli E, Tett A, Asnicar F, Gorfer V, Fedi S, Armanini F, Truong DT, Manara S, Zolfo M (2018) Mother-to-infant microbial transmission from different body sites shapes the developing infant gut microbiome. Cell Host Microbe 24(1):133–145. e5 Feuerstein JD, Cheifetz AS (2014) Ulcerative colitis: epidemiology, diagnosis, and management. Mayo Clin Proc 89(11):1553–1563 Foulks GN, Forstot SL, Donshik PC, Forstot JZ, Goldstein MH, Lemp MA, Nelson JD, Nichols KK, Pflugfelder SC, Tanzer JM (2015) Clinical guidelines for management of dry eye associated with Sjögren disease. Ocul Surf 13:118–132 Franceschi F, Ojetti V, Candelli M, Covino M, Cardone S, Potenza A, Simeoni B, Gabrielli M, Sabia L, Gasbarrini G (2019) Microbes and Alzheimer’disease: lessons from H. pylori and GUT microbiota. Eur Rev Med Pharmacol Sci 23:426–430 Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med 354:942–955 Fujio-Vejar S, Vasquez Y, Morales P, Magne F, Vera-Wolf P, Ugalde JA, Navarrete P, Gotteland M (2017) The gut microbiota of healthy chilean subjects reveals a high abundance of the phylum verrucomicrobia. Front Microbiol 8:1221 Garcia-Gutierrez E, Mayer MJ, Cotter PD, Narbad A (2019) Gut microbiota as a source of novel antimicrobials. Gut Microbes 10:1–21 Gaudino SJ, Kumar P (2019) Cross-talk between antigen presenting cells and T cells impacts intestinal homeostasis, bacterial infections, and tumorigenesis. Front Immunol 10:360 Gordon YJ, Romanowski EG, McDermott AM (2005) A review of antimicrobial peptides and their therapeutic potential as anti-infective drugs. Curr Eye Res 30:505–515 Goverman JM (2011) Immune tolerance in multiple sclerosis. Immunol Rev 241:228–240 Goyal D, Ali SA, Singh RK (2020) Emerging role of gut microbiota in modulation of neuroinflammation and neurodegeneration with emphasis on Alzheimer's disease. Prog Neuro-Psychopharmacol Biol Psychiatry 106:110112 Grimshaw KE, Maskell J, Oliver EM, Morris RC, Foote KD, Mills EC, Roberts G, Margetts BM (2013) Introduction of complementary foods and the relationship to food allergy. Pediatrics 132: e1529–e1538 Guo M, Wang H, Xu S, Zhuang Y, An J, Su C, Xia Y, Chen J, Xu ZZ, Liu Q (2020) Alteration in gut microbiota is associated with dysregulation of cytokines and glucocorticoid therapy in systemic lupus erythematosus. Gut Microbes 11:1758–1773 Halverson R, Torres RM, Pelanda R (2004) Receptor editing is the main mechanism of B cell tolerance toward membrane antigens. Nat Immunol 5:645–650 Han D, Walsh MC, Cejas PJ, Dang NN, Kim YF, Kim J, Charrier-Hisamuddin L, Chau L, Zhang Q, Bittinger K (2013) Dendritic cell expression of the signaling molecule TRAF6 is critical for gut microbiota-dependent immune tolerance. Immunity 38:1211–1222 Han D, Walsh MC, Kim KS, Hong S-W, Lee J, Yi J, Rivas G, Choi Y, Surh CD (2017) Dendritic cell expression of the signaling molecule TRAF6 is required for immune tolerance in the lung. Int Immunol 29:71–78 Harbison JE, Roth-Schulze AJ, Giles LC, Tran CD, Ngui KM, Penno MA, Thomson RL, Wentworth JM, Colman PG, Craig ME (2019) Gut microbiome dysbiosis and increased intestinal permeability in children with islet autoimmunity and type 1 diabetes: a prospective cohort study. Pediatr Diabetes 20:574–583 Harbo HF, Gold R, Tintoré M (2013) Sex and gender issues in multiple sclerosis. Ther Adv Neurol Disord 6:237–248

3

The Link Between Gut Microbiota and Autoimmune Diseases

61

Hasan N, Yang H (2019) Factors affecting the composition of the gut microbiota, and its modulation. PeerJ 7:e7502 Hasan AU, Rahman A, Kobori H (2019) Interactions between host PPARs and gut microbiota in health and disease. Int J Mol Sci 20:387 Hatayama H, Iwashita J, Kuwajima A, Abe T (2007) The short chain fatty acid, butyrate, stimulates MUC2 mucin production in the human colon cancer cell line, LS174T. Biochem Biophys Res Commun 356:599–603 He Z, Shao T, Li H, Xie Z, Wen C (2016) Alterations of the gut microbiome in Chinese patients with systemic lupus erythematosus. Gut pathogens 8:1–7 Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17: 629–638 Hendler A, Mulli T, Hughes F, Perrett D, Bombardieri M, Houri-Haddad Y, Weiss E, Nissim A (2010) Involvement of autoimmunity in the pathogenesis of aggressive periodontitis. J Dent Res 89:1389–1394 Hevia A, Milani C, López P, Cuervo A, Arboleya S, Duranti S, Turroni F, González S, Suárez A, Gueimonde M (2014) Intestinal dysbiosis associated with systemic lupus erythematosus. MBio 5:e01548–e01614 Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G (2005) Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 11:90–94 Hoffmann AR, Proctor L, Surette M, Suchodolski J (2016) The microbiome: the trillions of microorganisms that maintain health and cause disease in humans and companion animals. Vet Pathol 53:10–21 Hold GL, Mukhopadhya I, Monie TP (2011) Innate immune sensors and gastrointestinal bacterial infections. Clin Dev Immunol 2011:579650. https://doi.org/10.1155/2011/579650 Huang C, Shi G (2019) Smoking and microbiome in oral, airway, gut and some systemic diseases. J Transl Med 17:1–15 Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–498 Jain N, Walker WA (2015) Diet and host–microbial crosstalk in postnatal intestinal immune homeostasis. Nat Rev Gastroenterol Hepatol 12:14 Janeiro MH, Ramírez MJ, Milagro FI, Martínez JA, Solas M (2018) Implication of trimethylamine N-oxide (TMAO) in disease: potential biomarker or new therapeutic target. Nutrients 10:1398 Jiang Z, Jacob JA, Li J, Wu X, Wei G, Vimalanathan A, Mani R, Nainangu P, Rajadurai UM, Chen B (2018) Influence of diet and dietary nanoparticles on gut dysbiosis. Microb Pathog 118:61–65 Kang D-W, Adams JB, Vargason T, Santiago M, Hahn J, Krajmalnik-Brown R (2020) Distinct fecal and plasma metabolites in children with autism spectrum disorders and their modulation after microbiota transfer therapy. Msphere 5(5):e00314–e00320 Kato LM, Kawamoto S, Maruya M, Fagarasan S (2014) The role of the adaptive immune system in regulation of gut microbiota. Immunol Rev 260:67–75 Kespohl M, Vachharajani N, Luu M, Harb H, Pautz S, Wolff S, Sillner N, Walker A, SchmittKopplin P, Boettger T (2017) The microbial metabolite butyrate induces expression of Th1-associated factors in CD4+ T cells. Front Immunol 8:1036 Khalloufi A, Ouarssani A, Er-Rami M, Fellah H, Sebti F, Moudden M (2018) A rare infectious etiology of COPD exacerbation. Rev Mal Respir 35:956–958 Kho ZY, Lal SK (2018) The human gut microbiome—a potential controller of wellness and disease. Front Microbiol 9:1835 Kim YG, Udayanga KG, Totsuka N, Weinberg JB, Núñez G, Shibuya A (2014) Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE2. Cell Host Microbe 15:95–102

62

D. Goyal et al.

Kim TK, Lee J-C, Im S-H, Lee M-S (2020) Amelioration of autoimmune diabetes of NOD mice by immunomodulating probiotics. Front Immunol 11:1832 King CG, Kobayashi T, Cejas PJ, Kim T, Yoon K, Kim GK, Chiffoleau E, Hickman SP, Walsh PT, Turka LA (2006) TRAF6 is a T cell–intrinsic negative regulator required for the maintenance of immune homeostasis. Nat Med 12:1088–1092 Kinnebrew MA, Ubeda C, Zenewicz LA, Smith N, Flavell RA, Pamer EG (2010) Bacterial flagellin stimulates toll-like receptor 5—dependent defense against vancomycin-resistant Enterococcus infection. J Infect Dis 201:534–543 Koeth RA, Levison BS, Culley MK, Buffa JA, Wang Z, Gregory JC, Org E, Wu Y, Li L, Smith JD (2014) γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab 20:799–812 Kong Q, Wang B, Tian P, Li X, Zhao J, Zhang H, Chen W, Wang G (2021) Daily intake of Lactobacillus alleviates autistic-like behaviors by ameliorating the 5-hydroxytryptamine metabolic disorder in VPA-treated rats during weaning and sexual maturation. Food Funct 12:2591– 2604 Kościuczuk EM, Lisowski P, Jarczak J, Strzałkowska N, Jóźwik A, Horbańczuk J, Krzyżewski J, Zwierzchowski L, Bagnicka E (2012) Cathelicidins: family of antimicrobial peptides. A review. Mol Biol Rep 39:10957–10970 Kosiewicz MM, Zirnheld AL, Alard P (2011) Gut microbiota, immunity, and disease: a complex relationship. Front Microbiol 2:180 Kroemer G, Martínez AC (1992) Clonal deletion, anergy and immunosuppressionare connected in series to guarantee self-tolerance. Res Immunol 143:335–340 Lai M-C, Szatmari P (2020) Sex and gender impacts on the behavioural presentation and recognition of autism. Curr Opin Psychiatry 33:117–123 Lai H-C, Lin T-L, Chen T-W, Kuo Y-L, Chang C-J, Wu T-R, Shu C-C, Tsai Y-H, Swift S, Lu C-C (2022) Gut microbiota modulates COPD pathogenesis: role of anti-inflammatory Parabacteroides goldsteinii lipopolysaccharide. Gut 71(2):309–321 Landry RM, An D, Hupp JT, Singh PK, Parsek MR (2006) Mucin–Pseudomonas aeruginosa interactions promote biofilm formation and antibiotic resistance. Mol Microbiol 59:142–151 Lappin DF, Apatzidou D, Quirke AM, Oliver-Bell J, Butcher JP, Kinane DF, Riggio MP, Venables P, McInnes IB, Culshaw S (2013) Influence of periodontal disease, Porphyromonas gingivalis and cigarette smoking on systemic anti-citrullinated peptide antibody titres. J Clin Periodontol 40:907–915 Larmonier CB, Laubitz D, Hill FM, Shehab KW, Lipinski L, Midura-Kiela MT, McFadden R-MT, Ramalingam R, Hassan KA, Golebiewski M (2013) Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice. Am J Physiol-Gastrointest Liver Physiol 305: G667–G677 Lazar V, Ditu L-M, Pircalabioru GG, Gheorghe I, Curutiu C, Holban AM, Picu A, Petcu L, Chifiriuc MC (2018) Aspects of gut microbiota and immune system interactions in infectious diseases, immunopathology, and cancer. Front Immunol 9:1830 Leader G, Tuohy E, Chen JL, Mannion A, Gilroy SP (2020) Feeding problems, gastrointestinal symptoms, challenging behavior and sensory issues in children and adolescents with autism spectrum disorder. J Autism Dev Disord 50(4):1–10 Lee JH, Cheon JH, Kim ES, Chung MJ, Kang W, Kim DH, Ha YJ, Park JJ, Kim TI, Kim WH (2010) The prevalence and clinical significance of perinuclear anti-neutrophil cytoplasmic antibody in Korean patients with ulcerative colitis. Dig Dis Sci 55:1406–1412 Lernmark Å, Larsson HE (2013) Immune therapy in type 1 diabetes mellitus. Nat Rev Endocrinol 9: 92–103 Li Y, Luo Z-Y, Hu Y-Y, Bi Y-W, Yang J-M, Liu M-A, Zou W-J, Li S, Shen T, Li S-J (2019) EphB6 regulates social behavior through gut microbiota-mediated vitamin B6 metabolism and excitation/inhibition balance of medial prefrontal cortex in mice. bioRxiv:787622

3

The Link Between Gut Microbiota and Autoimmune Diseases

63

Li N, Yang Z, Liao B, Pan T, Pu J, Hao B, Fu Z, Cao W, Zhou Y, He F (2020a) Chronic exposure to ambient particulate matter induces gut microbial dysbiosis in a rat COPD model. Respir Res 21: 1–10 Li Y, Luo Z-Y, Hu Y-Y, Bi Y-W, Yang J-M, Zou W-J, Song Y-L, Li S, Shen T, Li S-J (2020b) The gut microbiota regulates autism-like behavior by mediating vitamin B 6 homeostasis in EphB6deficient mice. Microbiome 8:1–23 Liu X-J, Yu R, Zou K-F (2019) Probiotic mixture VSL# 3 alleviates dextran sulfate sodium-induced colitis in mice by downregulating T follicular helper cells. Curr Med Sci 39:371–378 Loreto C, La Rocca G, Anzalone R, Caltabiano R, Vespasiani G, Castorina S, Ralph DJ, Cellek S, Musumeci G, Giunta S (2014) The role of intrinsic pathway in apoptosis activation and progression in Peyronie’s disease. BioMed Res Int 2014:616149 Lu B, Finn O (2008) T-cell death and cancer immune tolerance. Cell Death Differ 15:70–79 Luo XM, Edwards MR, Mu Q, Yu Y, Vieson MD, Reilly CM, Ahmed SA, Bankole AA (2018) Gut microbiota in human systemic lupus erythematosus and a mouse model of lupus. Appl Environ Microbiol 84(4):e02288–e02317 Lurie-Weinberger MN, Gomez-Valero L, Merault N, Glöckner G, Buchrieser C, Gophna U (2010) The origins of eukaryotic-like proteins in Legionella pneumophila. Int J Med Microbiol 300: 470–481 Madra M, Ringel R, Margolis KG (2020) Gastrointestinal issues and autism spectrum disorder. Child Adolesc Psychiatric Clin 29:501–513 Maher SE, O’brien EC, Moore RL, Byrne DF, Geraghty AA, Saldova R, Murphy EF, Van Sinderen D, Cotter PD, McAuliffe FM (2020) The association between the maternal diet and the maternal and infant gut microbiome: a systematic review. Br J Nutr:1–29 Mandal M, Olson DJ, Sharma T, Vadlamudi RK, Kumar R (2001) Butyric acid induces apoptosis by up-regulating Bax expression via stimulation of the c-Jun N-terminal kinase/activation protein-1 pathway in human colon cancer cells. Gastroenterology 120:71–78 Mandl T, Marsal J, Olsson P, Ohlsson B, Andréasson K (2017) Severe intestinal dysbiosis is prevalent in primary Sjögren’s syndrome and is associated with systemic disease activity. Arthritis Res Ther 19:1–7 Matsuyama M, Gomez-Arango L, Fukuma N, Morrison M, Davies P, Hill R (2019) Breastfeeding: a key modulator of gut microbiota characteristics in late infancy. J Dev Orig Health Dis 10:206– 213 Mazmanian SK, Round JL, Kasper DL (2008) A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453:620–625 Meade E, Slattery MA, Garvey M (2020) Bacteriocins, potent antimicrobial peptides and the fight against multi drug resistant species: resistance is futile? Antibiotics 9:32 Meier J, Sturm A (2011) Current treatment of ulcerative colitis. World J Gastroenterol 17:3204 Mellanby RJ, Thomas DC, Lamb J (2009) Role of regulatory T-cells in autoimmunity. Clin Sci 116: 639–649 Mendez R, Banerjee S, Bhattacharya SK, Banerjee S (2019) Lung inflammation and disease: a perspective on microbial homeostasis and metabolism. IUBMB Life 71:152–165 Miller PL, Carson TL (2020) Mechanisms and microbial influences on CTLA-4 and PD-1-based immunotherapy in the treatment of cancer: a narrative review. Gut Pathogens 12:1–10 Mirza A, Mao-Draayer Y (2017) The gut microbiome and microbial translocation in multiple sclerosis. Clin Immunol 183:213–224 Miyake S, Yamamura T (2019) Gut environmental factors and multiple sclerosis. J Neuroimmunol 329:20–23 Mohanta L, Das BC, Patri M (2020) Microbial communities modulating brain functioning and behaviors in zebrafish: a mechanistic approach. Microb Pathog 145:104251 Mok C, Lau C (2003) Pathogenesis of systemic lupus erythematosus. J Clin Pathol 56:481–490 Mondino S, Schmidt S, Buchrieser C (2020) Molecular mimicry: a paradigm of host-microbe coevolution illustrated by Legionella. mBio 11(5):e01201–e01220

64

D. Goyal et al.

Moon J, Choi SH, Yoon CH, Kim MK (2020) Gut dysbiosis is prevailing in Sjögren’s syndrome and is related to dry eye severity. PLoS One 15:e0229029 Morais LH, Schreiber HL, Mazmanian SK (2020) The gut microbiota–brain axis in behaviour and brain disorders. Nat Rev Microbiol:1–15 Morris G, Berk M, Carvalho A, Caso JR, Sanz Y, Walder K, Maes M (2017) The role of the microbial metabolites including tryptophan catabolites and short chain fatty acids in the pathophysiology of immune-inflammatory and neuroimmune disease. Mol Neurobiol 54: 4432–4451 Mortaz E, Adcock IM, Ricciardolo FL, Varahram M, Jamaati H, Velayati AA, Folkerts G, Garssen J (2015) Anti-inflammatory effects of lactobacillus rahmnosus and bifidobacterium breve on cigarette smoke activated human macrophages. PLoS One 10:e0136455 Nair P, Lu M, Petersen S, Ashkenazi A (2014) Apoptosis initiation through the cell-extrinsic pathway. Methods Enzymol 544:99–128 Nicastro L, Tükel Ç (2019) Bacterial amyloids: the link between bacterial infections and autoimmunity. Trends Microbiol 27:954–963 Nielen MM, Van Schaardenburg D, Reesink HW, Van De Stadt RJ, Van Der Horst-Bruinsma IE, De Koning MH, Habibuw MR, Vandenbroucke JP, Dijkmans BA (2004) Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 50:380–386 Nishida A, Inoue R, Inatomi O, Bamba S, Naito Y, Andoh A (2018) Gut microbiota in the pathogenesis of inflammatory bowel disease. Clin J Gastroenterol 11:1–10 Ohashi PS, Defranco AL (2002) Making and breaking tolerance. Curr Opin Immunol 14:744–759 Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Yoshida S (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506: 376–381 Oksenberg JR (2013) Decoding multiple sclerosis: an update on genomics and future directions. Expert Rev Neurother 13:11–19 Oldenburg KS, O'shea TM, Fry RC (2020) Genetic and epigenetic factors and early life inflammation as predictors of neurodevelopmental outcomes. In: Seminars in fetal and neonatal medicine. Elsevier, p 101115 Pagliari D, Piccirillo CA, Larbi A, Cianci R (2015) The interactions between innate immunity and microbiota in gastrointestinal diseases. J Immunol Res. Hindawi Palomares O, Martin-Fontecha M, Lauener R, Traidl-Hoffmann C, Cavkaytar O, Akdis M, Akdis C (2014) Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-β. Genes Immunity 15:511–520 Paluch C, Santos AM, Anzilotti C, Cornall RJ, Davis SJ (2018) Immune checkpoints as therapeutic targets in autoimmunity. Front Immunol 9:2306 Pan P-Y, Ozao J, Zhou Z, Chen S-H (2008) Advancements in immune tolerance. Adv Drug Deliv Rev 60:91–105 Paone P, Cani PD (2020) Mucus barrier, mucins and gut microbiota: the expected slimy partners? Gut 69:2232–2243 Papoutsopoulou S, Satsangi J, Campbell BJ, Probert CS (2020) impact of cigarette smoking on intestinal inflammation—direct and indirect mechanisms. Aliment Pharmacol Ther 51:1268– 1285 Park Y, Lee SW, Sung YC (2002) Cutting edge: CpG DNA inhibits dendritic cell apoptosis by up-regulating cellular inhibitor of apoptosis proteins through the phosphatidylinositide-30 -OH kinase pathway. J Immunol 168:5–8 Parker A, Lawson MA, Vaux L, Pin C (2018) Host-microbe interaction in the gastrointestinal tract. Environ Microbiol 20:2337–2353 Pascucci T, Colamartino M, Fiori E, Sacco R, Coviello A, Ventura R, Puglisi-Allegra S, Turriziani L, Persico AM (2020) P-cresol alters brain dopamine metabolism and exacerbates autism-like behaviors in the BTBR mouse. Brain Sci 10:233

3

The Link Between Gut Microbiota and Autoimmune Diseases

65

Paun A, Danska JS (2016) Modulation of type 1 and type 2 diabetes risk by the intestinal microbiome. Pediatr Diabetes 17:469–477 Pelanda R, Piccirillo CA (2008) Tolerance, immune regulation, and autoimmunity: cells and cytokines that make a difference. Curr Opin Immunol 20:629 Pelanda R, Torres RM (2012) Central B-cell tolerance: where selection begins. Cold Spring Harb Perspect Biol 4:a007146 Peterson DA, McNulty NP, Guruge JL, Gordon JI (2007) IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2:328–339 Pieterse E, Van Der Vlag J (2014) Breaking immunological tolerance in systemic lupus erythematosus. Front Immunol 5:164 Porter RJ, Kalla R, Ho G-T (2020) Ulcerative colitis: recent advances in the understanding of disease pathogenesis. F1000Res 9. https://doi.org/10.12688/f1000research.20805.1 Power ML, Schulkin J (2013) Maternal regulation of offspring development in mammals is an ancient adaptation tied to lactation. Appl Transl Genomics 2:55–63 Psichas A, Sleeth M, Murphy K, Brooks L, Bewick G, Hanyaloglu A, Ghatei M, Bloom S, Frost G (2015) The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int J Obes 39:424–429 Quaderi S, Hurst J (2018) The unmet global burden of COPD. Global Health Epidemiol Genom 3: e4. https://doi.org/10.1017/gheg.2018.1 Ramsdell F, Fowlkes B (1990) Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance. Science 248:1342–1348 Rantapää-Dahlqvist S, De Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, Sundin U, Van Venrooij WJ (2003) Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 48:2741–2749 Retter MW, Nemazee D (1998) Receptor editing occurs frequently during normal B cell development. J Exp Med 188:1231–1238 Ricci MS, El-Deiry WS (2007) The extrinsic pathway of apoptosis. Apoptosis, senescence and cancer. Springer Rolando M, Escoll P, Nora T, Botti J, Boitez V, Bedia C, Daniels C, Abraham G, Stogios PJ, Skarina T (2016) Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy. Proc Natl Acad Sci 113:1901–1906 Rutayisire E, Huang K, Liu Y, Tao F (2016) The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants' life: a systematic review. BMC Gastroenterol 16:1–12 Sabit H, Tombuloglu H, Rehman S, Almandil NB, Cevik E, Abdel-Ghany S, Rashwan S, Abasiyanik MF, Waye MMY (2021) Gut microbiota metabolites in autistic children: an epigenetic perspective. Heliyon 7:e06105 Saboo B, Singh R, Hasnani D, Maheshwari A, Verma N, Rahelić D (2016) Environmental modulators of type 1 diabetes mellitus. Endocrine Oncol Metab 2:122–137 Salehipour Z, Haghmorad D, Sankian M, Rastin M, Nosratabadi R, Dallal MMS, Tabasi N, Khazaee M, Nasiraii LR, Mahmoudi M (2017) Bifidobacterium animalis in combination with human origin of Lactobacillus plantarum ameliorate neuroinflammation in experimental model of multiple sclerosis by altering CD4+ T cell subset balance. Biomed Pharmacother 95:1535– 1548 Santaolalla R, Abreu MT (2012) Innate immunity in the small intestine. Curr Opin Gastroenterol 28:124 Santocchi E, Guiducci L, Prosperi M, Calderoni S, Gaggini M, Apicella F, Tancredi R, Billeci L, Mastromarino P, Grossi E (2020) Effects of probiotic supplementation on gastrointestinal, sensory and core symptoms in autism spectrum disorders: a randomized controlled trial. Front Psychiatry 11:944 Saurman V, Margolis KG, Luna RA (2020) Autism spectrum disorder as a brain-gut-microbiome axis disorder. Dig Dis Sci 65:818–828

66

D. Goyal et al.

Schepici G, Silvestro S, Bramanti P, Mazzon E (2019) The gut microbiota in multiple sclerosis: an overview of clinical trials. Cell Transplant 28:1507–1527 Schütte A, Ermund A, Becker-Pauly C, Johansson ME, Rodriguez-Pineiro AM, Bäckhed F, Müller S, Lottaz D, Bond JS, Hansson GC (2014) Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus. Proc Natl Acad Sci 111:12396–12401 Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ (1999) Peptidoglycan-and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem 274: 17406–17409 Schwiertz A, Taras D, Schäfer K, Beijer S, Bos NA, Donus C, Hardt PD (2010) Microbiota and SCFA in lean and overweight healthy subjects. Obesity 18:190–195 Seo M-D, Won H-S, Kim J-H, Mishig-Ochir T, Lee B-J (2012) Antimicrobial peptides for therapeutic applications: a review. Molecules 17:12276–12286 Serra D, Almeida LM, Dinis TC (2020) Polyphenols in the management of brain disorders: modulation of the microbiota-gut-brain axis, Advances in food and nutrition research. Elsevier Sharon G, Cruz NJ, Kang D-W, Gandal MJ, Wang B, Kim Y-M, Zink EM, Casey CP, Taylor BC, Lane CJ (2019) Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell 177(6):1600–1618 Shen Z-H, Zhu C-X, Quan Y-S, Yang Z-Y, Wu S, Luo W-W, Tan B, Wang X-Y (2018) Relationship between intestinal microbiota and ulcerative colitis: mechanisms and clinical application of probiotics and fecal microbiota transplantation. World J Gastroenterol 24:5 Shukla SD, Budden KF, Neal R, Hansbro PM (2017) Microbiome effects on immunity, health and disease in the lung. Clin Transl Immunol 6:e133 Silva YP, Bernardi A, Frozza RL (2020) The role of short-chain fatty acids from gut microbiota in gut-brain communication. Front Endocrinol 11:25 Simons A, Alhanout K, Duval RE (2020) Bacteriocins, antimicrobial peptides from bacterial origin: overview of their biology and their impact against multidrug-resistant bacteria. Microorganisms 8:639 Smith P, Garrett W (2011) The gut microbiota and mucosal T cells. Front Microbiol 2:111 Snethlage CMF, Nieuwdorp M, Van Raalte DH, Rampanelli E, Verchere BC, Hanssen NM (2021) Auto-immunity and the gut microbiome in type 1 diabetes: lessons from rodent and human studies. Best Pract Res Clin Endocrinol Metab 35(3):101544 Song Q, Chen P, Liu X-M (2021) The role of cigarette smoke-induced pulmonary vascular endothelial cell apoptosis in COPD. Respir Res 22:1–15 Soyer O, Akdis M, Ring J, Behrendt H, Crameri R, Lauener R, Akdis C (2013) Mechanisms of peripheral tolerance to allergens. Allergy 68:161–170 Sprouse ML, Bates NA, Felix KM, Wu HJJ (2019) Impact of gut microbiota on gut-distal autoimmunity: a focus on T cells. Immunology 156:305–318 Stewart L, Dm Edgar J, Blakely G, Patrick S (2018) Antigenic mimicry of ubiquitin by the gut bacterium Bacteroides fragilis: a potential link with autoimmune disease. Clin Exp Immunol 194:153–165 Strang JF, Van Der Miesen AI, Caplan R, Hughes C, Davanport S, Lai M-C (2020) Both sex-and gender-related factors should be considered in autism research and clinical practice. SAGE Publications, London, England Suárez LJ, Garzón H, Arboleda S, Rodríguez A (2020) Oral dysbiosis and autoimmunity: from local periodontal responses to an imbalanced systemic immunity. A review. Front Immunol 11: 591255 Sublette MG, Cross T-WL, Korcarz CE, Hansen KM, Murga-Garrido SM, Hazen SL, Wang Z, Oguss MK, Rey FE, Stein JH (2020) Effects of smoking and smoking cessation on the intestinal microbiota. J Clin Med 9:2963 Sugi Y, Takahashi K, Kurihara K, Nakano K, Kobayakawa T, Nakata K, Tsuda M, Hanazawa S, Hosono A, Kaminogawa S (2017) α-Defensin 5 gene expression is regulated by gut microbial metabolites. Biosci Biotechnol Biochem 81:242–248

3

The Link Between Gut Microbiota and Autoimmune Diseases

67

Sun M, Wu W, Chen L, Yang W, Huang X, Ma C, Chen F, Xiao Y, Zhao Y, Ma C (2018) Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis. Nat Commun 9:1–15 Tanaka S, Nemoto Y, Takei Y, Morikawa R, Oshima S, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Stutte S (2020) High-fat diet-derived free fatty acids impair the intestinal immune system and increase sensitivity to intestinal epithelial damage. Biochem Biophys Res Commun 522:971–977 Tang F-I, Wei I-L (2004) Vitamin B-6 deficiency prolongs the time course of evoked dopamine release from rat striatum. J Nutr 134:3350–3354 Taniguchi M, Geng X, Glazier KD, Dasgupta A, Lin JJ, Das KM (2001) Cellular immune response against tropomyosin isoform 5 in ulcerative colitis. Clin Immunol 101:289–295 Valladares R, Sankar D, Li N, Williams E, Lai K-K, Abdelgeliel AS, Gonzalez CF, Wasserfall CH, Larkin Iii J, Schatz D (2010) Lactobacillus johnsonii N6. 2 mitigates the development of type 1 diabetes in BB-DP rats. PLoS One 5:e10507 Vaughan A, Frazer ZA, Hansbro PM, Yang IA (2019) COPD and the gut-lung axis: the therapeutic potential of fibre. J Thorac Dis 11:S2173 Vejdani R, Bahari A, Zadeh AM, Azmi M, Ebrahimi-Daryani N, Hashtroudi AA, Mehr AJ, Abdollahi M, Sayyah A, Zali MR (2017) Effects of lactobacillus casei probiotic on mild to moderate ulcerative colitis: a placebo controlled study. Indian J Med Sci 69:24–28 Vinolo MA, Rodrigues HG, Nachbar RT, Curi R (2011) Regulation of inflammation by short chain fatty acids. Nutrients 3:858–876 Virtanen SM, Kenward MG, Erkkola M, Kautiainen S, Kronberg-Kippilä C, Hakulinen T, Ahonen S, Uusitalo L, Niinistö S, Veijola R (2006) Age at introduction of new foods and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes. Diabetologia 49:1512–1521 Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA (2012) Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig Dis Sci 57:2096–2102 Wang L, Hao K, Yang T, Wang C (2017) Role of the lung microbiome in the pathogenesis of chronic obstructive pulmonary disease. Chin Med J 130:2107 Wang C, Li W, Wang H, Ma Y, Zhao X, Zhang X, Yang H, Qian J, Li J (2019a) Saccharomyces boulardii alleviates ulcerative colitis carcinogenesis in mice by reducing TNF-α and IL-6 levels and functions and by rebalancing intestinal microbiota. BMC Microbiol 19:1–12 Wang L, Zhu L, Qin S (2019b) Gut microbiota modulation on intestinal mucosal adaptive immunity. J Immunol Res 2019:735040 Wang Y, Yin Y, Chen X, Zhao Y, Wu Y, Li Y, Wang X, Chen H, Xiang C (2019c) Induction of intestinal Th17 cells by Flagellins from segmented filamentous bacteria. Front Immunol 10: 2750 Wang Y, Li N, Yang J-J, Zhao D-M, Chen B, Zhang G-Q, Chen S, Cao R-F, Yu H, Zhao C-Y (2020) Probiotics and fructo-oligosaccharide intervention modulate the microbiota-gut brain axis to improve autism spectrum reducing also the hyper-serotonergic state and the dopamine metabolism disorder. Pharmacol Res 157:104784 Wehkamp J, Harder J, Weichenthal M, Schwab M, Schäffeler E, Schlee M, Herrlinger K, Stallmach A, Noack F, Fritz P (2004) NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal α-defensin expression. Gut 53:1658–1664 Wei S-H, Chen Y-P, Chen M-J (2015) Selecting probiotics with the abilities of enhancing GLP-1 to mitigate the progression of type 1 diabetes in vitro and in vivo. J Funct Foods 18:473–486 Wei F, Xu H, Yan C, Rong C, Liu B, Zhou H (2019) Changes of intestinal flora in patients with systemic lupus erythematosus in northeast China. PLoS One 14:e0213063 Weiner HL (1997) Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today 18:335–343 Wu H-J, Wu E (2012) The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 3:4–14

68

D. Goyal et al.

Wu H-J, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, Benoist C, Mathis D (2010) Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32:815–827 Xu H, Zhao H, Fan D, Liu M, Cao J, Xia Y, Ju D, Xiao C, Guan Q (2020a) Interactions between gut microbiota and immunomodulatory cells in rheumatoid arthritis. Mediat Inflamm 2020:1430605 Xu N, Wang L, Li C, Ding C, Li C, Fan W, Cheng C, Gu B (2020b) Microbiota dysbiosis in lung cancer: evidence of association and potential mechanisms. Transl Lung Cancer Res 9:1554 Yanagibashi T, Hosono A, Oyama A, Tsuda M, Hachimura S, Takahashi Y, Itoh K, Hirayama K, Takahashi K, Kaminogawa S (2009) Bacteroides induce higher IgA production than Lactobacillus by increasing activation-induced cytidine deaminase expression in B cells in murine Peyer’s patches. Biosci Biotechnol Biochem 73:372–377 Yang S-R, Chida AS, Bauter MR, Shafiq N, Seweryniak K, Maggirwar SB, Kilty I, Rahman I (2006) Cigarette smoke induces proinflammatory cytokine release by activation of NF-κB and posttranslational modifications of histone deacetylase in macrophages. Am J Phys Lung Cell Mol Phys 291:L46–L57 Yi R, Tan F, Suo H, Li W, Zhou X, Mu J, Xie P, Zhao X (2020) Prophylactic effect of Lactobacillus plantarum YS4 on oxazolone-induced colitis in BALB/c mice. Evid-Based Complem Altern Med 2020:9048971 Yoon SH, Choi J, Lee WJ, Do JT (2020) Genetic and epigenetic etiology underlying autism spectrum disorder. J Clin Med 9:966 Zen Y, Harada K, Sasaki M, Tsuneyama K, Katayanagi K, Yamamoto Y, Nakanuma Y (2002) Lipopolysaccharide induces overexpression of MUC2 and MUC5AC in cultured biliary epithelial cells: possible key phenomenon of hepatolithiasis. Am J Pathol 161:1475–1484 Zhang H, Sparks JB, Karyala SV, Settlage R, Luo XM (2015) Host adaptive immunity alters gut microbiota. ISME J 9:770–781 Zhao Q, Elson CO (2018) Adaptive immune education by gut microbiota antigens. Immunology 154:28–37 Zheng D, Liwinski T, Elinav E (2020) Interaction between microbiota and immunity in health and disease. Cell Res 30:492–506 Zong X, Fu J, Xu B, Wang Y, Jin M (2020) Interplay between gut microbiota and antimicrobial peptides. Anim Nutr 6(4):389–396

4

The Factors Influencing Gut Microbiota in Autoimmune Diseases Syed Afroz Ali, Samir Ranjan Panda, Mangaldeep Dey, Ashok Kumar Datusalia, V. G. M. Naidu, and Rakesh Kumar Singh

Abstract

Recent advances in the field of omics have largely improved the understanding about the dynamic interplay between the gut microbiota and host immune cells. Such interactions are critical and are bound to cover an important aspect of biological homeostasis regulating immune functions. However, immunological stimulations are essential to fight against infectious agents. The intestinal mucosal surfaces are the major site of communications between the symbiotic and diseasecausing agents. Research on animal models has demonstrated that any abnormalities in the composition of gut microflora exacerbate the dysregulated immune homeostasis and inflammation-mediated autoimmune diseases. Several factors have been studied supporting that the dialogue altered microbiota and disease state. In particular, diet, feeding habits, antibiotic usage, and mode of delivery have been reported to structure and modulate the composition of the gut

These authors have contributed equally in the preparation of this manuscript. S. A. Ali · M. Dey · R. K. Singh (*) Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow, Uttar Pradesh, India e-mail: [email protected] S. R. Panda · V. G. M. Naidu Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam, India A. K. Datusalia Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow, Uttar Pradesh, India Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow, Uttar Pradesh, India # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_4

69

70

S. A. Ali et al.

microbiota under circumstances. This chapter also highlights the recent evidences to support that how microbiota and immunological consequences perturbate autoimmune diseases. Promoting the likelihood of host immune cells that structure the immunity to fight against pathogens seems to be governed by gut microbiota. Keywords

Gut microbiota · Immunity · Autoimmune diseases · Inflammation · Inflammatory bowel diseases · Host · microbiota interactions

4.1

Introduction

Unicellular organisms play a significant role in the evolution and commensalism of biological ecosystems. The coevolution of bacteria including several other organisms existed from a trillion years ago, with an estimated population of >100 trillion concentrated distinctly in the distal ileum and colon (Maynard et al. 2012; Schopf and Packer 1987). In particular, every individual by birth is exposed to diverse microbial population from the mother microbiota, which in response builds the microenvironment of the body ecosystem, i.e., mucosal, respiratory, urogenital, and skin with distinct microflora that share mutual benefits throughout the life (Maynard et al. 2012). Recent scientific contributions have led to the characterization of specific reciprocal microbes populated in the gut (Ferreira et al. 2018). This genomic analysis demonstrated the complex interactions between the microbes, host, and inter-individual variability. However, the interdependency of host and microbes is decisive in normal human physiology and pathological distinctions (Blaser and Falkow 2009). Hippocrates, a great ancient Greek physician cautioned that ‘everything starts in the gut’. Interestingly, in the present era of advancement, all the scientific communities started acknowledging his sayings after 2 millenniums. Recently, the concept of gut microbiota has garnered foremost attention as research has opened the doors to the next challenges by uncovering the conceptual understanding on the crucial importance of microbial populations is just ahead of digestion, supplying nutrients, mobilizing intoxicated products, providing a shield against unscrupulous pathogens and structuring the intestinal consortia. In addition, healthy gut microbes have been found to play an indefinite role in the development and regulation of immune responses through the complex dynamic interactions (Round and Mazmanian 2009). Classically, human microbiota harbours almost >ten-fold enhanced genes, which potentially encode immune responses via the production of antigens that exceed the self and pathogen-derived antigens. Thus, such interactions are central in the conservation of biological homeostasis.

4

The Factors Influencing Gut Microbiota in Autoimmune Diseases

71

Host immunity is another important aspect, responsible for identifying and tackling the internal and external stimuli during health and disease. The concept of immunomodulation by microbiota is emerging and several successful stories have been reported (Fung et al. 2017). Additionally, synergistic microbes during the process of evolution and colonization are reported to avert the inflammatory ailments. However, the normal bacterial population elicits inflammatory responses under circumstances. And the potential to modulate both pro- and anti-inflammatory mediators reflect the importance of healthy microbiota and its association with the regulation of immune responses and colonic epithelial barriers. Similarly, changes in the diversity of the microbial population due to diet, antibiotic usage or even due to any foreign substance compromises the ability of the gut to restrict it from invading the host organs inducing pathological abnormalities. The compromised frameworks subsequently favour the extension of potentially infectious constituents. The alterations in the composition of the gut (referred to as ‘dysbiosis’) damage normal defences that usually restrict the intestinal inflammation, which in turn facilitates the perturbations of immune-related diseases including ulcerative colitis, neurodegenerative diseases, rheumatoid arthritis (RA), obesity, and several other metabolic disorders (Opazo et al. 2018). Substantially, studies on germ-free (GF) mice further illustrated the importance of microbiota in the induction and maturation of immune functions which sequentially lacks the developed gut-associated lymphoid tissue (Round and Mazmanian 2009). The potential understanding on the basic consequential events associated with the diseases remains elusive. However, it is still thoughtful in determining the factors mediating the diverse pathologies regardless of their basis. Herein, we highlight the improvement in our understandings of the dynamic interactions that have been evolved over the time between host–gut microbiota axis and immune system, and the collapses that result in the progression of autoimmune diseases.

4.2

Microbiota and Immunity

The emergence of omics tools (metabolomics, proteomics, and metagenomics) and next-generation sequencing (phylogenetic analysis) have enabled the researchers to understand the composition, cellular and molecular communications between host microbiota and immunity. The omics approaches have also contributed to evaluate the potential biomarkers intricated in the progression of disease for better diagnosis and treatment (Franzosa et al. 2014; Langille et al. 2013). The intestinal mucosal site in the human body faces ample challenges from external agents; thus, warrants a need for an effective and efficient barrier to eliminate the harmful substances from the body. Such protections are relied upon the gut-associated lymphoid tissue (GALT), entailing most active immunological cells like intestinal intraepithelial lymphocytes (IELs), Peyer’s patch lymphocytes (PPLs), and mesenteric lymph nodes (MLNs). Apart from this, microflora-induced IgA antibodies eliminate toxins by binding on the intestinal surfaces (Macpherson and Uhr 2004). Numerous intestinal disorders accompanying the gut axis are a result of altered protein/

72

S. A. Ali et al.

metabolite synthesis. Recent research insights on the role of microbiota in shaping the immunological perspectives have transformed our limited understanding that how genes, ecological factors, and microbiota network shape autoimmunity (Sommer and Bäckhed 2013; Brestoff and Artis 2013). Maintenance of a healthy gut is essential for proper immune surveillance and any abnormalities in this process lead to disease state. The complex immune system (innate/adaptive) is endowed with the ability to acclimate and retort diverse challenges. When functioning optimally, the immune cells and gut connect both the arms of immune surveillance in a dialogue that regulate and fire the responses against the microbial pathogens. Undoubtedly, several approaches have been made to understand the immune sensing by the host microbes. Remarkably, research conducted on GF-mice and specific pathogen-free mice nurtured in the hygienic settings revealed the importance of gut microorganisms (Bacteroides, Firmicutes, etc.) in the induction, maturation and maintenance of proper immune signalling networks (Molloy et al. 2012). In addition, bacterial metabolic end products like short-chain fatty acids (SCFAs) such as, acetic acid, butyric acid and propionic acid have been shown to modulate the immune functions. SCFAs are abundantly produced by undigested complex carbohydrates (20–140 mM concentration), varying largely on the gut composition, metabolic fate and the fibre content in the diet. SCFA serves as an excellent source of energy for both microbes and intestinal epithelial cells (IECs) regulating physiological functions including immune cell differentiation and inflammatory process. The challenging role of SCFAs and its implication in the physiology and immunological responses on the host is the topic of current research. For instance, studies identified SCFAs as histone deacetylases inhibitors and the ligands for G-protein coupled receptors (GPCRs) (Rooks and Garrett 2016; Cummings et al. 1987; Augeron and Laboisse 1984). Thus, the above mentioned findings supports the notion that gut microbiota modulate immune functions and can be epigenetic modulator of host physiology. Evidences suggested that SCFAs promote the IECs to secrete mucin enhancing the mucosal immunity. Several other studies have shown the inhibitory effects of SCFAs on the macrophages, dendritic cells (DCs) modulating nuclear factor-(NF)-κB signalling and pro-inflammatory cytokines (Rooks and Garrett 2016). Another study demonstrated that SCFAs activate inflammasome complex and interleukin-(IL)-18 production by interacting with G-protein coupled receptor-(GPR)-43 and GPR109A on IECs (Elinav et al. 2011). Altogether, these evidences suggested that SCFAs play a prominent role in the regulation of local and systemic immune responses. Besides these, few other metabolites have been studied to bind with aryl hydrocarbon receptors (AHRs) expressed by immune and epithelial cells. Apart from breaking down the xenobiotics, they have also emerged as the modulators of mucosal immunity (Rooks and Garrett 2016). IECs express a multitude of receptors for the recognition of foreign substances such as, pattern recognition receptors (PPRs) that arbitrate the communications between the innate immune cells and holobionts. The characteristic immune responses (innate) get initiated early after the exposure of an unknown substance. Typically, antigen presenting cells (APCs) target infectious cells while preserving

4

The Factors Influencing Gut Microbiota in Autoimmune Diseases

73

the integrity of host microbial immunity. APCs like DCs from PPLs stimulate the production of IL-10 and differentiation of T-helper (Th) cells relatively higher than that of observed in the spleen (Iwasaki and Kelsall 1999). A recent finding showed the recognition of peptidoglycan by the nucleotide oligomerization domain-1 (NOD-1) in the microbiota, reduces bone marrow neutrophils. Similarly, natural killer (NK) cells from innate immune lymphoid cells and its subsets ILC1–3 stimulate the production of IFN-γ and antimicrobial peptides like cathelicins, granulysins, and chemokines. These peptides are critical in the regulation of immunity and any imbalances in the former cells might progress to exacerbate several inflammatory regulated autoimmune diseases (Ostaff et al. 2013). Microbes are certainly linked with the production of TNF-α and IL-1β the perilous inflammatory mediators (Webb et al. 2016; Clemente et al. 2012). The second line of defence (adaptive) gets activated based on the ability of the antigens to evade the first line defence (innate). The T and B cells are identified as the major contributors of adaptive immune responses. Unlike the normal microbiota, animals harbour smaller Peyer’s patches and downregulated IgA secretory, T-helper, and regulatory T cells (Tregs) in the intestinal lumen. These evidences further strengthened the importance of microbiota in the maturation and differentiation of T-cell responses and a small change in the microenvironment may lead to dysregulate the physiology of immune signalling networks (Webb et al. 2016). The Polysaccharide A (PSA) from Bacteroides fragilis was found to kindle the generation of FOXP3+ Treg cells via Toll-like receptor-(TLR)-2 stimulation (Round et al. 2011). Convincingly, polyamines have also been shown to centre the host mucosal and systemic adaptive immune responses. For instance, polyamine rich breast milk supplemented to pups confirmed the enhanced development of CD8+ T cells from intraepithelial cells, CD4+ T cells from lamina propria and B cells in the spleen (Perez-Cano et al. 2010). However, the precise mechanism by which the gut microbes mediate the immune responses remains unknown. But still, GF-mice lacking typical microbiota showed reduced levels of Th17 and Treg immune cells (Atarashi et al. 2011; Ivanov et al. 2009). Evidence from a growing number of studies suggests the imbalance of Treg/Th17 in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). A study conducted in C57BL/6 mice showed that depletion in Treg cells caused aggravation of delayed-type hypersensitivity arthritis which could be attenuated by IL-17 monoclonal antibody, a pro-inflammatory cytokine produced by Th17 that participates in autoimmunity (Atkinson et al. 2016; Qu et al. 2013). Another study showed a reduction in the severity of arthritis and Th17 cell number primarily in the intestinal lamina propria in K/BxN arthritis mouse models under GF conditions (Wu et al. 2010). Studies confirm gut dysbiosis may contribute to the initiation of autoimmune diseases via Th17 cells and increased cytokine levels. Similarly, studies indicate the regulation of autoimmune diseases by the gut microbiota through follicular helper T (Tfh) cells (Block et al. 2016). Inline T-cell subtypes, such as Th1, protect against intracellular microbial attacks and, Th2, attack the parasitic bacteria. The imbalanced Th1/Th2 cytokines is linked with the intestinal and systemic autoimmune diseases

74

S. A. Ali et al.

(Wu and Wu 2012). Collectively, the given evidences highlight the imperative role of microbiota and immunity.

4.3

Interaction Between Host Microbiota and Immune System During Autoimmune Diseases

The intricate symbiotic relationship linking the host–microbiome in the human gut has evolved from the beginning of life. The commensal microbiota in particular functions to control metabolism, structural integrity, development, and proper functioning of the host immune system (Zheng et al. 2020). Dynamic interactions between the microbiota and the innate and adaptive immune system play a crucial role in maintaining and nurturing intestinal homeostasis and attenuating inflammation. In contrast, the continuous supply of food and the local environment promote microbiome growth (Belkaid and Hand 2014). Gut microbiota controls various host functions like maintaining the integrity of the gut mucosal barrier, drug metabolism, nutrient metabolism, immunomodulation, and protecting multiple invading pathogens (Thursby and Juge 2017). While the defence mechanism of the gut produces a mucosal barrier that segregates the microbiota from the host’s immune cells, resulting in reduced intestinal permeability. Several studies have found significant correlations between the impaired interaction of the gut microbiome with the mucosal immune system initiating an increased abundance of the gram-negative pathogenic bacteria and its close associations with the disruption of the epithelial barrier, metabolic changes, and increased susceptibility to pathogenic infections (Shi et al. 2017). A dysbiotic state of the gut microbiome can lead to oxidative stress, inflammation and dysregulation of the immune responses (Kho and Lal 2018). A dysbiosis in the state of the microbial community substantially affects both local and systemic cells of the immune system generating a feedback loop where the host microbiota and the immune cells cross regulate each other. Thus, the signalling cascades and inflammatory mechanisms involved in the immune activation can cause epigenetic remodelling, along with an altered gene expression profile (Levy et al. 2017). One of the widely studied interfaces for the host–microbiome interactions is the intestinal mucosa, with a remarkable capacity to establish immune homeostasis across a constantly changing microbial flora environment. During a healthy state in the host’s immune system, the mucosal surface controls both innate and adaptive immune responses.

4.3.1

Crosstalk Between Innate Immune System and Microbiota

The microbiome influences the innate immune system of the host via its metabolites and the microbial cell components (Thaiss et al. 2016). While a dysbiotic state in the microbiome flora can cause alterations in the microbial community and its metabolite production that can lead to a change in the activation state of the host innate

4

The Factors Influencing Gut Microbiota in Autoimmune Diseases

75

immune system (Belkaid and Hand 2014). A research study identified that the increasing cases of autoimmune diseases in the Western countries are caused by early-life microbial changes, ultimately leading to altered immune maturation (Vatanen et al. 2016). The gut microbiome development in relation to the hygiene hypothesis was studied from birth until age three in 222 infants in Northern Europe. The study found an abundance of Bacteroides in Estonian and Finnish infants compared to Russian infants, where it was present in lower amounts, suggesting that Bacteroides are majorly involved in the increased lipopolysaccharide (LPS) exposures in the infants, thereby stimulating TLR4, tolerating endotoxins, and activating NF-κB (Tanaka and Nakayama 2017; Vatanen et al. 2016). These results suggested a direct link between the microbiome changes, immune activation, leading to an increased susceptibility to autoimmune diseases. The bacterial eradication due to tissue inflammation explores the role of a single commensal bacterium disrupting the host–microbiota homeostasis and persistent dysbiosis (Zeng et al. 2017). Additionally, the bacterium Porphyromonas gingivalis can transform the host oral microbiome to a dysbiotic and inflammatory state (Lamont et al. 2018). The bacteria are said to control the immune response; thereby advancing the degradation of MYD88, and thus inhibiting antimicrobial response and prolonging inflammation by bidirectional involvement of the complement receptor C5aR and TLR2 (Maekawa et al. 2014). Similarly, TLR and NLR signalling are controlled by the signals originated from the microbiota. In comparison, NLRP6 is critically involved in constructing the intestinal microbiome colonization niche by secreting mucus and antimicrobial peptides (Kim et al. 2017; Levy et al. 2015b). Enhanced secretion of IL-18 due to NLRP6 associated inflammasome activation in the gut regulates epithelial repair, intestinal inflammation, and the host defence against pathogens and infections (Levy et al. 2015b). Similar observations were reported with IL-22. While its absence leads to altered and enhanced levels in the disease-promoting microbiota, the wild-type mice cohousing with IL-22 deficient mice attenuated the levels of IL-22 mediated antimicrobial proteins similar to the levels observed in IL-22-deficient mice (Zenewicz et al. 2013; Couturier-Maillard et al. 2018). These targeted studies represent novel strategies indicating that altered microbial flora may contribute to self-maintenance due to regulation of certain specific factors involved in the mucosal immunity orchestration.

4.3.2

Crosstalk Between Adaptive Immune System and Microbiota

Microbial modulation through sophisticated mechanisms has played a vital role in the evolution of the adaptive immune system (Kato et al. 2014). One of the critical mechanisms by which microbiota affects the colonization niche is by degradation of the secretory IgA in association with Sutterella species (Levy et al. 2017). The species can degrade both IgA and associated stabilizing peptides. Cohousing or faecal microbiota transplantation from mice having low faecal IgA levels to other mice can cause intestinal environmental changes in the new host along with an

76

S. A. Ali et al.

increased susceptibility to chemical-induced intestinal inflammation (Planer et al. 2016; Zhang et al. 2015). These observations collectively dictate fine shreds of evidence that the intestinal microorganisms shape the mechanisms involved in the microbiome colonization, primarily the production of mucus and secretory IgA and antimicrobial peptides. A variety of autoimmune diseases such as type-1 diabetes (T1D), multiple sclerosis (MS), and RA originate due to the dysregulation of the adaptive immune system (Lee and Mazmanian 2010). While the altered diet and enhanced antibiotics use, environmental pollution and several other factors have caused a widespread shift in the microbiome‘s healthy composition, leading to microbial colonization and dysbiosis (Lee and Mazmanian 2010). Evidence from numerous mice studies suggests the potential role of a dysbiotic microbiota state and the initiation of autoimmune diseases probably by altering the inflammatory and tolerogenic mediators of the microbiome. The genus Bacteroides and its members are prominently present in the gastrointestinal tract (GIT) of the mammalian system. These function as potent stimulators of the mucosal immune system. A gut microorganism known as Bacteroides fragilis has potentially emerged as a recent model system for the study of host immunebacterial symbiosis (Bäumler and Sperandio 2016). The mice colonized with B. fragilis have shown higher amounts of the release of polysaccharide A (PSA), which is known to direct the molecular and cellular development of the immune system. The PSA molecule has attenuated experimental colitis in the gut and has even been shown to prevent and cure autoimmune encephalomyelitis (EAE) a widely used experimental animal model to mimic multiple sclerosis (Mazmanian et al. 2005). Moreover, the oral treatment with PSA prevented Th17 cell development along with an increase in the number of Treg cells in the central nervous system (CNS). Studies have found a plausible link between the inflammation in RA and EAE are promoted due to Th17 cells and attenuated by Tregs (Fasching et al. 2017). Recent studies dictate the role of GF-mice and the presence of its reduced number of TH17 cells in the spinal cords and spleen causing the animals to resistant against RA or EAE. All these theories suggest the role and direct involvement of the microbiota on adaptive immunity and its close influence with autoimmune diseases (Fasching et al. 2017).

4.4

Factors Affecting Microbiome Homeostasis and Autoimmune Diseases

As mentioned earlier, the colonization of gut begins early after the birth and continues to expand for a period of 2–3 years and remains constant throughout life. Based on the earlier research findings, it can be anticipated that the reciprocal interactions and microbial homeostasis get altered under the influence of several factors like diet, xenobiotics, gender, feeding habits, etc., potentiating several autoimmune pathologies. Autoimmune diseases are identified as the inappropriate response of immune cells against the body’s own tissues triggering local and

4

The Factors Influencing Gut Microbiota in Autoimmune Diseases

77

Fig. 4.1 Influence of factors under health and diseases condition. Diet and environmental factors play a characteristic role in regulating gut homeostasis and under circumstances may even aggravate to disease state by disrupting the mucosal barriers and immunity

systemic aberrations that lead to organ damage (Fig. 4.1). However, no clear mechanism is well documented, and here we discuss the factors that contribute to the aforementioned consequences.

4.4.1

Host-Induced Factors Causing the Origin of Dysbiosis

4.4.1.1 Mode of Delivery The composition of gut microbiota varies dramatically in new-borns delivered through caesarean section and vaginal delivery (Dominguez-Bello et al. 2016; Kulas et al. 2013; Tamburini et al. 2016). The infants delivered vaginally are exposed to the mother’s microflora during birth and their microflora is influenced with Lactobacillus and Prevotella. In addition, the vaginally delivered babies have shown enhanced production of white blood cells and immune cells as compared to C-section delivered babies. Moreover, infants born via caesarean procedure are dominated with Streptococcus, Corynebacterium, and Propionibacterium bacteria and are more vulnerable to the risk of obesity and diabetes, as the microbiota analysis have shown reduced inflammatory proteins mediating neonatal immunity (Portela et al. 2015; Dominguez-Bello et al. 2010). Moreover, the babies delivered via caesarean section lack the pre-exposure of the vaginal and faecal microbiota of the parent and are mostly colonized by skin microbiota and environmental surroundings.

78

S. A. Ali et al.

In accordance, it can be suggested that babies born via vaginal delivery develop strong immunological features compared to caesarean delivered babies.

4.4.1.2 Feeding Patterns Infant feeding plays a significant role in establishing a healthy microflora. Human breast milk is the richest source of early nutrition, containing probiotic and commensal flora (>700 species) essential for active development of microbiota. It helps in the growth of several types of useful bacteria and transfers the bacteria and immune cells into the colon as most of the dietary products get digested in the colon. Milk improves the immune factors that it carries and also promotes the growth of immune cells (Boix-Amorós et al. 2016; Cabrera-Rubio et al. 2012). Obese mothers feeding their babies showed the reduced bacterial diversity and increased pro-inflammatory effects (Panagos et al. 2016). The ability of breast milk to modulate host immune functions in the gut reflects the increased B. infantis and secretory IgA antibody in the initial few months might be challenging against several diseasecausing agents promoting damage (Hanson et al. 1978). 4.4.1.3 Gender Immune responses against antigenic attacks showed increased sensitivity in females than males. In particular, increased T-cell stimulation, cytokine production, and APCs are seen in female individuals compared to males (Eidinger and Garrett 1972; Taneja et al. 2007). Sex hormones such as androgens and oestrogens have been found to influence Th1/Th2 immune response (González et al. 2010). Recent findings suggested that testosterone reduces NK cell activity and TLR4 expression; while oestrogen showed the improved features of immunological responses and proinflammatory cytokine production (Chervonsky 2010). Recent research contributions have outlined that the interaction of microbiota and sex hormones largely affect the disease state in the genetically modified animals (Markle et al. 2013; Yurkovetskiy et al. 2013). However, the core features pertinent to the gender and immunity remain to be explored largely. But still, it can be understood that females are more resilient towards the pathogenic attacks with an outlook on increased susceptibility to infections (Mangalam et al. 2013). 4.4.1.4 Diet Diet is a primary factor that has both short and long-term influence on the composition of the gut microbiome (Wu et al. 2011; David et al. 2014). Advances in scientific research have played a significant role in revealing the connection between diet and mucosal immunity. The daily dietary intake of the so-called Western diet is high in proteins, saturated fat, sugar, alcohol, etc., and is strongly associated with the risk of gastrointestinal abnormalities, obesity, and type 2 diabetes (Statovci et al. 2017). The recently improved understandings of the link between diet and microbiota made it a target to manipulate and treat diseases. From the beginning of consumption of solid foods in infants, the microbiota abundance and composition undergo significant modifications due to the presence of new substrates that can cause proliferation in certain types of microbes and a decrease in Enterobacteria and

4

The Factors Influencing Gut Microbiota in Autoimmune Diseases

79

Bifidobacteria (Arrieta et al. 2014). Animals supplemented with a saturated fat rich diet modulated Th1 immune responses and increased vulnerability to colitis (Devkota et al. 2012). Mice fed with a low-fibre diet showed a progressive reduction in microbial diversity (Sonnenburg et al. 2016). While similar results were observed in mice fed with a high-fat diet (David et al. 2014). Dietary xenobiotics hold the potential to alter the commensal microbiome homeostasis (Yoshimoto et al. 2013). Similarly, the intake of long chain fatty acids has negative effects on the central nervous system as it worsens autoimmunity via changing the composition of the microbiota. The increased susceptibility to infections through diet grabbed more attention when intermittent fasting improved autoimmune encephalitis and MS by regulating the production of IL-17 and Treg cells through the microbiota (Cignarella et al. 2018).

4.4.1.5 Antibiotics These are the most widely used therapeutic agents in the treatment of infectious diseases. However, antibiotics function as dual-edge swords as they destroy both the host and foreign substances and compromise the integrity of gut microbiota. The unregulated use of antibiotics in the early developmental stages of life has been found to alter the cellular processes inducing long lasting disease pathologies. The vancomycin used in the treatment of C. difficile infection has been found to alter the composition of gut microbiota and resulted in the repeated attack of C. difficile infection (Zar et al. 2007). Antibiotics (cefalexin, ampicillin, and gentamycin) treatment to children altered the diversity of gut microflora. In particular, it resulted in the augmented growth of Proteobacteria, subsequently reducing the Lactobacillus and Bifidobacterium bacteria (Fouhy et al. 2012; Tanaka et al. 2009). Moreover, studies suggested that the overuse of antibiotics can cause genetic resistance leading to multi-drug resistant microorganisms, which is a primary concern (Alós 2015). New-borns whose mothers have been prescribed antibiotics perinatally have been found to have a microbiome composition different from new-borns whose mothers have not been treated with antibiotics (Mueller et al. 2015). The long-term consequences observed due to overuse of antibiotics treatment can cause potential alterations in both the microbiota and immune system. Thus, the significant alteration in the gut axis persists longer and results in the progression of immune and inflammation regulated pathologies. 4.4.1.6 Genetic Factors Host genetics is reported to play a major role in shaping the biochemical and immune milieu of the gut microbiota (Levy et al. 2015a; Wells et al. 2019). Multiple taxa of the intestinal microbiota were identified in a twin study reporting microbiome is influenced by the host genetics (Goodrich et al. 2014). Genome-wide studies revealed the close associations between the Bifidobacterium genus and locus of the human genome encoding lactase (Bonder et al. 2016). Additionally, the locus involved in encoding the vitamin D receptor (VDR) in humans and a vast number of other loci involved in metabolic and immune functions are potential drivers in controlling the microbiome through the host genetics (Wang et al. 2016). Another

80

S. A. Ali et al.

study identified the influence of genetics on the microbiome composition and manifestation of phenotypes as observed for low body mass index and Christensenellaceae ultimately causing a dysbiotic state (Turpin et al. 2016). However, the impact of diet was found to outweigh the genetic predisposition in mouse models.

4.4.1.7 Infections Gut microbiome modulates the various immune cells that augment the sensitivity to perceive pathogenic attacks. The secretory IgA antibodies released from gut deactivate retroviruses and also challenges Clostridium difficile colonization (Kamada et al. 2013). Moreover, the diversity of gut microbiota seems to be altered drastically even by the use of antibiotics. For instance, the use of anti-tubercular drugs like isoniazid, rifampicin and pyrazinamide, reduced the Clostridia in gut microbiota in both the infected and uninfected animals with Mycobacterium tuberculosis (Namasivayam et al. 2017). In addition, microbiota-based therapy is also reported to change the composition of microbiome efficiently leading to Clostridium difficile infection (Britton and Young 2014). Another study reported the reduced gut bacteria in HIV-1 patients, while in contrast the anti-retroviral therapy was ineffective in reversing the gut bacteria changes (Lozupone et al. 2013).

4.4.2

Effect of Cytokine Dysregulation on Microbiome Perturbation

Interactions between the host’s immune system and a dysbiotic microbiome state in susceptible individuals can contribute significantly to the development of several immune-mediated diseases (Belkaid and Hand 2014). The most studied diseases in context to microbiota and autoimmune diseases are IBD, systemic autoimmune diseases, cancer, and cardiometabolic diseases. Various mechanisms have been proposed to link the microbiome dysbiosis, the initiation of auto-immune diseases, and multifactorial diseases (De Luca and Shoenfeld 2019).

4.4.2.1 Inflammation-Mediated Gut Dysbiosis Enteric infection-mediated dysbiosis was initially observed in mouse models after infecting with Salmonella enterica and Citrobacter rodentium (Lupp et al. 2007; Stecher et al. 2007). The commensal bacterium causes colonization resistance against the invading microorganisms. Dextran sodium sulphate-treated mice or genetically deficit mice with the IL-10 production showed homogenous changes in the microbial environment, favouring the growth of harmful epigenetic pathogens (Stecher et al. 2007; Lupp et al. 2007). The Enterobacteriaceae family and its members were found to promote the initiation and development of sepsis and colorectal cancer in association with intestinal infection and inflammation (Arthur et al. 2012). The probable mechanisms involved in dysbiosis could be attributed to the use of metal ions, horizontal gene transfer, harnessing aerobic and anaerobic cellular respiration and exploiting antimicrobial peptides (Ng et al. 2013; Deriu et al. 2013; Stecher et al. 2012).

4

The Factors Influencing Gut Microbiota in Autoimmune Diseases

81

4.4.2.2 Molecular Mimicry DR4-IE-transgenic mice immunized with Porphyromonas gingivalis enolase caused the production of antibodies against human alpha-enolase and arthritis occurrence (Kinloch et al. 2011). Epstein-Barr virus infection has been implicated with SLE and studies have shown its antigens have close similarity with the antigens commonly involved in causing SLE (James and Robertson 2012). The Sjogren’s syndrome antigen A (SSA/Ro60) can cause the generation of anti-Ro60 antibodies which is an important marker in diseases such as SLE and Sjogren’s syndrome (Szymula et al. 2014). The human oral, skin, intestinal and vaginal bacteria can activate Ro60reactive T cells present in HLA-DR3 transgenic mice (Szymula et al. 2014). These aforementioned studies suggest that cross-reactions caused by molecular mimicry may be a crucial factor involved in the occurrence of autoimmune diseases.

4.4.3

Modulatory Factors of Gut Microbiota

Modulatory factors of the gut microbiota are important in different diseases pertaining to any imbalances in gut microbiota. These modulating factors include probiotics, prebiotics, and FMT.

4.4.3.1 Probiotics Probiotics are living microorganisms that improve human health when taken in appropriate doses (Kristensen et al. 2016). Lactobacillus spp., Bifidobacterium spp., several Bacillus spp., E. coli, and Streptococcus spp. strains are considered as the most beneficial microbial species isolated from the human microbiota and are the most used probiotics for the prevention of diseases (Rokka and Rantamäki 2010; Salminen et al. 2006). Probiotics primarily improve health by promoting favourable types of gut microbes. Some probiotics such as Lactobacillus reuteri, produces antimicrobial compounds ‘reuterin’ that protects against harmful microbes directly and induces immune responses in the host (Cleusix et al. 2007). Studies have shown that in Lactobacillus strain, cell surface molecules exhibit tumour necrosis factor-α (TNF-α)-inducing activities in macrophages via TLR2 signalling (Mikelsaar et al. 2011). Moreover, Bifidobacterium reduces inflammation of the intestine by enhancing the function of mucous intestinal barrier, and increasing the serum IgA (Mohan et al. 2006). The Bifidobacterium has also been reported to reduce the number of harmful bacteria in stool samples (Mohan et al. 2008). Several systematic reviews showed substantial evidence for the beneficial effects of probiotic supplementation in urinary tract infections (UTIs), reduction of total cholesterol and low-density lipoprotein cholesterol (Schwenger et al. 2015; Wu et al. 2017). Interestingly, the probiotic administration decreased cardiovascular risk and reduced fasting blood glucose and HbA1in type-2 diabetic patients (Akbari and Hendijani 2016; Hendijani and Akbari 2018). Studies on experimental mice demonstrated that utilization of mucins by gut microbiota under dietary fibre deficiency causes the erosion of the colonic mucus barrier and administration of Akkermansia muciniphila and mucin degradation lead to the restoration of the gut mucus barrier (Desai et al. 2016;

82

S. A. Ali et al.

Everard et al. 2013; Li et al. 2016). A new approach in probiotic therapy is represented by bioengineered probiotics. Probiotic strains can be utilized as vehicles for the expression of foreign genes. Researchers showed the advantages of recombinant probiotics in treating enteric infection, but such strains are regarded as genetically modified organisms (GMOs), raising ethical issues regarding their use (Culligan et al. 2009; Mathipa and Thantsha 2017).

4.4.3.2 Prebiotics Prebiotics specifically consist of non-digestible carbohydrates, oligosaccharides, or short polysaccharides like oligofructose, galactofructose, and inulin. These components cause specific changes in the structure or activity of gut microbiota and provide benefits to the host (Tabibian et al. 2013; Rossen et al. 2015). Prebiotics are mainly absorbed by the upper tract of the digestive system, fermented by gut microbiota and it induces the useful species of the gut microbiota (Quraishi et al. 2017). Prebiotics specifically target the Lactobacilli and Bifidobacterium and increases the production of SCFAs with decreasing pH (Tabibian et al. 2013; De Vrese and Offick 2010). Dietary fibres consumption has the most direct effects on gut microbial colonization and it maintains the intact mucosal barrier function in the gut (Gibson et al. 2004). Studies have shown that inulin administration can prevent the damaging effects of high fat diets on penetrability of the mucus layer and metabolic functions (Zhou 2017; Schroeder et al. 2018). Evidence indicates that low fibre in the Western diet weakens the colonic mucus barrier and cause increased pathogen susceptibility, inflammation and chronic diseases. The mixture of galacto-oligosaccharides and fructo-oligosaccharides increases Bifidobacteria in the gut while galactooligosaccharides alone increase Lactobacillus (Vandenplas et al. 2015). 4.4.3.3 Faecal Microbiota Transplantation (FMT) Faecal microbiota transplantation (FMT) is the administration of faecal bacteria from healthy donors to recipients with intestinal diseases to restore gut microbial composition for health benefit (Smits et al. 2013; Bakken et al. 2011). The FMT therapy was first described by Ge Hong in fourth-century China for the treatment of a variety of diseases including diarrhoea (Zhang et al. 2012). In modern medicine, Eiseman first showed that FMT has successfully treated many patients with pseudomembranous colitis by enema (Gs and Aj 1958). Clinical findings suggest that FMT can treat patients with RA through the reconstruction of a beneficial microbiota which can alleviate and prevent the process of inflammation (Zeng et al. 2021).

4.4.4

Other Potential Mechanisms Involved

Several other proposed mechanisms can be found to participate in the interactions between the microbiome and the immune system. The gut microbiome removes auto-reactive B cells. However, this procedure was found to be defective in SLE

4

The Factors Influencing Gut Microbiota in Autoimmune Diseases

83

patients (Vossenkämper et al. 2013). Microbiota further promotes the differentiation of Breg cells and enhances the production of IL-10 through IL-6 and IL-1β activation, whereas mice that lacked IL-6 or IL-1β receptor specifically on the B cells produced significantly less IL-10-producing B cells with exacerbated arthritis compared to normal controls (Rosser et al. 2014). These results indicate the presence of Breg-promoting bacteria in arthritic patients.

4.5

Possible Role of SARS-CoV-2 in Affecting the Gut Microbiota and Its Possible Link to Immunity

Gut microbiota is also anticipated to play a crucial role in sufferers with SARS-CoV2. Zuo et al. reported that gut microbiota of COVID-19 patients was enriched with opportunistic pathogens (Zuo et al. 2021). Studies in past have shown that depletion of intestinal flora with neomycin increased the severity of influenza virus and allergic infections (Pang et al. 2018). SARS-CoV-2 effectively escapes the host cells through the communication of spike proteins with ACE2. The characteristic presence of ACE2 in gut establishes a crucial link between gut dysbiosis and increased severity in COVID-19 individuals with gastrointestinal abnormalities (He et al. 2020). Few other emerging studies using faecal specimens identified that SARS-CoV2 modulates the immune and other related host cells and gets localized in the intestinal flora, even after getting cleared from the upper respiratory tract (Ahlawat and Sharma 2020). Altogether, the given evidences suggest that manipulating gut axis to enhance gut microflora and immune cells might serve effectively in reducing/ preventing the severity of infection in fatal cases.

4.6

Conclusion and Future Perspective

Maintaining the gut microbiome homeostasis is very important to human health. Different factors may directly or indirectly affect the gut microbiota composition. Other factors, such as geographical location, lifestyle may contribute to gut microbiota homeostasis. The disorder of the gut microbiota is associated with several diseases and manipulating its composition and diversity is an important element to control the development of these diseases. However, further studies are needed regarding the manoeuvre of gut microbiota that can enhance health. In summary, knowledge of gut microbiota-associated approaches in both healthy and disease states may contribute to prevent the progression of autoimmune diseases in host. The understanding of the dynamic interplay between the gut microbiota and the host will establish a highly personalized management for autoimmune disease and aids in finding better therapeutic management. Conflicts of Interest The authors declare that there is no conflict of interest.

84

S. A. Ali et al.

References Ahlawat S, Sharma KK (2020) Immunological co-ordination between gut and lungs in SARS-CoV2 infection. Virus Res 198103 Akbari V, Hendijani F (2016) Effects of probiotic supplementation in patients with type 2 diabetes: systematic review and meta-analysis. Nutr Rev 74:774–784 Alós JI (2015) Antibiotic resistance: a global crisis. Enferm Infecc Microbiol Clin 33:692–699 Arrieta MC, Stiemsma LT, Amenyogbe N, Brown EM, Finlay B (2014) The intestinal microbiome in early life: health and disease. Front Immunol 5:427 Arthur JC, Perez-Chanona E, Mühlbauer M, Tomkovich S, Uronis JM, Fan TJ, Campbell BJ, Abujamel T, Dogan B, Rogers AB, Rhodes JM, Stintzi A, Simpson KW, Hansen JJ, Keku TO, Fodor AA, Jobin C (2012) Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338:120–123 Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331:337–341 Atkinson SM, Hoffmann U, Hamann A, Bach E, Danneskiold-Samsøe NB, Kristiansen K, Serikawa K, Fox B, Kruse K, Haase C, Skov S, Nansen A (2016) Depletion of regulatory T cells leads to an exacerbation of delayed-type hypersensitivity arthritis in C57BL/6 mice that can be counteracted by IL-17 blockade. Dis Model Mech 9:427–440 Augeron C, Laboisse CL (1984) Emergence of permanently differentiated cell clones in a human colonic cancer cell line in culture after treatment with sodium butyrate. Cancer Res 44:3961– 3969 Bakken JS, Borody T, Brandt LJ, Brill JV, Demarco DC, Franzos MA, Kelly C, Khoruts A, Louie T, Martinelli LP (2011) Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 9:1044–1049 Bäumler AJ, Sperandio V (2016) Interactions between the microbiota and pathogenic bacteria in the gut. Nature 535:85–93 Belkaid Y, Hand TW (2014) Role of the microbiota in immunity and inflammation. Cell 157:121– 141 Blaser MJ, Falkow S (2009) What are the consequences of the disappearing human microbiota? Nat Rev Microbiol 7:887–894 Block KE, Zheng Z, Dent AL, Kee BLH, H. (2016) Gut microbiota regulates K/BxN autoimmune arthritis through follicular helper T but not Th17 cells. J Immunol 196:1550–1557 Boix-Amorós A, Collado MC, Mira A (2016) Relationship between milk microbiota, bacterial load, macronutrients, and human cells during lactation. Front Microbiol 7:492 Bonder MJ, Kurilshikov A, Tigchelaar EF, Mujagic Z, Imhann F, Vila AV, Deelen P, Vatanen T, Schirmer M, Smeekens SP, Zhernakova DV, Jankipersadsing SA, Jaeger M, Oosting M, Cenit MC, Masclee AA, Swertz MA, Li Y, Kumar V, Joosten L, Harmsen H, Weersma RK, Franke L, Hofker MH, Xavier RJ, Jonkers D, Netea MG, Wijmenga C, Fu J, Zhernakova A (2016) The effect of host genetics on the gut microbiome. Nat Genet 48:1407–1412 Brestoff JR, Artis D (2013) Commensal bacteria at the interface of host metabolism and the immune system. Nat Immunol 14:676–684 Britton RA, Young VB (2014) Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology 146:1547–1553 Cabrera-Rubio R, Collado MC, Laitinen K, Salminen S, Isolauri E, Mira A (2012) The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery. Am J Clin Nutr 96:544–551 Chervonsky AV (2010) Influence of microbial environment on autoimmunity. Nat Immunol 11:28– 35 Clemente JC, Ursell LK, Parfrey LW, Knight R (2012) The impact of the gut microbiota on human health: an integrative view. Cell 148:1258–1270

4

The Factors Influencing Gut Microbiota in Autoimmune Diseases

85

Cleusix V, Lacroix C, Vollenweider S, Duboux M, Le Blay G (2007) Inhibitory activity spectrum of reuterin produced by Lactobacillus reuteri against intestinal bacteria. BMC Microbiol 7:1–9 Couturier-Maillard A, Froux N, Piotet-Morin J, Michaudel C, Brault L, Le Bérichel J, Sénéchal A, Robinet P, Chenuet P, Jejou S, Dumoutier L, Renauld JC, Iovanna J, Huber S, Chamaillard M, Quesniaux V, Sokol H, Chamaillard M, Ryffel B (2018) Interleukin-22-deficiency and microbiota contribute to the exacerbation of Toxoplasma gondii-induced intestinal inflammation. Mucosal Immunol 11:1181–1190 Culligan EP, Hill C, Sleator RD (2009) Probiotics and gastrointestinal disease: successes, problems and future prospects. Gut Pathogens 1:1–12 Cummings J, Pomare E, Branch W, Naylor C, Macfarlane G (1987) Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28:1221–1227 David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:559–563 De Luca F, Shoenfeld Y (2019) The microbiome in autoimmune diseases. Clin Exp Immunol 195: 74–85 De Vrese M, Offick B (2010) Probiotics and prebiotics: effects on diarrhea. Bioactive Foods Promoting Health:205–227 Deriu E, Liu JZ, Pezeshki M, Edwards RA, Ochoa RJ, Contreras H, Libby SJ, Fang FC, Raffatellu M (2013) Probiotic bacteria reduce salmonella typhimurium intestinal colonization by competing for iron. Cell Host Microbe 14:26–37 Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M, Pudlo NA, Kitamoto S, Terrapon N, Muller A (2016) A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167(1339–1353):e21 Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, Antonopoulos DA, Jabri B, Chang EB (2012) Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10 / mice. Nature 487:104–108 Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, Knight R (2010) Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci 107:11971–11975 Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, Cox LM, Amir A, Gonzalez A, Bokulich NA, Song SJ, Hoashi M, Rivera-Vinas JI (2016) Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med 22:250 Eidinger D, Garrett TJ (1972) Studies of the regulatory effects of the sex hormones on antibody formation and stem cell differentiation. J Exp Med 136:1098–1116 Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI (2011) NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:745–757 Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM (2013) Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci 110:9066–9071 Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J (2017) Therapeutic potential of targeting the Th17/Treg axis in autoimmune disorders. Molecules 22 Ferreira RM, Pereira-Marques J, Pinto-Ribeiro I, Costa JL, Carneiro F, Machado JC, Figueiredo C (2018) Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota. Gut 67:226–236 Fouhy F, Guinane CM, Hussey S, Wall R, Ryan CA, Dempsey EM, Murphy B, Ross RP, Fitzgerald GF, Stanton C (2012) High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin. Antimicrob Agents Chemother 56:5811 Franzosa EA, Morgan XC, Segata N, Waldron L, Reyes J, Earl AM, Giannoukos G, Boylan MR, Ciulla D, Gevers D (2014) Relating the metatranscriptome and metagenome of the human gut. Proc Natl Acad Sci 111:E2329–E2338

86

S. A. Ali et al.

Fung TC, Olson CA, Hsiao EY (2017) Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci 20:145 Gibson GR, Probert HM, Van Loo J, Rastall RA, Roberfroid MB (2004) Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev 17:259–275 González DA, Díaz BB, Pérez MDCR, Hernández AG, Chico BND, De León AC (2010) Sex hormones and autoimmunity. Immunol Lett 133:6–13 Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, Beaumont M, Van Treuren W, Knight R, Bell JT, Spector TD, Clark AG, Ley RE (2014) Human genetics shape the gut microbiome. Cell 159:789–799 Gs B, Aj K (1958) Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 44:854–859 Hanson L, Ahlstedt S, Carlsson B, Fällström S, Kaijser B, Lindblad B, Åkerlund AS, Eden CS (1978) New knowledge in human milk immunoglobulin. Acta Paediatr 67:577–582 He L-H, Ren L-F, Li J-F, Wu Y-N, Li X, Zhang L (2020) Intestinal flora as a potential strategy to fight SARS-CoV-2 infection. Front Microbiol 11:1388 Hendijani F, Akbari V (2018) Probiotic supplementation for management of cardiovascular risk factors in adults with type II diabetes: a systematic review and meta-analysis. Clin Nutr 37:532– 541 Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–498 Iwasaki A, Kelsall BL (1999) Freshly isolated Peyer's patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells. J Exp Med 190:229–240 James JA, Robertson JM (2012) Lupus and Epstein-Barr. Curr Opin Rheumatol 24:383–388 Kamada N, Seo S-U, Chen GY, Núñez G (2013) Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol 13:321–335 Kato LM, Kawamoto S, Maruya M, Fagarasan S (2014) The role of the adaptive immune system in regulation of gut microbiota. Immunol Rev 260:67–75 Kho ZY, Lal SK (2018) The human gut microbiome – a potential controller of wellness and disease. Front Microbiol 9:1835 Kim S, Covington A, Pamer EG (2017) The intestinal microbiota: Antibiotics, colonization resistance, and enteric pathogens. Immunol Rev 279:90–105 Kinloch AJ, Alzabin S, Brintnell W, Wilson E, Barra L, Wegner N, Bell DA, Cairns E, Venables PJ (2011) Immunization with Porphyromonas gingivalis enolase induces autoimmunity to mammalian α-enolase and arthritis in Dr4-Ie-transgenic mice. Arthritis Rheum 63:3818–3823 Kristensen NB, Bryrup T, Allin KH, Nielsen T, Hansen TH, Pedersen OJGM (2016) Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials 8:1–11 Kulas T, Bursac D, Zegarac Z, Planinic-Rados G, Hrgovic Z (2013) New views on cesarean section, its possible complications and long-term consequences for children’s health. Med Arch 67:460 Lamont RJ, Koo H, Hajishengallis G (2018) The oral microbiota: dynamic communities and host interactions. Nat Rev Microbiol 16:745–759 Langille MG, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA, Clemente JC, Burkepile DE, Thurber RLV, Knight R (2013) Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol 31:814–821 Lee YK, Mazmanian SK (2010) Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 330:1768–1773 Levy M, Thaiss CA, Elinav E (2015a) Metagenomic cross-talk: the regulatory interplay between immunogenomics and the microbiome. Genome Med 7:120 Levy M, Thaiss CA, Zeevi D, Dohnalová L, Zilberman-Schapira G, Mahdi JA, David E, Savidor A, Korem T, Herzig Y, Pevsner-Fischer M, Shapiro H, Christ A, Harmelin A, Halpern Z, Latz E, Flavell RA, Amit I, Segal E, Elinav E (2015b) Microbiota-modulated metabolites shape the

4

The Factors Influencing Gut Microbiota in Autoimmune Diseases

87

intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163:1428– 1443 Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E (2017) Dysbiosis and the immune system. Nat Rev Immunol 17:219–232 Li J, Lin S, Vanhoutte PM, Woo CW, Xu A (2016) Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe / mice. Circulation 133:2434–2446 Lozupone CA, Li M, Campbell TB, Flores SC, Linderman D, Gebert MJ, Knight R, Fontenot AP, Palmer BE (2013) Alterations in the gut microbiota associated with HIV-1 infection. Cell Host Microbe 14:329–339 Lupp C, Robertson ML, Wickham ME, Sekirov I, Champion OL, Gaynor EC, Finlay BB (2007) Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2:119–129 Macpherson AJ, Uhr T (2004) Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303:1662–1665 Maekawa T, Krauss JL, Abe T, Jotwani R, Triantafilou M, Triantafilou K, Hashim A, Hoch S, Curtis MA, Nussbaum G, Lambris JD, Hajishengallis G (2014) Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis. Cell Host Microbe 15:768–778 Mangalam AK, Taneja V, David CS (2013) Hla class Ii molecules influence susceptibility versus protection in inflammatory diseases by determining the cytokine profile. J Immunol 190:513– 519 Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, Von Bergen M, Mccoy KD, Macpherson AJ, Danska JS (2013) Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339:1084–1088 Mathipa MG, Thantsha MS (2017) Probiotic engineering: towards development of robust probiotic strains with enhanced functional properties and for targeted control of enteric pathogens. Gut Pathogens 9:1–17 Maynard CL, Elson CO, Hatton RD, Weaver CT (2012) Reciprocal interactions of the intestinal microbiota and immune system. Nature 489:231–241 Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL (2005) An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122:107–118 Mikelsaar M, Lazar V, Onderdonk A, Donelli G (2011) Do probiotic preparations for humans really have efficacy? Microb Ecol Health Dis 22:10128 Mohan R, Koebnick C, Schildt J, Schmidt S, Mueller M, Possner M, Radke M, Blaut M (2006) Effects of Bifidobacterium lactis Bb12 supplementation on intestinal microbiota of preterm infants: a double-blind, placebo-controlled, randomized study. J Clin Microbiol 44:4025–4031 Mohan R, Koebnick C, Schildt J, Mueller M, Radke M, Blaut M (2008) Effects of Bifidobacterium lactis Bb12 supplementation on body weight, fecal pH, acetate, lactate, calprotectin, and IgA in preterm infants. Pediatr Res 64:418–422 Molloy MJ, Bouladoux N, Belkaid Y (2012) Intestinal microbiota: shaping local and systemic immune responses. Semin Immunol 24(1):58–66 Mueller NT, Bakacs E, Combellick J, Grigoryan Z, Dominguez-Bello MG (2015) The infant microbiome development: mom matters. Trends Mol Med 21:109–117 Namasivayam S, Maiga M, Yuan W, Thovarai V, Costa DL, Mittereder LR, Wipperman MF, Glickman MS, Dzutsev A, Trinchieri G (2017) Longitudinal profiling reveals a persistent intestinal dysbiosis triggered by conventional anti-tuberculosis therapy. Microbiome 5:1–17 Ng KM, Ferreyra JA, Higginbottom SK, Lynch JB, Kashyap PC, Gopinath S, Naidu N, Choudhury B, Weimer BC, Monack DM, Sonnenburg JL (2013) Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502:96–99 Opazo MC, Ortega-Rocha EM, Coronado-Arrázola I, Bonifaz LC, Boudin H, Neunlist M, Bueno SM, Kalergis AM, Riedel CA (2018) Intestinal microbiota influences non-intestinal related autoimmune diseases. Front Microbiol 9:432

88

S. A. Ali et al.

Ostaff MJ, Stange EF, Wehkamp J (2013) Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med 5:1465–1483 Panagos P, Vishwanathan R, Penfield-Cyr A, Matthan N, Shivappa N, Wirth M, Hebert J, Sen S (2016) Breastmilk from obese mothers has pro-inflammatory properties and decreased neuroprotective factors. J Perinatol 36:284–290 Pang P, Yu B, Shi Y, Deng L, Xu H, Wu S, Chen X (2018) Alteration of intestinal flora stimulates pulmonary microRNAs to interfere with host antiviral immunity in influenza. Molecules 23: 3151 Perez-Cano FJ, González-Castro A, Castellote C, Franch À, Castell M (2010) Influence of breast milk polyamines on suckling rat immune system maturation. Dev Comp Immunol 34:210–218 Planer JD, Peng Y, Kau AL, Blanton LV, Ndao IM, Tarr PI, Warner BB, Gordon JI (2016) Development of the gut microbiota and mucosal IgA responses in twins and gnotobiotic mice. Nature 534:263–266 Portela DS, Vieira TO, Matos SM, De Oliveira NF, Vieira GO (2015) Maternal obesity, environmental factors, cesarean delivery and breastfeeding as determinants of overweight and obesity in children: results from a cohort. BMC Pregnancy Childbirth 15:1–10 Qu N, Xu M, Mizoguchi I, Furusawa J, Kaneko K, Watanabe K, Mizuguchi J, Itoh M, Kawakami Y, Yoshimoto T (2013) Pivotal roles of T-helper 17-related cytokines, IL-17, IL-22, and IL-23, in inflammatory diseases. Clin Dev Immunol 2013:968549 Quraishi MN, Sergeant M, Kay G, Iqbal T, Chan J, Constantinidou C, Trivedi P, Ferguson J, Adams DH, Pallen M (2017) The gut-adherent microbiota of PSC–IBD is distinct to that of IBD. Gut 66:386–388 Rokka S, Rantamäki P (2010) Protecting probiotic bacteria by microencapsulation: challenges for industrial applications. Eur Food Res Technol 231:1–12 Rooks MG, Garrett WS (2016) Gut microbiota, metabolites and host immunity. Nat Rev Immunol 16:341–352 Rossen NG, Fuentes S, Boonstra K, D’haens GR, Heilig HG, Zoetendal EG, De Vos WM, Ponsioen CY (2015) The mucosa-associated microbiota of PSC patients is characterized by low diversity and low abundance of uncultured Clostridiales II. J Crohn's Colitis 9:342–348 Rosser EC, Oleinika K, Tonon S, Doyle R, Bosma A, Carter NA, Harris KA, Jones SA, Klein N, Mauri C (2014) Regulatory B cells are induced by gut microbiota-driven interleukin-1β and interleukin-6 production. Nat Med 20:1334–1339 Round JL, Mazmanian SK (2009) The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9:313–323 Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK (2011) The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332:974– 977 Salminen MK, Rautelin H, Tynkkynen S, Poussa T, Saxelin M, Valtonen V, Järvinen A (2006) Lactobacillus bacteremia, species identification, and antimicrobial susceptibility of 85 blood isolates. Clin Infect Dis 42:e35–e44 Schopf JW, Packer BM (1987) Early Archean (3.3-billion to 3.5-billion-year-old) microfossils from Warrawoona Group, Australia. Science 237:70–73 Schroeder BO, Birchenough GM, Ståhlman M, Arike L, Johansson ME, Hansson GC, Bäckhed F (2018) Bifidobacteria or fiber protects against diet-induced microbiota-mediated colonic mucus deterioration. Cell Host Microbe 23(27–40):e7 Schwenger EM, Tejani AM, Loewen PS (2015) Probiotics for preventing urinary tract infections in adults and children. Cochrane Database Syst Rev Shi N, Li N, Duan X, Niu H (2017) Interaction between the gut microbiome and mucosal immune system. Mil Med Res 4:14 Smits LP, Bouter KE, De Vos WM, Borody TJ, Nieuwdorp M (2013) Therapeutic potential of fecal microbiota transplantation. Gastroenterology 145:946–953 Sommer F, Bäckhed F (2013) The gut microbiota—masters of host development and physiology. Nat Rev Microbiol 11:227–238

4

The Factors Influencing Gut Microbiota in Autoimmune Diseases

89

Statovci D, Aguilera M, Macsharry J, Melgar S (2017) The impact of western diet and nutrients on the microbiota and immune response at mucosal interfaces. Front Immunol 8:838 Stecher B, Robbiani R, Walker AW, Westendorf AM, Barthel M, Kremer M, Chaffron S, Macpherson AJ, Buer J, Parkhill J, Dougan G, Von Mering C, Hardt WD (2007) Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol 5:2177–2189 Stecher B, Denzler R, Maier L, Bernet F, Sanders MJ, Pickard DJ, Barthel M, Westendorf AM, Krogfelt KA, Walker AW, Ackermann M, Dobrindt U, Thomson NR, Hardt WD (2012) Gut inflammation can boost horizontal gene transfer between pathogenic and commensal Enterobacteriaceae. Proc Natl Acad Sci U S A 109:1269–1274 Szymula A, Rosenthal J, Szczerba BM, Bagavant H, Fu SM, Deshmukh US (2014) T cell epitope mimicry between Sjögren's syndrome Antigen A (SSA)/Ro60 and oral, gut, skin and vaginal bacteria. Clin Immunol 152:1–9 Tabibian JH, Talwalkar JA, Lindor KD (2013) Role of the microbiota and antibiotics in primary sclerosing cholangitis. BioMed Res Int 2013 Tamburini S, Shen N, Wu HC, Clemente JC (2016) The microbiome in early life: implications for health outcomes. Nat Med 22:713–722 Tanaka M, Nakayama J (2017) Development of the gut microbiota in infancy and its impact on health in later life. Allergol Int 66:515–522 Tanaka S, Kobayashi T, Songjinda P, Tateyama A, Tsubouchi M, Kiyohara C, Shirakawa T, Sonomoto K, Nakayama J (2009) Influence of antibiotic exposure in the early postnatal period on the development of intestinal microbiota. FEMS Immunol Med Microbiol 56:80–87 Taneja V, Behrens M, Mangalam A, Griffiths MM, Luthra HS, David CS (2007) New humanized HLA–DR4–transgenic mice that mimic the sex bias of rheumatoid arthritis. Arthritis Rheum 56: 69–78 Thaiss CA, Zmora N, Levy M, Elinav E (2016) The microbiome and innate immunity. Nature 535: 65–74 Thursby E, Juge N (2017) Introduction to the human gut microbiota. Biochem J 474:1823–1836 Turpin W, Espin-Garcia O, Xu W, Silverberg MS, Kevans D, Smith MI, Guttman DS, Griffiths A, Panaccione R, Otley A, Xu L, Shestopaloff K, Moreno-Hagelsieb G, Paterson AD, Croitoru K (2016) Association of host genome with intestinal microbial composition in a large healthy cohort. Nat Genet 48:1413–1417 Vandenplas Y, Zakharova I, Dmitrieva Y (2015) Oligosaccharides in infant formula: more evidence to validate the role of prebiotics. Br J Nutr 113:1339–1344 Vatanen T, Kostic AD, D'hennezel E, Siljander H, Franzosa EA, Yassour M, Kolde R, Vlamakis H, Arthur TD, Hämäläinen AM, Peet A, Tillmann V, Uibo R, Mokurov S, Dorshakova N, Ilonen J, Virtanen SM, Szabo SJ, Porter JA, Lähdesmäki H, Huttenhower C, Gevers D, Cullen TW, Knip M, Xavier RJ (2016) Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 165:1551 Vossenkämper A, Blair PA, Safinia N, Fraser LD, Das L, Sanders TJ, Stagg AJ, Sanderson JD, Taylor K, Chang F, Choong LM, D'cruz DP, Macdonald TT, Lombardi G, Spencer J (2013) A role for gut-associated lymphoid tissue in shaping the human B cell repertoire. J Exp Med 210: 1665–1674 Wang J, Thingholm LB, Skiecevičienė J, Rausch P, Kummen M, Hov JR, Degenhardt F, Heinsen FA, Rühlemann MC, Szymczak S, Holm K, Esko T, Sun J, Pricop-Jeckstadt M, Al-Dury S, Bohov P, Bethune J, Sommer F, Ellinghaus D, Berge RK, Hübenthal M, Koch M, Schwarz K, Rimbach G, Hübbe P, Pan WH, Sheibani-Tezerji R, Häsler R, Rosenstiel P, D'amato M, Cloppenborg-Schmidt K, Künzel S, Laudes M, Marschall HU, Lieb W, Nöthlings U, Karlsen TH, Baines JF, Franke A (2016) Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet 48:1396– 1406 Webb CR, Koboziev I, Furr KL, Grisham MB (2016) Protective and pro-inflammatory roles of intestinal bacteria. Pathophysiology 23:67–80

90

S. A. Ali et al.

Wells PM, Williams FM, Matey-Hernandez M, Menni C, Steves CJ (2019) RA and the microbiome: do host genetic factors provide the link? J Autoimmun 99:104–115 Wu H-J, Wu E (2012) The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 3:4–14 Wu HJ, Ivanov I, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, Benoist C, Mathis D (2010) Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32:815–827 Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, Bewtra M, Knights D, Walters WA, Knight R, Sinha R, Gilroy E, Gupta K, Baldassano R, Nessel L, Li H, Bushman FD, Lewis JD (2011) Linking long-term dietary patterns with gut microbial enterotypes. Science 334:105– 108 Wu Y, Zhang Q, Ren Y, Ruan Z (2017) Effect of probiotic Lactobacillus on lipid profile: a systematic review and meta-analysis of randomized, controlled trials. PLoS One 12:e0178868 Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, Antonopoulos D, Umesaki Y, Chervonsky AV (2013) Gender bias in autoimmunity is influenced by microbiota. Immunity 39:400–412 Zar FA, Bakkanagari SR, Moorthi K, Davis MB (2007) A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile–associated diarrhea, stratified by disease severity. Clin Infect Dis 45:302–307 Zenewicz LA, Yin X, Wang G, Elinav E, Hao L, Zhao L, Flavell RA (2013) IL-22 deficiency alters colonic microbiota to be transmissible and colitogenic. J Immunol 190:5306–5312 Zeng MY, Inohara N, Nuñez G (2017) Mechanisms of inflammation-driven bacterial dysbiosis in the gut. Mucosal Immunol 10:18–26 Zeng J, Peng L, Zheng W, Huang F, Zhang N, Wu D, Yang Y (2021) Fecal microbiota transplantation for rheumatoid arthritis: A case report. Clin Case Rep 9:906–909 Zhang F, Luo W, Shi Y, Fan Z, Ji G (2012) Should we standardize the 1,700-year-old fecal microbiota transplantation? Am J Gastroenterol 107(1755):1755–1756 Zhang YJ, Li S, Gan RY, Zhou T, Xu DP, Li HB (2015) Impacts of gut bacteria on human health and diseases. Int J Mol Sci 16:7493–7519 Zheng D, Liwinski T, Elinav E (2020) Interaction between microbiota and immunity in health and disease. Cell Res 30:492–506 Zhou K (2017) Strategies to promote abundance of Akkermansia muciniphila, an emerging probiotics in the gut, evidence from dietary intervention studies. J Funct Foods 33:194–201 Zuo T, Liu Q, Zhang F, Lui GC-Y, Tso EY, Yeoh YK, Chen Z, Boon SS, Chan FK, Chan PK (2021) Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19. Gut 70:276–284

Part II Microorganisms in Pathogenesis & Management of Autoimmune Liver Diseases

5

Microorganisms in Pathogenesis and Management of Autoimmune Hepatitis (AIH) Tanuj Upadhyay and Shvetank Bhatt

Abstract

Autoimmune hepatitis (AIH) is the inflammation of the liver that occurs when your body’s immune system turns against liver cells. AIH is more destructive as compared to hepatitis following automatic damage to the parenchyma cells of the liver. After observing many immunopathogenic studies, some potential pathogens are identified, but the etiology of the disease is still not very clear. AIH occurs due to abnormality in genes and also triggered by the introduction of viruses. Both the factors lead to activation of the T lymphocytes against the patient’s own liver cells. Some risk factors, such as specific human leukocyte antigen (HLA) haplotypes, improve AIH susceptibility or impact the pathogenicity of the AIH. Inadequate regulatory immune control that causes loss of tolerance is allowable for this immune response. In addition, environment, exercise, and nutrition are also responsible for triggers of AIH such as exposure to daylight, healthy diet, micro, etc. Increased serum transaminase and immunoglobulin G levels, as well as the presence of autoantibodies and interface hepatitis on liver histology, are used to diagnose AIH. Immunosuppressive therapy is to be followed up soon after diagnosis. Standard treatments begin with primary large doses of corticosteroids (prednisone or prednisolone), which are step by step decreasing as azathioprine is added. The drugs mentioned have shown quite good efficacy results. Inclusion of good response in disease in the majority of individuals enhances their chance of survival.

T. Upadhyay · S. Bhatt (*) Amity Institute of Pharmacy, Amity University Madhya Pradesh (AUMP), Gwalior, India # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_5

93

94

T. Upadhyay and S. Bhatt

Keywords

Immunopathogenic · T lymphocytes · Immunoglobulin · Immunosuppressive · Autoantibodies · Autoimmune hepatitis (AIH)

5.1

Introduction

Autoimmune hepatitis (AIH) is an emergent disease that affects the hepatic cells in the liver accompanying by chronic inflammation, fibrosis, and jaundice. The first case was reported in 1950 by a Swedish physician named Jan Waldenstrom who discovered a young girl with hypergammaglobulinemia followed by chronic hepatitis (Mackay 2008). Overall, about 20% of individuals with AIH have a significant rate of acute liver failure (ALF). The diagnosis of AIH is clinicopathological and is based on a combination of biochemical, immunological, and histological features and exclusion of other causes of hepatic disease. Females are more severely affected as compared to male (female to male ratio: 3.6:1). Moreover, it influences infants and adults of all age groups (Manns et al. 2010a) AIH is characterized by increased transaminase, serum immunoglobulin G (IgG) levels, and infiltration of plasma cell in liver histology. In addition, autoantibodies such as smooth muscle antibodies (SMA) and antinuclear antibodies (ANA) are also detected in the serum. There is indeed a high prevalence rate in females (80%) and often present with other autoimmune conditions, especially thyroid (Hashimoto’s or Graves’ disease) and rheumatoid arthritis in female patients, who are first cousins. There are no phenotypic characters of AIH pathognomonic, but the histology of the past is that interface hepatitis with dense, largely lymphocytic, inflammatory infiltrate spread from the portal path into an environment with fragmentary necrosis in the absence of further traits (like damage to a bile duct) suggested by periportal hepatocytes (Johnson and McFarlane 1993). AIH is primarily treated with corticosteroids alone or in combination with azathioprine and this leads to increase the life expectancy of the patients (Baumann and Schlue 1980). Prior to the detection of the hepatitis C virus (HCV), the key studies demonstrating this treatment technique could not be excluded. A standard AIH therapy is recommended by the European Association for the Study of the Liver (EASL) for the medication of prednisone along with azathioprine. The next-generation glucocorticoid budesonide could be used as an alternative treatment approach to nonrespondents of the standard medication. However, budesonide treatment should be taken carefully as it has shown less efficacy in the first pass liver, and removing budesonide may lead to undesirable causes in cirrhosis or perihepatic shunting patients (Baumann and Schlue 1980). Standardization of the serum transaminase and immunoglobulin levels as an endpoint for AIH medication and for the definition of total remission is commonly accepted (Czaja and Manns 2010a, b, 2015). Animal models are of major value in order to understand the pathogenic pathways of AIH. Our increased demands of the cellular and molecular-based AIH would allow us in the future to regulate the condition left out significant harmful consequences. Further treatments will hopefully replace

5

Microorganisms in Pathogenesis and Management of Autoimmune Hepatitis (AIH)

95

nonspecific antidepressant drugs, which have significant detrimental effects, especially with long-term usage, despite their efficacy on treatment results. Moreover, it is necessary to define the relevant therapy targets and build appropriate treatment clinics for patients who are not responding to the standard of care or do not tolerate it. The epidemiological, pathogenic, and diagnostic features of AIH in the adult form and juvenile form, involving future researches and management, as well as the overall quality of life perspectives, are explained here (Manns et al. 2015).

5.2

Epidemiology

In all ages and ethnic groups in white and dark Asiatic or indigenous Americans, the AIH happens internationally in all ages groups (Mieli-Vergani and Vergani 2014). Due to the lack of population-based statistics, accurate numbers for the prevalence of AIH are practically hard to collect. Incidence statistics are heavily influenced by means of verification and difficulty over the decades in definitions, involves the lack of histological verification techniques and grading systems. Past numbers might indicate a nonalcoholic fatty liver disease and/or the associated chronic viral hepatitis. In addition, AIH is classified under 2 subtypes type 1 commonly existing histories of patients were found with rheumatoid arthritis or ulcerative colitis, inflammation of the liver which may lead to liver cirrhosis (Gregorio et al. 1997; Maggiore et al. 1993), and type 2 includes antiliver–kidney microsomes and antiliver cytosol bodies. The prevalence of AIH-2 is significantly greater in children and the corticosteroids are the first-line treatment (Maggiore et al. 1986). The prevalence of AIH-1 was estimated as A and interleukin-6 -174 G>C promoter polymorphisms and pemphigus. Hum Immunol 73:560–565 Mustafa MB, Porter SR, Smoller BR et al (2015) Oral mucosal manifestations of autoimmune skin diseases. Autoimmun Rev 14:930–951 Mustafi S, Sinha R, Hore S et al (2019) Pulse therapy: opening new vistas in treatment of pemphigus. J Fam Med Prim Care 8:793 Nguyen VT, Ndoye A, Grando SA (2000) Pemphigus vulgaris antibody identifies pemphaxin: a novel keratinocyte annexin-like molecule binding acetylcholine. J Biol Chem 275:29466– 29476 Ohki M, Kikuchi S (2017) Nasal, oral, and pharyngolaryngeal manifestations of pemphigus vulgaris: endoscopic ororhinolaryngologic examination. Ear Nose Throat J 96:120–127 Oliveira-Batista DP, Janini MER, Fernandes NC et al (2013) Laboratory diagnosis of herpesvirus infections in patients with pemphigus vulgaris lesions. Intervirology 56:231–236 O'Neill CA, Monteleone G, McLaughlin JT (2016) The gut-skin axis in health and disease: a paradigm with therapeutic implications. BioEssays 38:1167–1176 Ormond M, McParland H, Donaldson ANA et al (2018) An oral disease severity score validated for use in oral pemphigus vulgaris. Br J Dermatol 179:872–881 Paster BJ, Olsen I, Aas JA et al (2006) The breadth of bacterial diversity in the human periodontal pocket and other oral sites. Periodontol 2000 42:80–87 Pile HD, Yarrarapu SNS, Crane JS (2021) Drug induced pemphigus. Eur Handb Dermatologic Treat Third Ed 29:725–730 Pisanti S, Sharav Y, Kaufman E et al (1974) Pemphigus vulgaris: incidence in Jews of different ethnic groups, according to age, sex, and initial lesion. Oral Surg Oral Med Oral Pathol 38:382– 387 Porro AM, Caetano Lde V, Maehara Lde S et al (2014) Non-classical forms of pemphigus: pemphigus herpetiformis, IgA pemphigus, paraneoplastic pemphigus and IgG/IgA pemphigus. An Bras Dermatol 89:96–106 Porro AM, Seque CA, Ferreira MCC et al (2019) Pemphigus vulgaris. An Bras Dermatol 94:264– 278 Pozhitkov AE, Beikler T, Flemmig T et al (2011) High-throughput methods for analysis of the human oral microbiome. Periodontol 2000 55:70–86 Prüßmann W, Prüßmann J, Koga H et al (2015) Prevalence of pemphigus and pemphigoid autoantibodies in the general population. Orphanet J Rare Dis 10:63 Rahbar Z, Daneshpazhooh M, Mirshams-Shahshahani M et al (2014) Pemphigus disease activity measurements: pemphigus disease area index, autoimmune bullous skin disorder intensity score, and pemphigus vulgaris activity score. JAMA Dermatol 150:266–272 Rogers GB, Carroll MP, Serisier DJ et al (2006) Use of 16S rRNA gene profiling by terminal restriction fragment length polymorphism analysis to compare bacterial communities in sputum and mouthwash samples from patients with cystic fibrosis. J Clin Microbiol 44:2601–2604 Rosenthal M, Goldberg D, Aiello A et al (2011) Skin microbiota: microbial community structure and its potential association with health and disease. Infect Genet Evol 11:839–848 Ruocco V, Pisani M (1982) Induced pemphigus. Arch Dermatol Res 274:123–140

288

M. Zorba et al.

Ruocco, Pisani M, de Angelis E et al (1990) Biochemical acantholysis provoked by thiol drugs. Arch Dermatol 126:965–966 Ruocco V, de Angelis E, Lombardi ML (1993) Drug-induced pemphigus. II. Pathomechanisms and experimental investigations. Clin Dermatol 11:507–513 Ruocco V, Ruocco E, Lo Schiavo A et al (2013) Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies. Clin Dermatol 31:374–381 Salathiel AM, Brochado MJF, Kim O et al (2016) Family study of monozygotic twins affected by pemphigus vulgaris. Hum Immunol 77:600–604 Sardana K, Garg VK, Agarwal P (2013) Is there an emergent need to modify the desmoglein compensation theory in pemphigus on the basis of Dsg ELISA data and alternative pathogenic mechanisms? Br J Dermatol 168:669–674 Sarig O, Bercovici S, Zoller L et al (2012) Population-specific association between a polymorphic variant in ST18, encoding a pro-apoptotic molecule, and pemphigus vulgaris. J Invest Dermatol 132:1798–1805 Scaglione GL, Fania L, De Paolis E et al (2020) Evaluation of cutaneous, oral and intestinal microbiota in patients affected by pemphigus and bullous pemphigoid: a pilot study. Exp Mol Pathol 112:104331 Schiff E, Pick N, Oliven A et al (2003) Multiple liver abscesses after dental treatment. J Clin Gastroenterol 36:369–371 Schmidt E, Zillikens D (2010) Modern diagnosis of autoimmune blistering skin diseases. Autoimmun Rev 10:84–89 Schmidt E, Dahnrich C, Rosemann A et al (2010) Novel ELISA systems for antibodies to desmoglein 1 and 3: correlation of disease activity with serum autoantibody levels in individual pemphigus patients. Exp Dermatol 19:458–463 Scully C, Challacombe SJ (2002) Pemphigus vulgaris: update on etiopathogenesis, oral manifestations, and management. Crit Rev Oral Biol Med 13(5):397–408. https://doi.org/10. 1177/154411130201300504 Seerangaiyan K, Van Winkelhoff AJ, Harmsen HJM et al (2017) The tongue microbiome in healthy subjects and patients with intra-oral halitosis. J Breath Res 11:036010 Seerangaiyan K, Jüch F, Winkel EG (2018) Tongue coating: its characteristics and role in intra-oral halitosis and general health-a review. J Breath Res 12:034001 Seiffert-Sinha K, Khan S, Attwood K et al (2018) Anti-thyroid peroxidase reactivity is heightened in pemphigus vulgaris and is driven by human leukocyte antigen status and the absence of desmoglein reactivity. Front Immunol 9:625 Sender R, Fuchs S, Milo R (2016) Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 14:e1002533 Shahidi Dadras M, Qeisari M, Givrad S (2009) Pemphigus vulgaris manifesting as a sole persistent lesion on the lower lip: a case report. Dermatol Online J 15:7 Shimizu J, Kubota T, Takada E et al (2016) Bifidobacteria abundance-featured gut microbiota compositional change in patients with Behcet’s disease. PLoS One 11:e0153746 Shreiner AB, Kao J, Young VB (2015) The gut microbiome in health and in disease. Curr Opin Gastroenterol 31:69–75 Sinha AA (2011) The genetics of pemphigus. Dermatol Clin 29:381–391 Spindler V, Heupel WM, Efthymiadis A et al (2009) Desmocollin 3-mediated binding is crucial for keratinocyte cohesion and is impaired in pemphigus. J Biol Chem 284:30556–30564 Stahringer SS, Clemente JC, Corley RP et al (2012) Nurture trumps nature in a longitudinal survey of salivary bacterial communities in twins from early adolescence to early adulthood. Genome Res 22:2146–2152 Sugihara K, Kamada N (2021) Diet-microbiota interactions in inflammatory bowel disease. Nutrients 13:1533 Sukanjanapong S, Thongtan D, Kanokrungsee S et al (2020) A comparison of azathioprine and mycophenolate Mofetil as adjuvant drugs in patients with pemphigus: a retrospective cohort study. Dermatol Ther (Heidelb) 10:179–189

12

Microorganisms in Pathogenesis and Management of Pemphigus Vulgaris

289

Tamgadge S, Bhatt D, Pereira T et al (2011) Pemphigus vulgaris. Dent 2:134 Tirado-Sánchez A, León-Dorantes G (2006) Treatment of pemphigus vulgaris. An overview in Mexico. Allergol Immunopathol (Madr) 34:10–16 Torzecka JD, Wozniak K, Kowalewski C et al (2007) Circulating pemphigus autoantibodies in healthy relatives of pemphigus patients: coincidental phenomenon with a risk of disease development? Arch Dermatol Res 299:239–243 Tyler Patterson T, Grandhi R (2020) Gut microbiota and neurologic diseases and injuries. Adv Exp Med Biol 1238:73–91 Ursell LK, Metcalf JL, Parfrey LW et al (2012) Defining the human microbiome. Nutr Rev 70 (Suppl 1):S38–S44 Veloso DJ, Abrao F, Martins CHG et al (2020) Potential antibacterial and anti-halitosis activity of medicinal plants against oral bacteria. Arch Oral Biol 110:104585 Vodo D, Sarig O, Sprecher E (2018) The genetics of pemphigus vulgaris. Front Med 5:226 Wade WG (2013) The oral microbiome in health and disease. Pharmacol Res 69:137–143 Wantland WW, Wantland EM, Winquist DL (1963) Collection, identification, and cultivation of oral protozoa. J Dent Res 42:1234–1241 Warnakulasuriya S, Tilakaratne WM (2014) Oral medicine and pathology: a guide to diagnosis and management, 1st edn. JAYPEE Brothers Medical Publishers, New Delhi India, pp 346–351 Wolff K, Johnson RA, Roh EK (2017) Fitzpatrick’s color atlas and synopsis of clinical dermatology, 8th edn. McGraw-Hill Education, New York, pp 100–105 Wucherpfennig KW (2001) Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest 108:1097–1104 Zorba M, Melidou A, Patsatsi A et al (2020) The possible role of oral microbiome in autoimmunity. Int J Women’s Dermatol 6:357–364 Zorba, Melidou A, Patsatsi A et al (2021) The role of oral microbiome in pemphigus vulgaris. Arch Microbiol 203:2237–2247

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

13

Faith Ai Ping Zeng and Dedee F. Murrell

Abstract

Autoimmune blistering diseases (AIBD) are well accepted as a heterogeneous group of skin disease characterized by autoantibodies targeting adhesion molecules on the skin and/or mucous membranes. Among the AIBDs, bullous pemphigoid (BP) is the most common. The clinical manifestations of BP are protean and may vary from pruritus, urticarial plaques, and eczematous eruptions through to tense bullae on erythematous patches. Generally, it is recognized as a disease of the elderly and is defined by the presence of IgG and/or complement C3 against BP230 and BP180 which are structural components of hemidesmosomes. However, the exact mechanisms underlying the disease are complex and not entirely understood at present. High-dose systemic steroids are the mainstay of treatment but are associated with devastating steroid-induced side effects when used long term. The acknowledgment of these glucocorticoidrelated adverse events combined with the recent growing awareness of the relationship between cutaneous microbiota dysbiosis and autoimmune skin conditions has led to increased research on the potential benefits of live biotherapeutic products in their management. The therapeutic role of nutraceuticals in BP has yet to be elucidated, but its potential steroid-sparing benefit is worth exploring further.

F. A. P. Zeng Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia D. F. Murrell (*) Department of Dermatology, St George Hospital, Sydney, NSW, Australia University of New South Wales, Sydney, NSW, Australia The George Institute for Global Health, Sydney, NSW, Australia e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_13

291

292

F. A. P. Zeng and D. F. Murrell

Keywords

Bullous pemphigoid · Cutaneous microbiota · Gingivitis · Glucocorticoids · Immunosuppressant · Infections · Management · Oral cavity · Pathogenesis · Treatment

13.1

Introduction

The human skin is home to millions of bacteria, fungi, and viruses that comprise the cutaneous microbiota (CM)(Byrd et al. 2018). Microbiota refers to all the microorganisms that share our body space but colonize unique areas of the body such as the skin, oral cavity, nasal cavity, eyes, gastrointestinal, and genitourinary tract (Catinean et al. 2019). Moreover, the microbiome is defined as the collective genes of microbiota and is said to be 150 times larger than the human genome itself (Catinean et al. 2019; Adak and Khan 2019; Qin et al. 2010). As the skin is the human body’s largest and most exposed organ, the CM is critical as the first line of defense, serving as a physical barrier against the invasion of foreign pathogens (Belkaid and Segre 2014). In the healthy human body, there exists a balance between essential and opportunistic bacteria, while in pathological states, dysbiosis occurs (Catinean et al. 2019). In general, bacteria can cause autoimmune disease through different mechanisms, such as pathogen persistence, molecular mimicry, epitope spreading, toll-like receptor (TLR) activation, and many more (Nikitakis et al. 2017). Therefore, the disruption of this intricately balanced composition of beneficial and pathogenic cutaneous bacteria can lead to disturbances in the skin immune homeostasis (Bressa et al. 2017; Maeda and Takeda 2017). Autoimmune blistering skin diseases are a heterogeneous group of skin disease characterized and caused by autoantibodies targeting adhesion molecules on the skin and/or mucous membranes (Izumi et al. 2019). They can be further separated into two major groups depending on the clinical features and histological location of blister formation: intraepidermal blistering is characteristic of the pemphigus group while subepidermal blistering is the hallmark of the pemphigoid group (Alaibac 2019). Of the autoimmune bullous dermatoses, bullous pemphigoid (BP) is the most common with an increasing incidence over the past decade (Berkani et al. 2019; Ludwig et al. 2013). Classified as an autoimmune disease, BP is essentially caused by an inappropriate activation of the immune system against the BP180 and/or BP230 proteins in the skin and occasionally the mucous membranes. Therefore, if skin-resident microbes have the ability to modulate skin immune homeostasis, the CM could potentially play an important role in the mechanism behind BP (Vogelzang et al. 2018; Catinean et al. 2019). Although BP primarily affects the skin, it can occasionally present with mild oral mucosal lesions (Rashid et al. 2019). Thus, it may be worthwhile to consider the correlation between BP and the oral cavity microbiota as well. This chapter aims to explore the relationship between microbiota and BP, focusing on the pathogenesis and management of the disease. Due to limitations in

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

293

existing knowledge, the authors will discuss hypotheses and theories describing the relationship between BP and CM, present the most recent guidelines in the management of BP, and review the role of microorganisms in skin infections in BP. A better understanding of the aforementioned topics can help guide future developments in terms of targeted BP therapy.

13.2

Bullous Pemphigoid

13.2.1 Clinical Features BP typically affects the elderly population, often diagnosed in individuals above the age of 70 years (Joly et al. 2012; Jung et al. 1999). Although the exact underlying factors remain unclear, it is widely accepted that the clinical features of BP are protean and may mimic a variety of other chronic inflammatory dermatoses (Amber et al. 2018a). The wide spectrum of clinical presentations seen in BP is summarized in Table 13.1.

13.2.1.1 Cutaneous Pemphigoid The typical bullous presentation of BP comprises an intensely pruritic eruption with widespread tense blister formation (Di Zenzo et al. 2012; Daniel et al. 2011). The vesicles and bullae arise on apparently normal or erythematous skin together with urticarial and infiltrated papules and plaques or eczematous lesions (Schmidt et al. 2011). Prior to blistering, pruritus can occur as an early symptom with or without primary cutaneous lesions (Amber et al. 2018a). This observation is exemplified in a recent case series where BP was diagnosed (confirmed with immunopathological findings) in 15 anecdotal patients who presented with isolated pruritus (Bakker et al. Table 13.1 Clinical manifestations of bullous subtype and non-bullous subtype of cutaneous pemphigoid (left) and atypical variants of BP described in the literature (right); listed in alphabetical order (Amber et al. 2018a; Di Zenzo et al. 2012; Lamberts et al. 2018; Asbrink and Hovmark 1981; Borradori and Joly 2014; Castanet et al. 1990) Cutaneous pemphigoid Typical bullous clinical presentation

Tense blisters that arise on erythematous, urticarial plaques, accompanied by severe pruritus

Clinical manifestations in non-bullous variant Eczema Erythematous patches Excoriations Erythroderma Nodules Papules Urticarial plaques

Atypical variants of BP described in the literature Ecthyma gangrenosum-like BP Erythrodermic pemphigoid Lichen planus pemphigoides Localized presentations of BP (dyshidrosiform, hemiplegic, pretibial, radiation aggravated, stomal, stump, umbilical, vulvar) Pemphigoid gestationis Pemphigoid vegetans Purpuric BP Seborrheic pemphigoid Toxic epidermal necrolysis-like BP

294

F. A. P. Zeng and D. F. Murrell

2013). Moreover, blisters may either present concomitantly with the aforementioned cutaneous signs and symptoms or up to a few weeks or months after (Amber et al. 2018a). Of note, a prospective nationwide study carried out in Switzerland involving 160 BP patients revealed that up to 20% did not have obvious bullae at the time of diagnosis(Della Torre et al. 2012). Additionally, it is found in the literature that BP can unconventionally present with pruritus and various non-bullous findings on the skin such as erythematous patches, papules, urticarial plaques, nodules, excoriations, eczema, and erythroderma (Lamberts et al. 2018). These non-bullous skin lesions are described as prodromal symptoms that occur prior to bullous eruptions (Asbrink and Hovmark 1981; Amber et al. 2018a; Della Torre et al. 2012). The duration of these early symptoms varies according to type, where papular and/or urticarial types can last up to 6 weeks, and up to 2 years for eczematous-type eruptions (Asbrink and Hovmark 1981). Without obvious blistering, these non-bullous prodromal symptoms may represent the only manifestation of BP in the course of the disease for months or even years. This highlights how blister formation is not invariably a clinical manifestation of BP and has resulted in some field experts expressing the need to rename bullous pemphigoid. The term cutaneous pemphigoid has been proposed to encapsulate both bullous and non-bullous disease types (Borradori and Joly 2014; Lamberts et al. 2018; Amber et al. 2018a). Additionally, involvement of the oral cavity is observed in about 10–30% of patients with BP (Di Zenzo et al. 2012). This is illustrated in a European cohort multicenter prospective study which observed mucosal involvement, and almost invariably that of the oral cavity, in 8% of patients with newly diagnosed BP disease (Di Zenzo et al. 2008). The mucosae of the eyes, nose, pharynx, esophagus, and anogenital areas may be rarely affected (Di Zenzo et al. 2012). This is in contrast to mucous membrane pemphigoid which is predominantly an autoimmune blistering disorder of the subepidermal mucosa of the oral cavity, conjunctiva, anogenital tissues, and upper aerodigestive tract with sparing of the skin (Carey and Setterfield 2019).

13.2.1.2 Atypical Variants of BP Several atypical variants of BP have been described. Owing to the fact that a significant subset of patients possesses skin manifestations that are so distinctive and peculiar in terms of the extent, localization, or morphology of the lesions, that has resulted in the advent of various denominations to describe them (Castanet et al. 1990). However, it is controversial whether such unique subtyping for atypical presentations is justified and appropriate to describe the different facets of one same disease (Amber et al. 2018a). Lichen planus pemphigoides(LPP) describes the presence of concomitant lichen planus with BP. Lichen planus (LP) is a pruritic dermatosis of unclear etiology whose clinical phenotype, like BP, is polymorphic (Cohen et al. 2009). Bullous eruptions in LP were first described in 1982 by Kaposi, and since, two distinct forms of LP with bullae have been described – bullous lichen planus (BLP) and LPP (Kaposi 1892; Liakopoulou and Rallis 2017). BLP is characterized by vesicle or bullae which form on preexisting LP lesions caused by upper dermal inflammation

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

295

and liquefactive degeneration of the basal cell layer (Cohen et al. 2009; Liakopoulou and Rallis 2017). This is not to be confused with LPP where bullae affect the skin irrespective of LP lesions (Amber et al. 2018a; Cohen et al. 2009). Additionally, direct immunofluorescence (DIF) reveals subepidermal blistering with linear deposition of IgG and/or C3 along the dermal-epidermal junction in LPP histopathology, while indirect immunofluorescence (IIF) shows circulating autoantibodies against the basement membrane zone (BMZ) components – both of which are key in diagnosing BP and will be further discussed in later sections (Cohen et al. 2009). In both adults and children, there is a predilection of LPP bullae for the distal limbs in contrast to palmoplantar involvement which is more frequently seen in children (Cohen et al. 2009; Paige et al. 1993). A distinct subtype of LPP that is linked to the HLA-DR10 allele and habitation near the Senegal River has been described in Africans, with the development of a lichenoid erythrodermic presentation of BP (Joly et al. 1998). Erythrodermic pemphigoid has been elucidated as a rare subtype of BP from anecdotal evidence where biopsy of erythrodermic lesions in patients with erythroderma has immunohistological findings suggestive of BP (AlonsoLlamazares et al. 1998). Pemphigoid vegetans is a rare intertriginous variant of BP, first described in 1979 by Winkelmann and Su; it has a clinical resemblance to pemphigus vegetans but has histological and immunopathological features of BP (Winkelmann and Su 1979; Ueda et al. 1989; Kim et al. 2008). It is characterized by vegetative and purulent lesions at the groin, axillae, thighs, hands, eyelids, and perioral regions (Kim et al. 2008). Seborrheic pemphigoid is an exceptionally rare variant of BP, with only three cases described in the English literature (Castro-Fores et al. 2016; Errichetti et al. 2014; Tamaki et al. 1991). It clinically presents akin to pemphigus erythematosus with ruptured bullae, erosions, and crusts involving seborrheic areas (Amber et al. 2018a; Errichetti et al. 2014). In 2002, Cordel et al. described two unique and deviant clinical variations of BP, a toxic epidermal necrolysis-like and an ecthyma gangrenosum-like presentation (Cordel et al. 2002). These two cases were characterized by extensive erosive lesions without any blistering nor pruritic erythematous or urticarial lesions (Cordel et al. 2002). Even more recently, purpuric BP was described, where the patient had palmoplantar purpuric lesions concomitant to the typical blisters seen in BP (Marovt and El Shabrawi-Caelen 2015). Finally, several localized variants of BP have been well described in literature. Although these can eventually progress to more generalized disease, such localized clinical phenotypes are said to carry a better prognosis than those which initially present with widespread skin lesions (Amber et al. 2018a). Dyshidrosiform pemphigoid begins as pruritic, potentially hemorrhagic, or purpuric blisters on the palmoplantar regions, which is commonly followed by generalized bullous lesions (Cohen 2020). Stomal pemphigoid, as its name suggests, presents with BP limited to the area around the stoma – this form is said to follow a milder clinical course that is very responsive to glucocorticoid therapy (Batalla et al. 2011). Radiationaggravated pemphigoid is limited to the sites of radiotherapy and is particularly seen in women with breast cancer who have received radiation treatment, while

296

F. A. P. Zeng and D. F. Murrell

hemiplegic pemphigoid is confined to sites of neurological deficit (Nguyen et al. 2014; Mul et al. 2007; Tsuruta et al. 2012; Tay and Cheong 1993; Foureur et al. 2001). Similarly, stump pemphigoid, pretibial pemphigoid, and vulvar pemphigoid have been described in instances where the inflammatory BP lesions are confined to the respective named anatomical regions (Reilly et al. 1983; Brodell and Korman 1996; Muramatsu et al. 1991; Kakurai et al. 2007; Amber et al. 2018b; De Daruvar et al. 2020; Saad et al. 1992). Vulvar pemphigoid may mimic the clinical phenotype of genital lichen sclerosis (Farrell et al. 1999). Lastly, BP presenting with isolated umbilical involvement has been sparsely reported as umbilical pemphigoid, although this phenomenon is better described as an aspect of pemphigoid gestationis (PG). PG is a rare, specific dermatosis of pregnancy which is clinicopathologically similar to BP with peak occurrence in the third trimester (Fong et al. 2021).

13.2.2 Pathogenesis The pathogenesis of BP is complex, and while it is well established that autoantibodies against structural components of the BMZ underlie the pathophysiology of the disease, other ancillary mechanisms have yet to be elucidated (Schmidt et al. 2017). This section will cover key mechanisms and briefly mention most recent theories emerging from literature. BP is characterized by the presence of IgG and/or complement C3 against BP230 and BP180 which are structural components of hemidesmosomes (Berkani et al. 2019). The hemidesmosome is a multiprotein complex of the dermal-epidermal junction (DEJ), which serves to provide structural adhesion between basal keratinocytes and the dermal extracellular matrix (Genovese et al. 2019). BP180 is a transmembrane protein glycoprotein comprising an extracellular domain NC16A, which is the main antigenic epitope in BP (Miyamoto et al. 2019). Patients also develop IgG autoantibodies directed against other epitopes – notably, the C-terminal and intracellular epitopes are related to mucosal involvement in the early stages of the disease (Schmidt and Zillikens 2013). Binding of anti-NC16A autoantibodies to BP180 initiates several pathways, including complement activation and deposition, neutrophilic chemotaxis with the release of proteases, and elastases which disrupts the BMZ and causes blistering (Miyamoto et al. 2019). On the other hand, BP230 is a plakin protein which forms the intracellular component of the hemidesmosome – in BP disease, IgG autoantibodies target its globular C-terminal domains (Haeberle et al. 2018). Currently, there exists a wide array of clinical research outcomes indicating that anti-BP230 autoantibodies alone could contribute to the pathogenesis of BP, corroborated by its ability to disrupt assembly of hemidesmosomes in vivo (Shih et al. 2020). Additionally, patients with localized BP are shown to have high titers of anti-BP230 autoantibodies and low titers of anti-BP180 autoantibodies, suggesting that the response to BP230 maintains the immunological processes leading to the chronicity of the disease (Kohroh et al. 2007). However, the exact pathogenicity of anti-BP230 autoantibodies still remains unclear at present.

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

297

On top of complement-mediated mechanisms, there is increasing evidence emerging regarding complement-independent pathways in the pathogenesis of BP (Fig. 13.1) (Genovese et al. 2019). This is exemplified in the study carried out by Ujiie et al. which showed that passive transfer of BP autoantibodies in C3-deficient BP180-humanized mice resulted in blister formation via the ubiquitin/proteasome pathway (Ujiie et al. 2014). Furthermore, the presence of IgE autoantibodies in patients with urticarial lesions indirectly supports the hypothesis that activation of mast cells and basophil histamine release contributes to tissue damage, manifesting in certain distinct clinical features of BP (Yayli et al. 2011). Anti-BP180 IgG and IgE autoantibodies have been shown to induce the internalization of BP180 via pinocytic mechanisms (Hiroyasu et al. 2013; Messingham et al. 2011). Reactivity of the IgG autoantibodies to BP230 has also recently been shown to correlate with severity of the disease (Nakama et al. 2018). Mihai et al. demonstrated that IgG1 and IgG4 were the most common subtypes found along the DEJ – the former having a greater pathogenic potential to induce blistering via complement fixation, as compared to the latter which can only cause dermal-epidermal separation via activation of leukocytes (Mihai et al. 2007).

13.2.3 Treatment Outline This section discusses the treatment recommendations for the most common presentations of BP and is not intended to cover exhaustively all unique variants of BP due to their abundance and rarity. For completeness, this section also includes the initial evaluation and diagnosis of BP. The initial evaluation should entail a thorough physical examination as well as a patient history to search out features consistent with the diagnosis of BP and to assess the patient’s general condition and potential comorbidities (Table 13.2) (Feliciani et al. 2015). The BP Disease Area Index (BPDAI) was developed in 2012 to provide an objective measure of BP activity (Fig. 13.2) (Murrell et al. 2012; Masmoudi et al. 2021). The newer BPDAI is chosen over the traditional Autoimmune Blistering Skin Disorder Intensity Score (ABSIS) as the former is not only a collaborative effort by an international panel of experts but also takes into account items specific to BP (Masmoudi et al. 2021). The BDPAI is a score ranging from 0 to 360 points, with a higher score indicating greater severity. It was recently validated in a large-scale international study involving 285 patients with BP, where it was proposed that a cutoff BPDAI score of 20 differentiates mild and moderate BP and a score of 57 distinguishes moderate and severe BP (Masmoudi et al. 2021). The most critical test in the diagnosis of BP is a positive result from DIF microscopy (Di Zenzo et al. 2012; Schmidt and Zillikens 2013; Venning et al. 2012; Pohla-Gubo and Hintner 2011; Joly et al. 2004). The biopsy sample should be obtained from perilesional skin (blistered skin to be avoided), placed into either a cryotube in liquid nitrogen, Michel’s fixative or simply 0.9% NaCl solution for transportation (Feliciani et al.

Fig. 13.1 Summary of biochemical pathways in the pathogenesis of bullous pemphigoid. Reproduced with permission Genovese et al. (2019)

298 F. A. P. Zeng and D. F. Murrell

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

299

Table 13.2 Initial clinical evaluation of patient to guide diagnosis of bullous pemphigoid Clinical examination Patient’s history Date of onset Evaluation of signs and symptoms Recent drug intake (over 1–6 months) Refractory itch of unknown cause in elderly patients

Physical examinationa Classical bullous form: Symmetrical distribution of vesicles and bullae over erythematous and nonerythematous skin (flexural surfaces of the limbs, inner thighs, trunk) Rare oral mucosal involvement No atrophic scarring No Nikolsky sign Nonbullous and atypical forms: Excoriations, prurigo, prurigo nodularis-like lesions Localized bullae, erosions, eczematous and urticarial lesions, dyshidrosiform (acral)

Patient’s assessment Extension of BP: by Bullous Pemphigoid Disease Area Index (BPDAI) or daily blister count General condition and comorbidities Laboratory examinations and workup according to the patient’s condition and therapy choice

The following clinical features are diagnostically useful: (1) age >70 years; (2) absence of atrophic scars; (3) absence of mucosal involvement; and (4) absence of predominant bullous lesions on the neck and head Reproduced with permission Feliciani et al. (2015)

a

2015). A positive DIF would demonstrate linear deposits of IgG and/or C3 along the dermo-epidermal junction while occasionally showing IgA and IgE with a similar pattern (Pohla-Gubo and Hintner 2011; Joly et al. 2004). Systemic glucocorticoids (GCs) such as prednisone have been considered the mainstay of treatment for BP in the last five decades, although this has been based on extensive clinical experience due to lack of formal clinical trials in the past (Fontaine et al. 2003). Past literature usually recommends steroid dosages of 0.75–1 mg/kg body weight per day of prednisone equivalent (Yancey and Egan 2000). However, the potential for long-term systemic GCs to cause severe adverse events including mortality has been increasingly acknowledged by experts in the last 20 years. A Cochrane review carried out by Kirtschig et al. on 10 randomized controlled trials (a total of 1049 participants) concluded that starting doses of prednisolone greater than 0.75 mg/kg/day do not confer additional benefit, and lower dosages may be adequate to control the disease and reduce the incidence and severity of GC adverse events (GCAEs) (Kirtschig et al. 2010). Adjuvant therapy with steroid-sparing effects has thus been considered in combination with systemic GCs to reduce the burden of GCAEs. These steroid-sparing agents include azathioprine (AZA), cyclophosphamide (CTX), cyclosporin (CsA), dapsone, methotrexate (MTX), mycophenolate mofetil (MMF), intravenous immunoglobulin (IVIg), tetracyclines combined with nicotinamide (TCN), and rituximab (RTX) (Meurer 2012). Table 13.3 illustrates the recommended step-up approach for the therapeutic management of BP. Detailed therapeutic regimen recommendations will be covered in a later section. Further external skincare measures include the use of baths containing

300

F. A. P. Zeng and D. F. Murrell

Fig. 13.2 Bullous Pemphigoid Disease Area Index (BPDAI). Reproduced with permission Murrell et al. (2012)

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

301

Table 13.3 Recommended therapeutic ladder for management of bullous pemphigoid Therapeutic ladder for bullous pemphigoid Localized/limited disease with mild activity First choice Superpotent topical corticosteroids; in mild disease, on whole body except the face (1, validated) In localized disease, on lesions only (3, nonvalidated) Second choice Oral corticosteroids (1, validated for prednisone) Tetracycline + nicotinamide (2, nonvalidated) Dapsone, sulfonamides (3, nonvalidated) Topical immunomodulators (e.g., tacrolimus) (4, nonvalidated) Generalized disease First choice, primary treatment Superpotent topical corticosteroids on whole body sparing the face (1, validated) Oral corticosteroids (1, validated for prednisone) Second choice, as adjunctive therapy Combination with or introduction of: Azathioprine (1, nonvalidated) Mycophenolate (1, nonvalidated) Tetracycline + nicotinamide (2, nonvalidated) Methotrexate (3, nonvalidated) Chlorambucil (3, nonvalidated) Third choice Combination with and/or introduction of: Anti-CD20 or anti-IgE monoclonal antibody (4, nonvalidated) Intravenous immunoglobulins (3, nonvalidated) Immunoadsorption (4, nonvalidated) Plasma exchange (1, nonvalidated) Cyclophosphamide (3, nonvalidated) Level 1: randomized prospective single-center or multicenter studies. In the case of the latter, the intervention is shown to be effective and not contradicted by other studies – its use is considered validated. Level 2: randomized prospective single-center studies (in case of poor methodological quality), retrospective multicentre studies. Level 3: case series, retrospective single-center studies. Level 4: anecdotal case reports. Level 5: expert opinion Reproduced with permission Feliciani et al. (2015)

antiseptics and/or wheat starch, as well as nonadherent bandages for extensive erosive lesions to reduce the risk of bacterial superinfection and pain while promoting healing (Feliciani et al. 2015).

13.3

Microbiome of the Skin

The skin microbiota is made of two groups – the resident microorganisms and the transient microorganisms (Dreno et al. 2016). The resident microorganisms, otherwise known as the core microbiota, are a fixed group of microbes that are routinely found in the skin and reestablish themselves after perturbation. The core microbiota is said to be commensal, which implies that they are harmless and likely to be

302

F. A. P. Zeng and D. F. Murrell

beneficial to the host under physiological conditions (Kong and Segre 2012). On the other hand, the transient microorganisms come from the environment and usually only persist for hours to days on the skin, before being eradicated (Kong and Segre 2012). Under normal conditions, where proper hygiene is maintained and if the normal resident flora, immune responses, and the skin barrier are intact, the resident and transient groups of microbes are not pathogenic (Cogen et al. 2008). Both intrinsic and extrinsic factors have profound effects on the skin microbial communities – intrinsic factors include age, genetic makeup, and immune reactivity while examples of extrinsic factors are hygiene and climate (Kong and Segre 2012; Grice et al. 2009). Furthermore, the skin is said to host is better than inhabit the greatest diversity of bacterial colonies among all epithelial surfaces (Sanford and Gallo 2013), where its composition and abundance vary considerably across individuals, and over time, leading to an extremely dynamic and fluctuating microbiota (Grice et al. 2008). Genomic approaches to characterize skin bacteria have revealed four main phyla: Actinobacteria, Firmicutes, Proteobacteria, and Bacteroides and that the three most common genera are Corynebacterium, Propionibacterium, and Staphylococcus (Grice et al. 2009). Macroscopically, the skin is a complex landscape comprising abundant invaginations, pockets, and niches. It has been demonstrated that each anatomical niche provides a unique microenvironment which determines the distinct proportions of the bacterial phyla (Grice et al. 2009; Gao et al. 2007; Costello et al. 2009). Furthermore, the human skin can be further classified into three skin site types: moist, dry, and sebaceous (Fig. 13.3) (Grice et al. 2009; Grice and Segre 2011). Propionibacterium spp. are the dominant organisms in sebaceous areas like the alar crease, retro-auricular crease, and the back, while the Corynebacterium and Staphylococcus spp. are the most abundant microbes colonizing the moist regions such as the axilla, antecubital fossa, and inguinal fold (Kong and Segre 2012). Finally, dry areas such as the gluteal region are found to be the most diverse skin site having a mixed representation of all four phyla (Zeeuwen et al. 2013). Additionally, the microbiota of these dry areas possess the striking feature of having an abundance of gram-negative organisms, which were previously thought to colonize the skin only rarely, as contaminants from the gut (Kong and Segre 2012). Microscopically, within each skin site type are more distinct habitats such as eccrine and apocrine glands, sebaceous glands, and hair follicles (James et al. 2013). Furthermore, Nakatsuji et al. recently showed that the CM extends to subepidermal compartments, where it was previously unknown that routine physical interaction between commensal bacteria and dermal cells exists in adult skin (Nakatsuji et al. 2013). Interestingly, this relationship is also present between the deep dermal stroma and the superficial adipose tissue which is an area traditionally thought to be devoid of microbial community in the absence of skin injury (Nakatsuji et al. 2013). However, as the methods used were unable to distinguish between viable and dead cells, the study simply proves that commensal bacteria exist in the dermal layer which could have just been a result of microbiota translocating from the superficial layers or appendage structures into the subepidermal compartments via

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

303

Fig. 13.3 Topographical distribution of bacteria on anatomical skin sites of the human body. The family-level classification of bacteria colonizing an individual subject is shown, with the phyla in bold. The sites selected were those that show a predilection for skin bacterial infections and are grouped as sebaceous or oily (blue circles), moist (typically skin creases) (green circles), and dry, flat surfaces (red circles). Reproduced with permissionGrice and Segre (2011)

304

F. A. P. Zeng and D. F. Murrell

phagocytosis. Further studies are required to understand the mechanisms by which the skin permits the permeation of commensal bacteria across the epidermal barrier. It was not until recently that viruses have been actively studied as part of the CM. Interest in the human virome and commensal cutaneous viruses was piqued when anelloviruses and hepatitis G virus were first identified in the skin (Delwart 2007). This curiosity was also propelled by the demonstration of asymptomatic carriage of beta and gamma-human papillomaviruses on healthy skin of most individuals (Antonsson et al. 2003; Chen et al. 2008). Foulongne et al. reported that eukaryotic DNA viruses detected on normal skin samples displayed high diversity with various representatives of Papillomaviridae, Polyomaviridae, and Circoviridae (Foulongne et al. 2012). The physiological importance of viral microbiota has not yet been elucidated but has been hypothesized to encompass a combination of functions such as a direct antibacterial or antifungal action or an indirect protection against other, more aggressive virus through the competition mechanisms which are analogous to the skin bacterial microbiota (Foulongne et al. 2012). A small study found that the predominant fungus detected by using phylogenetic markers like 18S rRNA belongs to the species Malassezia including the most frequent isolates M. globosa, M. restricta, and M. sympodialis (Gioti et al. 2013). Malassezia spp. are lipophilic microbes that are frequently associated with the sebaceous areas of the skin – they are unable to produce their own nutrients and thus exploit the lipid-rich sebum for growth (Xu et al. 2007; Lunjani et al. 2019). The human skin is colonized by microorganisms from as early as birth, where the initial flora is low in diversity and resembles that of the delivery site – vaginal delivery will result in vaginal flora colonizing the fetal skin, while cesarean section infants harbored bacterial communities similar to that of cutaneous flora (Dominguez-Bello et al. 2010; Capone et al. 2011). Recently, Scharschmidt et al. showed that such microbial colonization of the skin in neonatal mice, but not of their adult counterparts, results in commensal-specific T-cell tolerance (Scharschmidt et al. 2015). The neonatal mice showed antigen-specific tolerance characterized by enrichment of commensal-specific activated regulatory T cells in the skin and skindraining lymph nodes, reduced commensal-specific CD4+effector T cells, and diminished inflammation (Scharschmidt et al. 2015). Finally, it was suggested that maintaining a healthy microbe-host immune dialogue in the skin has implications for both systemic and tissue-specific immune homeostasis which was based on the study findings that even across the intact skin, commensal-specific T cells are found both locally and systemically (Scharschmidt et al. 2015). It is critical to recognize the neonatal period as a defined developmental window for establishing tolerance to cutaneous commensal bacteria. This can help guide further research into how altering the composition of neonatal skin commensal microbiota could prevent the development of tolerance to a variety of antigens that could potentially lead to chronic cutaneous inflammation. Along with aging, changes in both the skin structure and cutaneous immune function occur. Physically, the epidermal layer becomes thinner due to keratinocyte atrophy which enhances the loss of trans-epidermal water, and finally causing increased skin dryness (Waller and Maibach 2005; Wilhelm et al. 1991). As time

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

305

passes, the skin also loses tensile strength and elasticity due to decreased total amount of collagen and increased elastin fragmentation, respectively (Shuster et al. 1975; Le Page et al. 2019). Dermal fibroblasts contribute to age-related dermal thinning as they undergo atrophy and consequently produce less procollagen while also having an increased expression of matrix metalloproteinase-1 which enhances collagen fragmentation (Fisher et al. 2016; Xia et al. 2015; Salzer et al. 2018). The physical weakening of the skin with aging may play a role in BP which otherwise known to be a disease of the elderly. Immunologically, cutaneous innate immunity decreases with age (Chambers and Vukmanovic-Stejic 2020). A variety of bacterial infections occurs more frequently in the older population, including cellulitis (especially in the lower limbs), erysipelas, folliculitis with or without furunculosis, impetigo, and necrotizing fasciitis (NF) (Castro and Ramos 2018). Staphylococcus aureus and β-hemolytic Streptococci are the most common pathogens in the elderly, noting that incidences of bacterial infections caused by Pseudomonas spp. and Klebsiella spp. are also increased (Laube 2004). Streptococcus spp. is commonly found in healthy CM and plays a functional role in maintaining skin health (Barnard and Li 2017). However, its increased abundance in the older population may cause them to be more susceptible to pathogenic invasions and resulting in greater incidence of skin disease (Stulberg et al. 2002). Similarly, there is a 25% greater prevalence of skin colonization by Proteus mirabilis and Pseudomonas aeruginosa as compared to younger individuals, contributing to an increased occurrence of skin disease in those over the age of 65 (Laube 2004). Finally, fungal infections like candidiasis and viral infections such as shingles, herpes simplex virus-1, and human papillomavirus are also more commonly seen in the elderly (Wessman et al. 2018).

13.4

Oral Microbiota, Gingivitis, and Bullous Pemphigoid

Similar to the skin, the oral microbiome is highly individualized and unique to each person. It is a complicated ecological environment with up to 750 types of microorganisms recognized: prevailing microbial populations of the mouth include Veillonella, Actinomyces, Streptococcus, and Neisseria (Wade 2013; Mosaddad et al. 2019). The oral cavity can be separated into hard faces of the teeth and soft tissues of the oral mucosa – they each have a characteristic composition of resident bacteria and are thus associated with different oral diseases (Mosaddad et al. 2019). Therefore, infections of the mouth can be classified into two broad categories: endodontic infections and periodontal disease. This section will focus on gingivitis, the mildest type of polymicrobial inflammation of the periodontium, and its association with BP. One of the earliest investigations found that clinical inflammation of the gingiva is associated with increased abundance in gram-negative morphotypes including rods, filaments, and spirochaetes after 2–3 weeks of undisturbed subgingival plaque accumulation (Theilade et al. 1966). These early findings have in recent times been supported by studies using 16S sRNA gene sequencing along with the same experimental plaque accumulation model to characterize gingivitis-associated shifts in

306

F. A. P. Zeng and D. F. Murrell

periodontal microbiota composition (Huang et al. 2014; Suthanthiran et al. 2013). Such gene sequencing studies have shown that the development of gingivitis occurs concomitantly with an increased bacterial biomass and associated depletion of species such as Rothia dentocariosa and enrichment of gram-negatives, notably Prevotella spp., Selenomonas spp., and Fusobacterium nucleatum ss. polymorphum, among others (Curtis et al. 2020). Involvement of the mucous membrane is considered an atypical physical manifestation of BP as per the French Bullous Study Group clinical criteria for diagnosis of BP established by Vaillant et al., which yields a positive predictive value of 95% for a clinical diagnosis of BP (Vaillant et al. 1998). Furthermore, mucosal lesions in BP are almost exclusively found in the oral mucosa which may be observed in up to 20% of patients (Della Torre et al. 2012; Schmidt et al. 2012; Clape et al. 2018). Mucosal involvement in BP is associated with extensive cutaneous disease, lower peripheral eosinophilia, and higher cumulative dosage of systemic GCs (Kridin and Bergman 2019). However, more aggressive GC treatment is associated with increased severity of steroid-induced side effects, which results in an increased risk of treatment-related mortality. Mucous membrane pemphigoid (MMP) is a variant of pemphigoid that is immuno-histologically similar to BP but predominantly affects the mouth, where the gingiva is affected in almost 90% of patients (Williams 1990). Due to the greater abundance of literature describing gingivitis in MMP, MMP will be used as a surrogate for BP in this section. Scully et al. recognized desquamative gingivitis (DG) as the main oral feature in MMP, noting that DG is a relatively common clinical feature of other diseases such as lichen planus, pemphigus vulgaris, and lupus erythematosus (Scully et al. 1999). DG is characterized by sloughing of epithelial surfaces, erythema, and pain that may be exacerbated by consumption of acidic foods (Tricamo et al. 2006). A small cohort, observational study of 20 patients with MMP diagnosis confirmed with clinical examination and histological evidence concluded that periodontal destruction is a function of time and duration where DG progressively worsens over the course of the disease (Tricamo et al. 2006). Additionally, it was found that enrollment in a periodontal maintenance program was effective in improving gingival inflammation, slowing the loss of periodontal supporting structures (Tricamo et al. 2006). This finding is corroborated by a recent systematic review of eight cohort studies and a randomized controlled trial which concluded that performing daily dental hygiene and professional prophylaxis, at least with supragingival scaling and polishing, significantly reduces DG and gingival bleeding in patients with oral lichen planus, MMP, plasma cell gingivitis, or pemphigus vulgaris (Garcia-Pola et al. 2019). Therefore, all patients with DG should have a thorough inspection of the oral cavity where the clinician conscientiously observes for accumulation of dental plaque, signs of gingival retraction, evidence of dental root exposure, and tooth loss; further evaluation and advice on dental hygiene should be supplemented by a dental professional (Maderal et al. 2018). All mucosal surfaces should be inspected for the presence of microbial colonization, including evaluation for the characteristic white plaques that can be easily scraped off in oral candidiasis, painful punched-out ulcers as seen in herpes simplex virus infection, or honey-colored crusts associated with impetigo. Finally, an antiseptic protocol with

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

307

antifungal prophylaxis is recommended in patients using local immunosuppressive treatment for their oral lesions. This can be done with twice-daily antiseptic mouth rinse containing hydrogen peroxide and daily use of antifungal troches (Maderal et al. 2018).

13.5

Bullous Pemphigoid and Skin Microbiome

When compared to the gut and stool, the skin microbiome is considerably less well studied where research and investigations pertaining to the skin microbiome and diseases have only recently taken flight in the last decade (Rosenthal et al. 2011; Gao et al. 2008; Zeeuwen et al. 2013). In contrast to the documented role of the gut commensals in the control of the development of gut-associated lymphoid structures, skin microbiota is not a requisite for the seeding of immune cells and overall organization of the tissue (Belkaid and Segre 2014). However, it is known that antimicrobial proteins (AMPs) are present in the keratinized regions of the mammalian epithelium, and their expression can be influenced by resident skin microbes (Belkaid and Segre 2014; Gallo and Hooper 2012). The crucial cutaneous AMPs are cathelicidins and human β-defensins (hBDs) (Gallo et al. 1994; Harder et al. 1997). The human cathelicidin antimicrobial peptide (CAMP) gene encodes the CAP18 precursor protein which can subsequently be cleaved to generate active AMPs, notably the 37-amino-acid peptide (LL37) and the murine peptide cathelin-related AMP (CRAMP) (Larrick et al. 1996; Gudmundsson et al. 1996; Gallo et al. 1997). CAP18 and CRAMP are abundantly expressed by resident mast cells of healthy skin, which are especially important for the defense against invasive bacterial infection in the skin, exemplified by an increased susceptibility to group A Streptococcus in CRAMP-deficient mice (Di Nardo et al. 2003; Nizet et al. 2001). Furthermore, LL37 is found directly on human skin keratinocytes with inflammation, suggesting that they function primarily in response to injury as opposed to modulating the skin microbiome (Frohm et al. 1997). Next, hBDs exert immunomodulatory and chemotactic functions where they have been reported to induce migration and proliferation of keratinocytes, promote wound closure, and improve the functional tight-junction barrier in keratinocytes (Niyonsaba et al. 2007; Frye et al. 2001; Hirsch et al. 2009; Kiatsurayanon et al. 2014). Although the exact mechanism is unclear, it is known that certain CM such as the Proprionibacterium spp. play a role in inducing various degrees of expression of these skin AMPs, illustrating a relationship between the skin microbial community and immunity (Belkaid and Segre 2014; Nagy et al. 2006; Lee et al. 2008). Toll-like receptor 3 (LTR3) is crucial for the detection of apoptosis and necrosis which is the hallmark of injury and subsequently to induce inflammation in the skin (Kono and Rock 2008). Lai et al. showed that staphylococcal lipoteichoic acid (LTA) of Staphylococcus epidermidis acts on toll-like receptor 2 (TLR2) on keratinocytes to activate the N-terminal fragment of TNF receptor-associated factor-1 (N-TRAF1) which serves as a negative regulatory factor to suppress TLR3 (Lai et al. 2009). However, in the presence of cells that are found in a sterile environment

308

F. A. P. Zeng and D. F. Murrell

and do not usually communicate with commensal Staphylococci such as macrophages, monocytes, and mast cells in the dermis, LTA acts as a proinflammatory factor (Timmerman et al. 1993; Yoshioka et al. 2007). Additionally, the structure of LTA appears to determine the nature of keratinocyte response, which is suggested by the fact that TLR2 ligands that form heterodimers with tolllike receptor 1 or toll-like receptor 6 have a proinflammatory effect in keratinocytes rather than inhibitory (Lai et al. 2009). This was later confirmed by Volz and colleagues who showed that Staphylococcus epidermidis LTA and Staphylococcus aureus LTA elicited opposing immune consequences where the latter enhanced the expression of proinflammatory molecules IL-6, IL-12p40, and IL-12p70 to a greater extent than the former – explaining the pathogenicity of Staphylococcus aureus to the human epidermis (Volz et al. 2018). In fact, Staphylococcus epidermidis actually amplifies the expression of hBDs to limit the growth of Staphylococcus aureus and also induces cutaneous IL-17 and IFN-γ responses needed for efficient pathogen control (Wanke et al. 2011; Naik et al. 2015). This further illustrates the crucial role that Staphylococcus epidermidis plays in priming keratinocytes to rapidly and effectively limit pathogen invasion. Despite its ability to enhance the innate barrier immunity of the skin, Staphylococcus epidermidis can also act as an opportunistic pathogen when it is allowed to invade the dermis (Otto 2009). Invasion of Staphylococcus epidermidis into the dermis is facilitated by any process which disrupts the skin barrier, evidenced by the presence of the significantly more abundant quantity of Staphylococcus epidermidis in the dermal compartment of lesional atopic dermatitis skin than nonatopic individuals (Nakatsuji et al. 2016). Since BP is characterized by dermal-epidermal disruption, the possibility of this being a mechanism for its pathogenesis has prompted further research recently. Alpha diversity is a measure of number (richness) and distribution (evenness) of taxa within a single population and is thus indicative of species diversity of the microbiota in the studied region. Drawing evidence from other well-studied autoimmune inflammatory conditions like inflammatory bowel disease, it has been hypothesized that there could be significant difference in alpha diversity of microbiota in perilesional (P) and non-lesional (N) skin of BP patients (Wright et al. 2015; Satokari 2015; Scher et al. 2015). This hypothesis was rejected in a study by Miodovnik et al. showing that both alpha diversity and phylogenetic distance between P and N sites or between P sites and any other sampled location were not statistically different (Miodovnik et al. 2017). The same study, however, showed that beta diversity – a representation of overlap or dissimilarities between multiple populations, was significantly different between BP patients and controls in P sites, and within patients between P and N sites (Miodovnik et al. 2017). There was an increased abundance of Firmicutes, especially of the Staphylococcus epidermidis species in P samples of BP patients, and a significant decrease in Actinobacteria abundance in the back, elbow, and P samples of BP patients compared to site-matched controls (Miodovnik et al. 2017). The difference in beta diversity between P and N sites in BP patients and controls suggests a distinct CM in each population, but this could theoretically be due to alternative reasons such as the presence of comorbidities or past medical therapies.

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

309

However, the difference in beta diversity between P and N sites within BP patients could imply that the change in skin microbiota is a direct result of the BP lesion. It is a plausible hypothesis that Staphylococcus epidermidis proliferation in the P regions occurs as an attempt to enhance the inhibition of inflammation, but the disrupted skin layers at the lesion counterproductively facilitates the invasion of Staphylococcus epidermidis instead, thereby worsening inflammation. To date, there has been no clear evidence on how dysbiosis may cause BP. Therefore, further research into this area would be insightful.

13.6

Before and After Treatment

Currently, there is limited literature found on the effects of potent topical corticosteroids (TCS) on the skin microbiome in AIBDs which leaves room for further research. This section will instead focus on the side effects of such topical steroids on the skin. Clobetasol-17-proprionate (Clobetasol) is an analogue of prednisone, and it is the most potent of the currently available topical GCs (Olsen and Cornell 1986; Pels et al. 2008). Clobetasol is the TCS of choice in BP. It was found that the peak absorption of 25 g of clobetasol is 5 and 15 h with the ointment formulation and 11 h for the cream formulation (Olsen and Cornell 1986). Skin atrophy is the most concerning local side effect arising from TCS use which is characterized by thinning of the skin, loss of elasticity, and skin marking, telangiectasia and purpura (Castela et al. 2012). Skin atrophy may therefore contribute to the weakening of the cutaneous epithelial barrier on top of the physiological consequence of aging along with the BP disease process itself. TCS can also cause systemic effects where the severity of these side effects is based on rate of systemic absorption, which varies according to duration and potency of the chosen steroid, location, and extent of skin lesions, as well as age (Castela et al. 2012; Bucks et al. 1985). Moreover, specific histopathological manifestations of different skin conditions need to be considered when evaluating the potential of clobetasol to cause systemic side effects – in particular, skin diseases associated with skin barrier damage such as BP have been associated with increased percutaneous absorption of topical steroid (Castela et al. 2012). The systemic side effects of TCS primarily arise from the suppression of the hypothalamic corticotropin-releasing hormone and pituitary adrenocorticotropic hormone. GCAEs can be best appreciated by looking at the components which make up the GC Toxicity Index (GTI), a tool developed by Miloslavky et al. to quantify the severity of steroid-induced side effects where a score is calculated based on the presence of specific signs and symptoms unique to GCAEs (Miloslavsky et al. 2017). GCAEs can be categorized according to the following organ systems: (1) metabolic and endocrine (adrenal suppression, cushingoid features, dyslipidemia, hyperglycemia, hypertension, weight gain); (2) musculoskeletal (myopathy, osteopenia, osteoporosis, osteonecrosis); (3) dermatological (acneiform rash, easy bruising, erosion, delayed wound healing, hair loss, hirsutism, striae, skin atrophy, skin ulceration, skin tear); (4) neuropsychiatric (anxiety, akathisia, cognitive impairment, depression, euphoria,

310

F. A. P. Zeng and D. F. Murrell

GC-induced violence, insomnia, irritability, mania, mood lability); (5) immunologic (increased risk of infections, reactivation of latent infections); (6) gastrointestinal (gastritis, gastrointestinal bleeding, hepatic steatosis, pancreatitis, peptic ulcer, visceral perforation); (7) ophthalmologic (cataract, glaucoma) (Miloslavsky et al. 2017; Oray et al. 2016). However, it was found that prolonged hypothalamic-pituitaryadrenal axis suppression is characterized by misuse of topical GCs – namely, longterm daily application over several years on extensive skin surface (Giannitelli et al. 2010). Therefore, it is imperative to taper the dosage of topical clobetasol (and oral GCs) as soon as possible in the treatment of BP.

13.7

Insights from Novel Skin Microbiome-Targeted Therapies in Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin condition that is characterized by decreased epidermal barrier function, immune and skin microbiota dysregulation, and susceptibility to Staphylococcus aureus infection (Myles et al. 2018). Superficially, this is similar to BP where there is also cutaneous dysbiosis and chronic inflammation of the skin. Furthermore, there is also an increased predilection for superimposed Staphylococcus aureus infections in the damaged skin of patients with BP (discussed further in later sections). A pilot animal study carried out by Myles et al. showed that isolates of Roseomonas mucosa, a commensal cutaneous bacterium collected from healthy human volunteers, improved outcomes in mouse and cell culture models of AD (Myles et al. 2016). This concept was then tested in a firstin-human, open-label phase I/II trial (NCT03018275) to test the therapeutic potential of topical administration of Roseomonas mucosa in human AD (Myles et al. 2018). The study concluded that Roseomonas mucosa was associated with clinical improvement and safety in both adult and pediatrics group; steroid-sparing effect was observed in the adult group; Roseomonas mucosa had direct anti-Staphylococcus aureus effects where there was decreased Staphylococcus aureus culture burden in the pediatric cohort (Myles et al. 2018). Importantly, clinical improvements and colonization of the skin by Roseomonas mucosa persisted for up to 8 months after treatment cessation and had not been associated with severe adverse events (Myles et al. 2020). The novel treatment is associated with anti-inflammatory outcomes, consistent with reductions in serum cytokine measurements of tumor necrosis factorα and interleukin-13 (Myles et al. 2020). Although achieving clinical benefits from live biotherapeutic products may still require conventional drug development processes, the traditional expectations of dose response may not be applicable to these agents that can adaptively oscillate in numbers to fit a biological niche and could be subject to quorum-mediated effects (Myles et al. 2020). While there are surface-level similarities in disease manifestation between BP and AD, it is critical to note that the underlying pathophysiology of the two is still substantially different – AD is characterized by IgE-mediated hypersensitivity and imbalances in Th1 and Th2 cytokines (David Boothe et al. 2017). The key takeaway of these findings lies in

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

311

the potential therapeutic benefit of microbiome treatment in chronic inflammatory skin diseases, warranting further clinical research.

13.8

Immunosuppressive Treatment for Bullous Pemphigoid

Systemic steroids are the cornerstone of treatment for BP, and their implementation in the management of BP 50 decades ago has considerably improved the survival of the disease (Kirtschig et al. 2010; Meurer 2012). However, chronic use of high-dose oral glucocorticoids (GCs) carries the risk of significant side effects which contributes to the mortality and morbidity of BP (Bilgic and Murrell 2019). Therefore, the reduction of an individual’s cumulative exposure to GCs via steroid-sparing adjuvant therapeutics remains a key objective in the management of BP (Izumi et al. 2019; Bilgic and Murrell 2019; Berkani et al. 2019). This section will review most recent evidenced-based and international expert recommendations for the management of BP. The 2015 European Dermatology Forum (EDF) consensus in collaboration with the European Academy of Dermatology and Venereology (EADV) categorizes BP treatment into three groups: (1) extensive BP, (2) localized/limited and mild BP, and (3) treatment-resistant BP (Feliciani et al. 2015).

13.8.1 Extensive BP At the time of this EDF-EADV consensus, an international definition for “extensive BP” had not been agreed on. Based on latest updates, this review will define extensive BP as BPDAI score greater than 57, in congruence with the 2020 international validation of BPDAI which distinguished moderate and severe BP using the same cutoff value (Masmoudi et al. 2021). Initial treatment with topical clobetasol 0.05% cream (or ointment), 30 40 g/day (20 g/day for individuals under 45 kg), administered in two applications, applied to the whole body (sparing the face) including both cutaneous lesions and normal skin is recommended (Joly et al. 2002, 2009). Topical steroids dosage should be first reduced within 15 days of disease control – defined as the cessation of pruritic symptoms or formation of blisters accompanied by the healing of established lesion (Murrell et al. 2012). The following tapering schedule is proposed: daily treatment in the first month; treatment every 2 days in the second month; treatment thrice per week in the third month; and treatment once a week starting from the fourth month (Feliciani et al. 2015). After 4 months of treatment, and without relapse, a maintenance dosage of 10 g once a week for 8 months is recommended (Joly et al. 2002; Feliciani et al. 2015). A relapse is defined as blisters, eczematous lesions, or urticarial plaques, or at least one large (10 cm diameter) eczematous lesion or urticarial plaque that does not heal within 1 week, or extension of established lesions or daily pruritus in a patient who has achieved disease control (Murrell et al. 2012). In the case of relapse, the following is proposed: 10 g daily in localized relapse; 20 g daily in mild BP presentation of

312

F. A. P. Zeng and D. F. Murrell

relapse; and 30 g daily in extensive BP presentation of relapse (Joly et al. 2009). However, this is not always feasible due to the time/costs related to extensive use of topical steroids and additional help with topical administration. Therefore, oral systemic GCs are more commonly used despite its association with higher mortality and greater GCAEs. 0.5–0.75 mg/kg/day of prednisone for initial treatment is suggested and tapered in the same manner as proposed for topical steroids (Feliciani et al. 2015). Additional adjuvant agents may or may not be added. The choice of steroid-sparing adjuvant agent is dependent on availability, financial ability, practical experience, and the presence of contraindications. They include oral azathioprine (AZA) 1 3 mg/kg/day (according to thiopurine methyltransferase activity) (Guillaume et al. 1993; Beissert et al. 2007; Bystryn 2008); oral chlorambucil 2 4 mg/day (Chave et al. 2004); oral dapsone up to 1.5 mg/kg/day (Bouscarat et al. 1996); oral, subcutaneous, or intramuscular methotrexate (MTX) up to 15 mg once a week (Du-Thanh et al. 2011); oral MMF 2 g/day or oral mycophenolic acid 1.44 g/day (Beissert et al. 2007; Bystryn 2008); and oral doxycycline (tetracycline) 200 mg/day alone or in combination with up to 2 g daily oral nicotinamide (Fivenson et al. 1994). Cyclosporine (CsA) is not recommended as its associated therapeutic benefit has not been proven to outweigh the risks due to potential side effects like nephrotoxicity and neurotoxicity (Feliciani et al. 2015).

13.8.2 Localized/Limited and Mild BP A BPDAI score under 20 differentiates mild from moderate BP (Masmoudi et al. 2021). Localized/limited BP should be preferentially treated initially with topical clobetasol 0.05% cream, 10 20 g/day, where application is limited to lesional skin only; while mild BP with few but dispersed lesions is recommended to be treated with 20 g/day (10 g/day in individuals under 45 kg) in a single application over the whole body (sparing the face) including normal and lesional skin (Joly et al. 2002, 2009). Time to first reduction of dosage of topical steroids after achieving disease control and subsequent tapering schedule are the same as for management of extensive BP. Similarly, systemic oral GCs are also commonly used where there is evidence that 0.5 mg/kg/day is effective in managing mild BP (Joly et al. 2002). Ideally, systemic GC dosages should be gradually tapered within 4–6 months from time of disease control with the aim of obtaining 0.1 mg/kg/day of prednisone, where the total duration of systemic GCs therapy should be no longer than 12 months (Feliciani et al. 2015). Recommendations for steroid-sparing adjuvant agents are the same as those for extensive BP. Although there was no proposed steroid regime for moderate BP, clinicians may exercise discretion and choose the starting dosage of prednisone either closer to 0.75 mg/kg/day or 0.5 mg/kg/day proportional to whether the BPDAI score is closer to 57 or 20, respectively.

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

313

13.8.3 Treatment-Resistant BP Infrequently, some cases of generalized BP may not achieve disease control despite several weeks of intensive topical and systemic GCs combination therapy. In such cases, steroid-sparing adjuvant agents are indicated where proposed dosage regimes are the same as in extensive BP. Additional adjuvant agents that may be considered in refractory disease but not mentioned in the management of extensive and mild BP are cyclophosphamide (CTX), intravenous immunoglobulin (IVIg), rituximab (RTX), and therapeutic plasma exchange (dosage recommendations were not included in the EDF-EADV consensus for these agents). The Spanish academy of dermatology and venereology (AEDV) recommends in their national consensus guidelines: oral CTX 1 3 mg/kg/day (up to 200 mg/day) or weekly intravenous CTX 500 1000 mg/m2; IVIg 2 g/kg spread out over 3–5 days (one cycle), each cycle repeated every 3 weeks, a total of two to four cycles; RTX 375 mg/m2 per week for 4 weeks (Fuertes De Vega et al. 2014). Evidence from an anecdotal case report has shown that dupilumab, a human monoclonal antibody against IL4Ra, is effective in ameliorating blistering and intractable pruritus in a patient with BP resistant to topical and systemic steroids, TCN, MMF, and omalizumab (human monoclonal antibody against IgE) therapy (Seidman et al. 2019).

13.9

Opportunistic Infections: Their Prevention and Treatment

A retrospective comparative study of 54 patients with pemphigoid disease revealed that the common skin and soft tissue infections are bacterial impetiginization, cellulitis/erysipelas, fungal, methicillin-resistant Staphylococcus aureus (MRSA), herpes zoster, and herpes simplex, while the common systemic infections are pneumonia, sepsis, upper respiratory tract infection, and urinary tract infection (Table 13.4) (Lehman et al. 2013). The same study concluded that 80% of patients had some form of skin or soft tissue infection, 91% of patients experienced a systemic infection, and 98% of patient experienced either localized or systemic infection (Lehman et al. 2013). This section will explore such opportunistic infections in further detail. A separate single-center retrospective study carried out to evaluate the relationship between potent TCS and cutaneous infections in patients with BP – it was found that 9 out of 30 patients (30%) receiving TCS experienced cutaneous superinfection, of which there were 3 cases of bacterial impetiginization and 3 cases of fatal necrotizing fasciitis (NF) due to either Staphylococcus aureus or group A Streptococcus (Boughrara et al. 2010). It is imperative to acknowledge the risk of infection from the use of TCS in BP especially since patients are typically elderly and fragile and often have concurrent well-known risk factors for such as widespread lesions and type 2 diabetes mellitus (Roujeau 2001). Where signs of cutaneous superinfection are present, bacteriological analysis should be conducted immediately. Treatment should be initiated promptly, especially when β-hemolytic Streptococcus spp. is detected to prevent severe complications with fatal outcomes (Boughrara et al.

314

F. A. P. Zeng and D. F. Murrell

Table 13.4 Common opportunistic infections seen in patients with bullous pemphigoid, categorized into skin and soft tissue infections; systemic infections; and localized and systemic infection (Lehman et al. 2013) Types of infection Skin and soft tissue infections Bacterial impetiginization Cellulitis/erysipelas Fungal Methicillin-resistant Staphylococcus aureus (MRSA) Herpes zoster Herpes simplex Any of the above Systemic infections Pneumonia Sepsis Upper respiratory tract infection Urinary tract infection Other systemic infection Any systemic infection Localized and systemic infection Any localized or systemic infection

No. of BP patients (%) 50 24 44 13 13 4 80 44 20 24 59 17 91 98

Listed infections in each category are organized in alphabetical order

2010). The key to successful treatment of NF is deliberate, radical, and early debridement of all involved tissues. Surgical intervention is the first-line therapy where the primary goal is to completely resect all infected portions of fascia, including a margin of unaffected healthy fascia (Wong et al. 2008). Antibiotic treatment alone is not sufficient and is rather an obligatory tool that supports surgical debridement (Leiblein et al. 2018). The current recommendations for initial antibiotic therapy is a combination of ampicillin  sulbactam, with clindamycin or metronidazole (Misiakos et al. 2014). The stratum corneum forms the most superficial layer of the skin, comprising dead skin cells that are essentially bags of relatively insoluble keratin filaments – this serves as a physical barrier and the first-line defense against invading pathogens (Roth and James 1988). Additionally, sebum which is especially found at sebaceous sites maintains the acidity of the skin between pH 4 and 6.8 and contains endogenous antibacterial substances which have functions to retard the growth of microorganisms (Wysocki 2002). Thus, open wounds provide a conducive host environment for bacterial invasion. Clinically, infection of an acute or chronic would is based on signs and symptoms of excessive inflammation at the site of infection calor, dolor, rubor, and tumor, on top of other manifestations like cellulitis, dehiscence, fever, foul-smelling draining, or pus. Moreover, it is important to understand that all open wounds are colonized with bacteria, but only some progress to an infection under favorable conditions (Wysocki 2002). Adequate medical management of open wounds can prevent bacterial infection or prevent

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

315

Table 13.5 Recommendations for management of open wounds to prevent bacterial infections (Wysocki 2002) Recommendations for management of open wounds Do’s Maintain adequate hydration by ensuring sufficient fluid intake and applying emollients to the skin Relieving pressure Counteracting the risks of any medication that is harmful to the skin where possible Ensure adequate dietary nutrition

Don’ts Using alkaline soaps Application of shear force when moving patients or changing bandages Using delipidizing agents such as alcohol or acetone Excessive bathing

them from progressing to life-threatening consequences like septicemia (Table 13.5). In particular, GCs are known to interfere with epidermal regeneration and collagen synthesis, where vitamin A has been shown to be counteractive of this (Ehrlich and Hunt 1968; Pollack 1982). Vitamin A is a family of retinoids that is available as preformed vitamin A (retinol, retinaldehyde, and retinoic acid) or as provitamin A (carotenoids), possessing the ability to stimulate epithelial growth, fibroblasts, and granulation tissue (Zinder et al. 2019). Additionally, they facilitate epithelial cell differentiation during the early phase of inflammation in open wounds by increasing the number of monocytes and macrophages, thus, acting as an anti-inflammatory agent (Molnar et al. 2014). However, despite its astounding ability to promote wound healing via cellular differentiation of skin keratinocytes, it is not indicated for use in BP. When its effects on the anchoring junction of the dermal layer were studied, vitamin A was shown to cause disintegration hemidesmosomes by reducing the expression of BP230 which is also the mechanism of blister formation in BP (Hatakeyama et al. 2004). Vitamin D3, on the other hand, has been demonstrated to downregulate BP230 gene expression through posttranscriptional regulation and independent of active protein synthesis (Yamamoto et al. 2008). Although the exact role of BP230 in the pathogenesis of BP is unclear, it is important to acknowledge that modulation of BP230 expression by vitamin D3 could potentially be beneficial in the management of BP. A single-center retrospective study of 252 patients with BP sets out to determine the risk factors for the infectious complications according to organ systems (respiratory, hematological, mucocutaneous) concluded that advanced age was a key risk factor for respiratory infections; mucosal involvement of BP was associated with only hematologic and not respiratory nor mucocutaneous infections; mucocutaneous infections were more significantly associated with GC dosage as compared to respiratory infections and bacteremia (Chen et al. 2020). There is a plethora of microorganisms capable of causing infections at different organ systems, but the most common pathogens across all sites according to prevalence are Staphylococcus spp., Candida spp., Pseudomonas spp., and Streptococcus spp. (Fig. 13.4) (Chen et al. 2020). A large population-based UK cohort analysis of 868 participants showed that patients with BP were three times more likely to develop pneumonia than matched

Fig. 13.4 Sites of infectious complications and associated pathogens in bullous pemphigoid. Reproduced with permission Chen et al. (2020)

316 F. A. P. Zeng and D. F. Murrell

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

317

controls, with a rate of pneumonia of 21 per 1000 person-years (Langan et al. 2009). Another retrospective large-scale cohort study of 359 patients carried out in Singapore to determine the 3-year mortality rate and causes of death in patients with BP revealed that infectious diseases were the most common cause of death (59.8%), especially pneumonia (42.7%) (Cai et al. 2014). Literature pertaining to common causative agents of pneumonia specifically in the context of BP patients is limited – instead, pneumonia in immunosuppressed patients will be discussed. All types of immunosuppression are risk factors for developing classic bacterial pneumonia, where one in five patients hospitalized for community-acquired pneumonia (CAP) is immunocompromised (Di Pasquale et al. 2019). Furthermore, long-term GC therapy defined as >10 mg/day of prednisone equivalent for 3 months or longer is the main cause of immunosuppression (Azoulay et al. 2020). Due to the susceptibility of patients with BP to develop pneumonia as well as its high risks of causing death, it is critical for dermatologists to have high suspicion of pneumonia in patients presenting with nonspecific symptoms such as cough, dyspnea, fever, sputum production, and pleuritic chest pain, and signs of pulmonary infiltrates. During the initial evaluation for CAP, the identification of possible risk factors for multidrugresistant (MDR) pathogen or atypical causative agent is critical; it has been documented that MDR pathogens are significantly more common in immunosuppressed individuals (Azoulay et al. 2020; Shindo et al. 2013). Since microbiological identification usually takes about 24–48 h to be processed, most patients are started on empiric antibiotics according to clinical practice guidelines and local resistance patterns – prompt treatment is especially important in immunocompromised patients. Moreover, delaying the initiation of appropriate empiric therapy is a known risk factor for worse clinical outcomes (Mandell et al. 2007; Woodhead et al. 2011). Interestingly, different literature quotes differing causative agents for pneumonia in immunocompromised patients. In some reports, it was found that patients with autoimmune diseases managed with systemic steroids and cytotoxic agents had higher incidence of infections caused by gram-negative bacteria, namely, Pseudomonas aeruginosa (Li et al. 2011; Di Pasquale et al. 2019). Among others, Streptococcus pneumoniae was listed as the most common pathogens in immunosuppressed patients (Azoulay et al. 2020; Di Pasquale et al. 2019). This could be explained by unique epidemiological patterns of different study sites. Ren et al. sought out to investigate the occurrence of serious infections in pemphigus and pemphigoid patients, based on a 10-year analysis of the Nationwide Inpatient Sample (a US database including a 20% representative sample of all US hospital inpatient admissions annually) – it was found that not only were serious infections more common in women with pemphigoid than their male counterparts; fall and winter seasons were associated with higher rates of infections in pemphigoid as compared to pemphigus; and Clostridium difficile infection was a significant predictor of inpatient mortality in pemphigoid patients (Ren et al. 2018). Since gender is a non-modifiable risk factor for serious infections, it may be suggested that dermatologists monitor female patients with BP more closely for signs and symptoms of infections, although this may be controversial since keeping a watchful eye for infections should be prioritized in all immunocompromised patients

318

F. A. P. Zeng and D. F. Murrell

regardless. Seasonal variations in the rate of infections can be explained by changes in environmental parameters and human behavior (Moriyama et al. 2020). It is important to note that while Ren et al. concluded that fall and winter seasons were associated with higher rates of infection, this was relative to those in pemphigus – in reality, different microorganisms which vary according to associated disease will follow different seasonal patterns. A systemic review of 41 studies (13 multi-center, 28 single institution studies) on the seasonal variation of Staphylococcus aureus, categorized into any infection, bacteremia only, skin and soft-tissue infection (SSTI), other specific infections, and human colonization, found that seasonal variation of Staphylococcus aureus was most commonly reported in studies of SSTI (Moriyama et al. 2020). Additionally, the peak occurrences of Staphylococcus aureus were found to be in summer and/or autumn (Dailiana et al. 2008; Kaimal et al. 2009; Tveten et al. 2002; Chen et al. 2006; Kakar et al. 1999; Rogers et al. 1987; Szczesiul et al. 2007). However, as a rule of thumb, every patient should be monitored closely all year round for signs and symptoms of infection. Finally, there has been increasing research carried out to study the probiotics-microbiota relationship in autoimmune blistering diseases. Probiotics are live microorganisms (bacteria or yeast) which work primarily through the gut to improve the immunity via both direct and indirect actions, although their exact mechanisms have yet to be elucidated. Direct effects are a consequence of interactions between the probiotics and innate immune receptors resulting in the decreased release of proinflammatory cytokines, while the indirect effects are a result of increased production short chain fatty acids (SCFA) and AMPs, or via restoration of the gut epithelial barrier (Lescheid 2018; Catinean et al. 2019). SCFAs help maintain the homeostasis between physiologic microbiota and pathogenic bacteria by preventing the overgrowth of pathogens and also inhibit the secretion of inflammatory cytokines by lipopolysaccharide-induced chemokines and cytokines (Liu et al. 2012). Therefore, probiotics have the ability to counteract potential disturbances in intestinal flora associated with antibiotic use, thereby reducing the risk of colonization by pathogenic bacteria (Sullivan and Nord 2002). This was corroborated by a systematic review and meta-analysis of 31 randomized controlled trials including a total of 8672 patients that concluded with moderate certainty evidence suggesting that the coadministration of probiotics with prescribed antibiotics is effective in preventing Clostridium difficile-associated diarrhea (Hamed and Miller 2019).

13.10 Conclusion High-dose systemic steroids are the mainstay of treatment for BP but are associated with devastating side effects when used long term. The knowledge of these glucocorticoid-related adverse events combined with the recent growing awareness of the relationship between cutaneous microbiota dysbiosis and autoimmune skin conditions has led to increased research on the potential benefits of live biotherapeutic products in their management. Although the therapeutic role of

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

319

nutraceuticals in BP has yet to be elucidated, they may have potential steroid-sparing benefit as seen in their application in AD, thus warranting further research.

References Adak A, Khan MR (2019) An insight into gut microbiota and its functionalities. Cell Mol Life Sci 76:473–493 Alaibac M (2019) Biological therapy of autoimmune blistering diseases. Expert Opin Biol Ther 19: 149–156 Alonso-Llamazares J, Dietrich SM, Gibson LE (1998) Bullous pemphigoid presenting as exfoliative erythroderma. J Am Acad Dermatol 39:827–830 Amber KT, Murrell DF, Schmidt E, Joly P, Borradori L (2018a) Autoimmune subepidermal bullous diseases of the skin and mucosae: clinical features, diagnosis, and management. Clin Rev Allergy Immunol 54:26–51 Amber KT, Valdebran M, Lu Y, De Feraudy S, Linden KG (2018b) Localized pretibial bullous pemphigoid arising in a patient on pembrolizumab for metastatic melanoma. J Dtsch Dermatol Ges 16:196–198 Antonsson A, Erfurt C, Hazard K, Holmgren V, Simon M, Kataoka A, Hossain S, Hakangard C, Hansson BG (2003) Prevalence and type spectrum of human papillomaviruses in healthy skin samples collected in three continents. J Gen Virol 84:1881–1886 Asbrink E, Hovmark A (1981) Clinical variations in bullous pemphigoid with respect to early symptoms. Acta Derm Venereol 61:417–421 Azoulay E, Russell L, Van De Louw A, Metaxa V, Bauer P, Povoa P, Montero JG, Loeches IM, Mehta S, Puxty K, Schellongowski P, Rello J, Mokart D, Lemiale V, Mirouse A, Nine-i I (2020) Diagnosis of severe respiratory infections in immunocompromised patients. Intensive Care Med 46:298–314 Bakker CV, Terra JB, Pas HH, Jonkman MF (2013) Bullous pemphigoid as pruritus in the elderly: a common presentation. JAMA Dermatol 149:950–953 Barnard E, Li H (2017) Shaping of cutaneous function by encounters with commensals. J Physiol 595:437–450 Batalla A, Peon G, De La Torre C (2011) Localized bullous pemphigoid at urostomy site. Indian J Dermatol Venereol Leprol 77:625 Beissert S, Werfel T, Frieling U, Bohm M, Sticherling M, Stadler R, Zillikens D, Rzany B, Hunzelmann N, Meurer M, Gollnick H, Ruzicka T, Pillekamp H, Junghans V, Bonsmann G, Luger TA (2007) A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid. Arch Dermatol 143:1536–1542 Belkaid Y, Segre JA (2014) Dialogue between skin microbiota and immunity. Science 346:954– 959 Berkani N, Joly P, Golinski ML, Colliou N, Lim A, Larbi A, Riou G, Caillot F, Bernard P, Bedane C, Delaporte E, Chaby G, Dompmartin A, Hertl M, Calbo S, Musette P (2019) Author correction: B-cell depletion induces a shift in self antigen specific B-cell repertoire and cytokine pattern in patients with bullous pemphigoid. Sci Rep 9:18991 Bilgic A, Murrell DF (2019) Toxicity of glucocorticosteroids in autoimmune blistering disease. Mucosa 2:59–67 Borradori L, Joly P (2014) Toward a practical renaming of bullous pemphigoid and all its variants: cutaneous pemphigoid. JAMA Dermatol 150:459 Boughrara Z, Ingen-Housz-Oro S, Legrand P, Duong TA, Roujeau JC (2010) Cutaneous infections in bullous pemphigoid patients treated with topical corticosteroids. Ann Dermatol Venereol 137:345–351

320

F. A. P. Zeng and D. F. Murrell

Bouscarat F, Chosidow O, Picard-Dahan C, Sakiz V, Crickx B, Prost C, Roujeau JC, Revuz J, Belaich S (1996) Treatment of bullous pemphigoid with dapsone: retrospective study of thirtysix cases. J Am Acad Dermatol 34:683–684 Bressa C, Bailen-Andrino M, Perez-Santiago J, Gonzalez-Soltero R, Perez M, MontalvoLominchar MG, Mate-Munoz JL, Dominguez R, Moreno D, Larrosa M (2017) Differences in gut microbiota profile between women with active lifestyle and sedentary women. PLoS One 12:E0171352 Brodell RT, Korman NJ (1996) Stump Pemphigoid. Cutis 57:245–246 Bucks DA, Maibach HI, Guy RH (1985) Percutaneous absorption of steroids: effect of repeated application. J Pharm Sci 74:1337–1339 Byrd AL, Belkaid Y, Segre JA (2018) The human skin microbiome. Nat Rev Microbiol 16:143–155 Bystryn JC (2008) Comparative effectiveness of azathioprine or mycophenolate Mofetil as an adjuvant for the treatment of bullous pemphigoid. Arch Dermatol 144:946 Cai SC, Allen JC, Lim YL, Chua SH, Tan SH, Tang MB (2014) Mortality of bullous pemphigoid in Singapore: risk factors and causes of death in 359 patients seen at the National Skin Centre. Br J Dermatol 170:1319–1326 Capone KA, Dowd SE, Stamatas GN, Nikolovski J (2011) Diversity of the human skin microbiome early in life. J Invest Dermatol 131:2026–2032 Carey B, Setterfield J (2019) Mucous membrane pemphigoid and oral blistering diseases. Clin Exp Dermatol 44:732–739 Castanet J, Lacour JP, Ortonne JP (1990) Atypical clinical forms of bullous pemphigoid. Ann Dermatol Venereol 117:73–82 Castela E, Archier E, Devaux S, Gallini A, Aractingi S, Cribier B, Jullien D, Aubin F, Bachelez H, Joly P, Le Maitre M, Misery L, Richard MA, Paul C, Ortonne JP (2012) Topical corticosteroids in plaque psoriasis: a systematic review of risk of adrenal axis suppression and skin atrophy. J Eur Acad Dermatol Venereol 26(Suppl 3):47–51 Castro MCR, Ramos ESM (2018) Cutaneous infections in the mature patient. Clin Dermatol 36: 188–196 Castro-Fores LL, Cruz JM, Jamora MJ, Canlas-Estrella KM (2016) Seborrheic pemphigoid. JAAD Case Rep 2:80–83 Catinean A, Neag MA, Mitre AO, Bocsan CI, Buzoianu AD (2019) Microbiota and immunemediated skin diseases-an overview. Microorganisms 7:279 Chambers ES, Vukmanovic-Stejic M (2020) Skin barrier immunity and ageing. Immunology 160: 116–125 Chave TA, Mortimer NJ, Shah DS, Hutchinson PE (2004) Chlorambucil as a steroid-sparing agent in bullous pemphigoid. Br J Dermatol 151:1107–1108 Chen AE, Goldstein M, Carroll K, Song X, Perl TM, Siberry GK (2006) Evolving epidemiology of pediatric Staphylococcus aureus cutaneous infections in a Baltimore hospital. Pediatr Emerg Care 22:717–723 Chen AC, Mcmillan NAJ, Antonsson A (2008) Human papillomavirus type spectrum in normal skin of individuals with or without a history of frequent Sun exposure. J Gen Virol 89:2891– 2897 Chen J, Mao X, Zhao W, Zhang B, Chen X, Yu C, Zheng Z, Jin H, Li L (2020) Assessment of the characteristics and associated factors of infectious complications in bullous pemphigoid. Front Immunol 11:1607 Clape A, Muller C, Gatouillat G, Le Jan S, Barbe C, Pham BN, Antonicelli F, Bernard P (2018) Mucosal involvement in bullous pemphigoid is mostly associated with disease severity and to absence of anti-BP230 autoantibody. Front Immunol 9:479 Cogen AL, Nizet V, Gallo RL (2008) Skin microbiota: a source of disease or defence? Br J Dermatol 158:442–455 Cohen PR (2020) Dyshidrosiform bullous pemphigoid: case reports and review. Cureus 12:E6630 Cohen DM, Ben-Amitai D, Feinmesser M, Zvulunov A (2009) Childhood lichen planus pemphigoides: a case report and review of the literature. Pediatr Dermatol 26:569–574

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

321

Cordel N, Courville P, Martel P, Musette P, Joly P (2002) Extensive erosive bullous pemphigoid: an atypical and serious clinical variant. Br J Dermatol 146:537–539 Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R (2009) Bacterial community variation in human body habitats across space and time. Science 326:1694–1697 Curtis MA, Diaz PI, Van Dyke TE (2020) The role of the microbiota in periodontal disease. Periodontol 2000(83):14–25 Dailiana ZH, Rigopoulos N, Varitimidis SE, Poultsides L, Petinaki E, Malizos KN (2008) Clinical and epidemiological features of upper-extremity infections caused by Staphylococcus aureus carrying the PVL gene: a four-year study in Greece. Med Sci Monit 14. Cr511-4 Daniel BS, Borradori L, Hall RP 3rd, Murrell DF (2011) Evidence-based management of bullous pemphigoid. Dermatol Clin 29:613–620 David Boothe W, Tarbox JA, Tarbox MB (2017) Atopic dermatitis: pathophysiology. Adv Exp Med Biol 1027:21–37 De Daruvar M, Benzaquen M, Berbis P, Delaporte E (2020) Localised pretibial pemphigoid secondary to skin haematoma. Ann Dermatol Venereol 147:905–906 Della Torre R, Combescure C, Cortes B, Marazza G, Beltraminelli H, Naldi L, Borradori L (2012) Clinical presentation and diagnostic delay in bullous pemphigoid: a prospective Nationwide cohort. Br J Dermatol 167:1111–1117 Delwart EL (2007) Viral Metagenomics. Rev Med Virol 17:115–131 Di Nardo A, Vitiello A, Gallo RL (2003) Cutting edge: mast cell antimicrobial activity is mediated by expression of cathelicidin antimicrobial peptide. J Immunol 170:2274–2278 Di Pasquale MF, Sotgiu G, Gramegna A, Radovanovic D, Terraneo S, Reyes LF, Rupp J, Gonzalez Del Castillo J, Blasi F, Aliberti S, Restrepo MI, Investigators G (2019) Prevalence and etiology of community-acquired pneumonia in immunocompromised patients. Clin Infect Dis 68:1482– 1493 Di Zenzo G, Thoma-Uszynski S, Fontao L, Calabresi V, Hofmann SC, Hellmark T, Sebbag N, Pedicelli C, Sera F, Lacour JP, Wieslander J, Bruckner-Tuderman L, Borradori L, Zambruno G, Hertl M (2008) Multicenter prospective study of the humoral autoimmune response in bullous pemphigoid. Clin Immunol 128:415–426 Di Zenzo G, Della Torre R, Zambruno G, Borradori L (2012) Bullous pemphigoid: from the clinic to the bench. Clin Dermatol 30:3–16 Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, Knight R (2010) Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 107:11971–11975 Dreno B, Araviiskaia E, Berardesca E, Gontijo G, Sanchez Viera M, Xiang LF, Martin R, Bieber T (2016) Microbiome in healthy skin, update for dermatologists. J Eur Acad Dermatol Venereol 30:2038–2047 Du-Thanh A, Merlet S, Maillard H, Bernard P, Joly P, Esteve E, Richard MA, Pauwels C, IngenHousz-Oro S, Guillot B, Dereure O (2011) Combined treatment with low-dose methotrexate and initial short-term superpotent topical steroids in bullous pemphigoid: an open, multicentre, retrospective study. Br J Dermatol 165:1337–1343 Ehrlich HP, Hunt TK (1968) Effects of cortisone and vitamin A on wound healing. Ann Surg 167: 324–328 Errichetti E, Stinco G, Pegolo E, Di Meo N, Trevisan G, Patrone P (2014) Seborrheic Pemphigoid. Case Rep Dermatol Med 2014:768217 Farrell AM, Kirtschig G, Dalziel KL, Allen J, Dootson G, Edwards S, Wojnarowska F (1999) Childhood vulval pemphigoid: a clinical and immunopathological study of five patients. Br J Dermatol 140:308–312 Feliciani C, Joly P, Jonkman MF, Zambruno G, Zillikens D, Ioannides D, Kowalewski C, Jedlickova H, Karpati S, Marinovic B, Mimouni D, Uzun S, Yayli S, Hertl M, Borradori L (2015) Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology. Br J Dermatol 172:867–877

322

F. A. P. Zeng and D. F. Murrell

Fisher GJ, Shao Y, He T, Qin Z, Perry D, Voorhees JJ, Quan T (2016) Reduction of fibroblast size/ mechanical force down-regulates TGF-beta type II receptor: implications for human skin aging. Aging Cell 15:67–76 Fivenson DP, Breneman DL, Rosen GB, Hersh CS, Cardone S, Mutasim D (1994) Nicotinamide and tetracycline therapy of bullous pemphigoid. Arch Dermatol 130:753–758 Fong M, Gandhi GR, Gharbi A, Hafsi W (2021) Pemphigoid gestationis. Statpearls, Treasure Island (FL) Fontaine J, Joly P, Roujeau JC (2003) Treatment of bullous pemphigoid. J Dermatol 30:83–90 Foulongne V, Sauvage V, Hebert C, Dereure O, Cheval J, Gouilh MA, Pariente K, Segondy M, Burguiere A, Manuguerra JC, Caro V, Eloit M (2012) Human skin microbiota: high diversity of DNA viruses identified on the human skin by high throughput sequencing. PLoS One 7:E38499 Foureur N, Descamps V, Lebrun-Vignes B, Picard-Dahan C, Grossin M, Belaich S, Crickx B (2001) Bullous pemphigoid in a leg affected with hemiparesia: a possible relation of neurological diseases with bullous pemphigoid? Eur J Dermatol 11:230–233 Frohm M, Agerberth B, Ahangari G, Stahle-Backdahl M, Liden S, Wigzell H, Gudmundsson GH (1997) The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J Biol Chem 272:15258–15263 Frye M, Bargon J, Gropp R (2001) Expression of human beta-defensin-1 promotes differentiation of keratinocytes. J Mol Med (Berl) 79:275–282 Fuertes De Vega I, Iranzo-Fernandez P, Mascaro-Galy JM (2014) Bullous pemphigoid: clinical practice guidelines. Actas Dermosifiliogr 105:328–346 Gallo RL, Hooper LV (2012) Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol 12:503–516 Gallo RL, Ono M, Povsic T, Page C, Eriksson E, Klagsbrun M, Bernfield M (1994) Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds. Proc Natl Acad Sci U S A 91:11035–11039 Gallo RL, Kim KJ, Bernfield M, Kozak CA, Zanetti M, Merluzzi L, Gennaro R (1997) Identification of CRAMP, a cathelin-related antimicrobial peptide expressed in the embryonic and adult mouse. J Biol Chem 272:13088–13093 Gao Z, Tseng CH, Pei Z, Blaser MJ (2007) Molecular analysis of human forearm superficial skin bacterial biota. Proc Natl Acad Sci U S A 104:2927–2932 Gao Z, Tseng CH, Strober BE, Pei Z, Blaser MJ (2008) Substantial alterations of the cutaneous bacterial biota in psoriatic lesions. PLoS One 3:E2719 Garcia-Pola MJ, Rodriguez-Lopez S, Fernanz-Vigil A, Bagan L, Garcia-Martin JM (2019) Oral hygiene instructions and professional control as part of the treatment of desquamative gingivitis. Systematic review. Med Oral Patol Oral Cir Bucal 24:E136–E144 Genovese G, Di Zenzo G, Cozzani E, Berti E, Cugno M, Marzano AV (2019) New insights into the pathogenesis of bullous pemphigoid: 2019 update. Front Immunol 10:1506 Giannitelli M, Maza A, Lahfa M, Meyer N, Livideanu C, Paul C (2010) Iatrogenic adrenal insufficiency associated with calcipotriol-betamethasone topical combination in psoriasis. Clin Exp Dermatol 35:E167–E168 Gioti A, Nystedt B, Li W, Xu J, Andersson A, Averette AF, Munch K, Wang X, Kappauf C, Kingsbury JM, Kraak B, Walker LA, Johansson HJ, Holm T, Lehtio J, Stajich JE, Mieczkowski P, Kahmann R, Kennell JC, Cardenas ME, Lundeberg J, Saunders CW, Boekhout T, Dawson TL, Munro CA, De Groot PW, Butler G, Heitman J, Scheynius A (2013) Genomic insights into the atopic eczema-associated skin commensal yeast Malassezia sympodialis. MBio 4:E00572–E00512 Grice EA, Segre JA (2011) The skin microbiome. Nat Rev Microbiol 9:244–253 Grice EA, Kong HH, Renaud G, Young AC, Program NCS, Bouffard GG, Blakesley RW, Wolfsberg TG, Turner ML, Segre JA (2008) A diversity profile of the human skin microbiota. Genome Res 18:1043–1050

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

323

Grice EA, Kong HH, Conlan S, Deming CB, Davis J, Young AC, Program NCS, Bouffard GG, Blakesley RW, Murray PR, Green ED, Turner ML, Segre JA (2009) Topographical and temporal diversity of the human skin microbiome. Science 324:1190–1192 Gudmundsson GH, Agerberth B, Odeberg J, Bergman T, Olsson B, Salcedo R (1996) The human gene FALL39 and processing of the Cathelin precursor to the antibacterial peptide LL-37 in granulocytes. Eur J Biochem 238:325–332 Guillaume JC, Vaillant L, Bernard P, Picard C, Prost C, Labeille B, Guillot B, Foldes-Pauwels C, Prigent F, Joly P et al (1993) Controlled trial of azathioprine and plasma exchange in addition to prednisolone in the treatment of bullous pemphigoid. Arch Dermatol 129:49–53 Haeberle S, Wei X, Bieber K, Goletz S, Ludwig RJ, Schmidt E, Enk AH, Hadaschik EN (2018) Regulatory T-cell deficiency leads to pathogenic bullous pemphigoid antigen 230 autoantibody and autoimmune bullous disease. J Allergy Clin Immunol 142(1831–1842):E7 Hamed A, Miller AC (2019) Coadministration of probiotics with prescribed antibiotics for preventing clostridium difficile diarrhea. Acad Emerg Med 26:454–456 Harder J, Bartels J, Christophers E, Schroder JM (1997) A peptide antibiotic from human skin. Nature 387:861 Hatakeyama S, Hayashi S, Yoshida Y, Otsubo A, Yoshimoto K, Oikawa Y, Satoh M (2004) Retinoic acid disintegrated desmosomes and hemidesmosomes in stratified oral keratinocytes. J Oral Pathol Med 33:622–628 Hiroyasu S, Ozawa T, Kobayashi H, Ishii M, Aoyama Y, Kitajima Y, Hashimoto T, Jones JC, Tsuruta D (2013) Bullous pemphigoid IgG induces BP180 internalization via a Macropinocytic pathway. Am J Pathol 182:828–840 Hirsch T, Spielmann M, Zuhaili B, Fossum M, Metzig M, Koehler T, Steinau HU, Yao F, Onderdonk AB, Steinstraesser L, Eriksson E (2009) Human beta-defensin-3 promotes wound healing in infected diabetic wounds. J Gene Med 11:220–228 Huang S, Li R, Zeng X, He T, Zhao H, Chang A, Bo C, Chen J, Yang F, Knight R, Liu J, Davis C, Xu J (2014) Predictive modeling of gingivitis severity and susceptibility via oral microbiota. ISME J 8:1768–1780 Izumi K, Bieber K, Ludwig RJ (2019) Current clinical trials in pemphigus and pemphigoid. Front Immunol 10:978 James AG, Austin CJ, Cox DS, Taylor D, Calvert R (2013) Microbiological and biochemical origins of human axillary odour. FEMS Microbiol Ecol 83:527–540 Joly P, Tanasescu S, Wolkenstein P, Bocquet H, Gilbert D, Thomine E, Wechsler J, Roujeau JC, Revuz J, Tron F, Lauret P (1998) Lichenoid erythrodermic bullous pemphigoid of the African patient. J Am Acad Dermatol 39:691–697 Joly P, Roujeau JC, Benichou J, Picard C, Dreno B, Delaporte E, Vaillant L, D'incan M, Plantin P, Bedane C, Young P, Bernard P, Bullous Diseases French Study, G (2002) A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 346:321–327 Joly P, Courville P, Lok C, Bernard P, Saiag P, Dreno B, Delaporte E, Bedane C, Picard C, Sassolas B, Plantin P, D'incan M, Chosidow O, Pauwels C, Lambert D, Loche F, Prost C, Tancrede-Bohin E, Guillaume JC, Roujeau JC, Gilbert D, Tron F, Vaillant L, French Bullous Study, G (2004) Clinical criteria for the diagnosis of bullous pemphigoid: a reevaluation according to immunoblot analysis of patient sera. Dermatology 208:16–20 Joly P, Roujeau JC, Benichou J, Delaporte E, D'incan M, Dreno B, Bedane C, Sparsa A, Gorin I, Picard C, Tancrede-Bohin E, Sassolas B, Lok C, Guillaume JC, Doutre MS, Richard MA, Caux F, Prost C, Plantin P, Chosidow O, Pauwels C, Maillard H, Saiag P, Descamps V, Chevrant-Breton J, Dereure O, Hellot MF, Esteve E, Bernard P (2009) A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study. J Invest Dermatol 129:1681–1687 Joly P, Baricault S, Sparsa A, Bernard P, Bedane C, Duvert-Lehembre S, Courville P, Bravard P, Remond B, Doffoel-Hantz V, Benichou J (2012) Incidence and mortality of bullous pemphigoid in France. J Invest Dermatol 132:1998–2004

324

F. A. P. Zeng and D. F. Murrell

Jung M, Kippes W, Messer G, Zillikens D, Rzany B (1999) Increased risk of bullous pemphigoid in male and very old patients: a population-based study on incidence. J Am Acad Dermatol 41: 266–268 Kaimal S, D'souza M, Kumari R, Parija SC, Sistla S, Badhe BA (2009) Dermatitis cruris pustulosa et atrophicans revisited: our experience with 37 patients in south India. Int J Dermatol 48:1082– 1090 Kakar N, Kumar V, Mehta G, Sharma RC, Koranne RV (1999) Clinico-bacteriological study of pyodermas in children. J Dermatol 26:288–293 Kakurai M, Demitsu T, Azuma R, Yamada T, Suzuki M, Yoneda K, Ishii N, Hashimoto T (2007) Localized pemphigoid (pretibial type) with IgG antibody to BP180 NC16a domain successfully treated with minocycline and topical corticosteroid. Clin Exp Dermatol 32:759–761 Kaposi M (1892) Lichen ruber pemphigoides. Arch Dermatol Syph (Berlin) 24:343–346 Kiatsurayanon C, Niyonsaba F, Smithrithee R, Akiyama T, Ushio H, Hara M, Okumura K, Ikeda S, Ogawa H (2014) Host defense (antimicrobial) peptide, human beta-defensin-3, improves the function of the epithelial tight-junction barrier in human keratinocytes. J Invest Dermatol 134: 2163–2173 Kim J, Chavel S, Girardi M, Mcniff JM (2008) Pemphigoid vegetans: a case report and review of the literature. J Cutan Pathol 35:1144–1147 Kirtschig G, Middleton P, Bennett C, Murrell DF, Wojnarowska F, Khumalo NP (2010) Interventions for bullous pemphigoid. Cochrane Database Syst Rev 2010:CD002292 Kohroh K, Suga Y, Mizuno Y, Ishii N, Hashimoto T, Ikeda S (2007) Case of localized bullous pemphigoid with unique clinical manifestations in the lower legs. J Dermatol 34:482–485 Kong HH, Segre JA (2012) Skin microbiome: looking back to move forward. J Invest Dermatol 132:933–939 Kono H, Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8: 279–289 Kridin K, Bergman R (2019) Assessment of the prevalence of mucosal involvement in bullous pemphigoid. JAMA Dermatol 155:166–171 Lai Y, Di Nardo A, Nakatsuji T, Leichtle A, Yang Y, Cogen AL, Wu ZR, Hooper LV, Schmidt RR, Von Aulock S, Radek KA, Huang CM, Ryan AF, Gallo RL (2009) Commensal bacteria regulate toll-like receptor 3-dependent inflammation after skin injury. Nat Med 15:1377–1382 Lamberts A, Meijer JM, Jonkman MF (2018) Nonbullous pemphigoid: a systematic review. J Am Acad Dermatol 78(989–995):E2 Langan SM, Hubbard R, Fleming K, West J (2009) A population-based study of acute medical conditions associated with bullous pemphigoid. Br J Dermatol 161:1149–1152 Larrick JW, Lee J, Ma S, Li X, Francke U, Wright SC, Balint RF (1996) Structural, functional analysis and localization of the human CAP18 gene. FEBS Lett 398:74–80 Laube S (2004) Skin infections and ageing. Ageing Res Rev 3:69–89 Le Page A, Khalil A, Vermette P, Frost EH, Larbi A, Witkowski JM, Fulop T (2019) The role of elastin-derived peptides in human physiology and diseases. Matrix Biol 84:81–96 Lee DY, Yamasaki K, Rudsil J, Zouboulis CC, Park GT, Yang JM, Gallo RL (2008) Sebocytes express functional cathelicidin antimicrobial peptides and can act to kill Propionibacterium acnes. J Invest Dermatol 128:1863–1866 Lehman JS, Khunger M, Lohse CM (2013) Infection in autoimmune bullous diseases: a retrospective comparative study. J Dermatol 40:613–619 Leiblein M, Marzi I, Sander AL, Barker JH, Ebert F, Frank J (2018) Necrotizing fasciitis: treatment concepts and clinical results. Eur J Trauma Emerg Surg 44:279–290 Lescheid DW (2018) Probiotics as regulators of inflammation: a review. Funct Foods Heal Dis 4: 299 Li F, Jin HZ, Su F, Jia L, Sun QN (2011) Pneumocystis pneumonia in patients with Immunobullous dermatoses. Int J Dermatol 50:1144–1149 Liakopoulou A, Rallis E (2017) Bullous lichen planus - a review. J Dermatol Case Rep 11:1–4

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

325

Liu T, Li J, Liu Y, Xiao N, Suo H, Xie K, Yang C, Wu C (2012) Short-chain fatty acids suppress lipopolysaccharide-induced production of nitric oxide and proinflammatory cytokines through inhibition of NF-KappaB pathway in RAW264.7 cells. Inflammation 35:1676–1684 Ludwig RJ, Kalies K, Kohl J, Zillikens D, Schmidt E (2013) Emerging treatments for pemphigoid diseases. Trends Mol Med 19:501–512 Lunjani N, Hlela C, O'mahony, L. (2019) Microbiome and skin biology. Curr Opin Allergy Clin Immunol 19:328–333 Maderal AD, Lee Salisbury P 3rd, Jorizzo JL (2018) Desquamative gingivitis: diagnosis and treatment. J Am Acad Dermatol 78:851–861 Maeda Y, Takeda K (2017) Role of gut microbiota in rheumatoid arthritis. J Clin Med 6:60 Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG, Infectious Diseases Society Of, A. & American Thoracic, S (2007) Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(Suppl 2):S27–S72 Marovt M, El Shabrawi-Caelen L (2015) Purpuric bullous pemphigoid. Am J Dermatopathol 37: E18–E20 Masmoudi W, Vaillant M, Vassileva S, Patsatsi A, Quereux G, Moltrasio C, Abasq C, ProstSquarcioni C, Kottler D, Kiritsi D, Litrowski N, Plantin P, Friedrichsen L, Zebrowska A, Duvert-Lehembre S, Hofmann S, Ferranti V, Jouen F, Joly P, Hebert V, Force EABSDT (2021) International validation of the bullous pemphigoid disease area index severity score and calculation of cut-off values for defining mild, moderate and severe types of bullous pemphigoid. Br J Dermatol 184(6):1106–1112 Messingham KN, Srikantha R, Degueme AM, Fairley JA (2011) FcR-independent effects of IgE and IgG autoantibodies in bullous pemphigoid. J Immunol 187:553–560 Meurer M (2012) Immunosuppressive therapy for autoimmune bullous diseases. Clin Dermatol 30: 78–83 Mihai S, Chiriac MT, Herrero-Gonzalez JE, Goodall M, Jefferis R, Savage CO, Zillikens D, Sitaru C (2007) IgG4 autoantibodies induce dermal-epidermal separation. J Cell Mol Med 11:1117– 1128 Miloslavsky EM, Naden RP, Bijlsma JW, Brogan PA, Brown ES, Brunetta P, Buttgereit F, Choi HK, Dicaire JF, Gelfand JM, Heaney LG, Lightstone L, Lu N, Murrell DF, Petri M, Rosenbaum JT, Saag KS, Urowitz MB, Winthrop KL, Stone JH (2017) Development of a glucocorticoid toxicity index (GTI) using multicriteria decision analysis. Ann Rheum Dis 76:543–546 Miodovnik M, Kunstner A, Langan EA, Zillikens D, Glaser R, Sprecher E, Baines JF, Schmidt E, Ibrahim SM (2017) A distinct cutaneous microbiota profile in autoimmune bullous disease patients. Exp Dermatol 26:1221–1227 Misiakos EP, Bagias G, Patapis P, Sotiropoulos D, Kanavidis P, Machairas A (2014) Current concepts in the management of necrotizing fasciitis. Front Surg 1:36 Miyamoto D, Santi CG, Aoki V, Maruta CW (2019) Bullous pemphigoid. An Bras Dermatol 94: 133–146 Molnar JA, Underdown MJ, Clark WA (2014) Nutrition and chronic wounds. Adv Wound Care (New Rochelle) 3:663–681 Moriyama M, Hugentobler WJ, Iwasaki A (2020) Seasonality of respiratory viral infections. Annu Rev Virol 7:83–101 Mosaddad SA, Tahmasebi E, Yazdanian A, Rezvani MB, Seifalian A, Yazdanian M, Tebyanian H (2019) Oral microbial biofilms: an update. Eur J Clin Microbiol Infect Dis 38:2005–2019 Mul VE, Van Geest AJ, Pijls-Johannesma MC, Theys J, Verschueren TA, Jager JJ, Lambin P, Baumert BG (2007) Radiation-induced bullous pemphigoid: a systematic review of an unusual radiation side effect. Radiother Oncol 82:5–9 Muramatsu T, Iida T, Shirai T (1991) Antibasement membrane zone antibodies in localized pretibial pemphigoid. Int J Dermatol 30:422–424

326

F. A. P. Zeng and D. F. Murrell

Murrell DF, Daniel BS, Joly P, Borradori L, Amagai M, Hashimoto T, Caux F, Marinovic B, Sinha AA, Hertl M, Bernard P, Sirois D, Cianchini G, Fairley JA, Jonkman MF, Pandya AG, Rubenstein D, Zillikens D, Payne AS, Woodley D, Zambruno G, Aoki V, Pincelli C, Diaz L, Hall RP, Meurer M, Mascaro JM Jr, Schmidt E, Shimizu H, Zone J, Swerlick R, Mimouni D, Culton D, Lipozencic J, Bince B, Grando SA, Bystryn JC, Werth VP (2012) Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts. J Am Acad Dermatol 66:479–485 Myles IA, Williams KW, Reckhow JD, Jammeh ML, Pincus NB, Sastalla I, Saleem D, Stone KD, Datta SK (2016) Transplantation of human skin microbiota in models of atopic dermatitis. JCI Insight 1:e86955 Myles IA, Earland NJ, Anderson ED, Moore IN, Kieh MD, Williams KW, Saleem A, Fontecilla NM, Welch PA, Darnell DA, Barnhart LA, Sun AA, Uzel G, Datta SK (2018) First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis. JCI Insight 3:e120608 Myles IA, Castillo CR, Barbian KD, Kanakabandi K, Virtaneva K, Fitzmeyer E, Paneru M, OtaizoCarrasquero F, Myers TG, Markowitz TE, Moore IN, Liu X, Ferrer M, Sakamachi Y, Garantziotis S, Swamydas M, Lionakis MS, Anderson ED, Earland NJ, Ganesan S, Sun AA, Bergerson JRE, Silverman RA, Petersen M, Martens CA, Datta SK (2020) Therapeutic responses to Roseomonas mucosa in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair. Sci Transl Med 12:eaaz8631 Nagy I, Pivarcsi A, Kis K, Koreck A, Bodai L, Mcdowell A, Seltmann H, Patrick S, Zouboulis CC, Kemeny L (2006) Propionibacterium acnes and lipopolysaccharide induce the expression of antimicrobial peptides and proinflammatory cytokines/chemokines in human sebocytes. Microbes Infect 8:2195–2205 Naik S, Bouladoux N, Linehan JL, Han SJ, Harrison OJ, Wilhelm C, Conlan S, Himmelfarb S, Byrd AL, Deming C, Quinones M, Brenchley JM, Kong HH, Tussiwand R, Murphy KM, Merad M, Segre JA, Belkaid Y (2015) Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature 520:104–108 Nakama K, Koga H, Ishii N, Ohata C, Hashimoto T, Nakama T (2018) Clinical and immunological profiles of 14 patients with bullous pemphigoid without IgG autoantibodies to the BP180 NC16A domain. JAMA Dermatol 154:347–350 Nakatsuji T, Chiang HI, Jiang SB, Nagarajan H, Zengler K, Gallo RL (2013) The microbiome extends to subepidermal compartments of normal skin. Nat Commun 4:1431 Nakatsuji T, Chen TH, Two AM, Chun KA, Narala S, Geha RS, Hata TR, Gallo RL (2016) Staphylococcus aureus exploits epidermal barrier defects in atopic dermatitis to trigger cytokine expression. J Invest Dermatol 136:2192–2200 Nguyen T, Kwan JM, Ahmed AR (2014) Relationship between radiation therapy and bullous pemphigoid. Dermatology 229:88–96 Nikitakis NG, Papaioannou W, Sakkas LI, Kousvelari E (2017) The autoimmunity-oral microbiome connection. Oral Dis 23:828–839 Niyonsaba F, Ushio H, Nakano N, Ng W, Sayama K, Hashimoto K, Nagaoka I, Okumura K, Ogawa H (2007) Antimicrobial peptides human beta-defensins stimulate epidermal keratinocyte migration, proliferation and production of Proinflammatory cytokines and chemokines. J Invest Dermatol 127:594–604 Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J, Dorschner RA, Pestonjamasp V, Piraino J, Huttner K, Gallo RL (2001) Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414:454–457 Olsen EA, Cornell RC (1986) Topical clobetasol-17-propionate: review of its clinical efficacy and safety. J Am Acad Dermatol 15:246–255 Oray M, Abu Samra K, Ebrahimiadib N, Meese H, Foster CS (2016) Long-term side effects of glucocorticoids. Expert Opin Drug Saf 15:457–465 Otto M (2009) Staphylococcus epidermidis--the ‘accidental’ pathogen. Nat Rev Microbiol 7:555– 567

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

327

Paige DG, Bhogal BS, Black MM, Harper JI (1993) Lichen planus pemphigoides in a child-immunopathological findings. Clin Exp Dermatol 18:552–554 Pels R, Sterry W, Lademann J (2008) Clobetasol propionate--where, when, why? Drugs Today (Barc) 44:547–557 Pohla-Gubo G, Hintner H (2011) Direct and indirect immunofluorescence for the diagnosis of bullous autoimmune diseases. Dermatol Clin 29:365–372, vii Pollack SV (1982) Systemic medications and wound healing. Int J Dermatol 21:489–496 Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Dore J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, Meta HITC, Bork P, Ehrlich SD, Wang J (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464:59–65 Rashid H, Lamberts A, Diercks GFH, Pas HH, Meijer JM, Bolling MC, Horvath B (2019) Oral lesions in autoimmune bullous diseases: an overview of clinical characteristics and diagnostic algorithm. Am J Clin Dermatol 20:847–861 Reilly GD, Boulton AJ, Harrington CI (1983) Stump pemphigoid: a new complication of the amputee. Br Med J (Clin Res Ed) 287:875–876 Ren Z, Narla S, Hsu DY, Silverberg JI (2018) Association of serious infections with pemphigus and pemphigoid: analysis of the Nationwide Inpatient Sample. J Eur Acad Dermatol Venereol 32: 1768–1776 Rogers M, Dorman DC, Gapes M, Ly J (1987) A three-year study of impetigo in Sydney. Med J Aust 147:63–65 Rosenthal M, Goldberg D, Aiello A, Larson E, Foxman B (2011) Skin microbiota: microbial community structure and its potential association with health and disease. Infect Genet Evol 11: 839–848 Roth RR, James WD (1988) Microbial ecology of the skin. Annu Rev Microbiol 42:441–464 Roujeau JC (2001) Necrotizing fasciitis. Clinical criteria and risk factors. Ann Dermatol Venereol 128:376–381 Saad RW, Domloge-Hultsch N, Yancey KB, Benson PM, James WD (1992) Childhood localized vulvar pemphigoid is a true variant of bullous pemphigoid. Arch Dermatol 128:807–810 Salzer MC, Lafzi A, Berenguer-Llergo A, Youssif C, Castellanos A, Solanas G, Peixoto FO, Stephan-Otto Attolini C, Prats N, Aguilera M, Martin-Caballero J, Heyn H, Benitah SA (2018) Identity noise and adipogenic traits characterize dermal fibroblast aging. Cell 175: 1575–1590.e22 Sanford JA, Gallo RL (2013) Functions of the skin microbiota in health and disease. Semin Immunol 25:370–377 Satokari R (2015) Contentious host-microbiota relationship in inflammatory bowel disease--can foes become friends again? Scand J Gastroenterol 50:34–42 Scharschmidt TC, Vasquez KS, Truong HA, Gearty SV, Pauli ML, Nosbaum A, Gratz IK, Otto M, Moon JJ, Liese J, Abbas AK, Fischbach MA, Rosenblum MD (2015) A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity 43:1011–1021 Scher JU, Ubeda C, Artacho A, Attur M, Isaac S, Reddy SM, Marmon S, Neimann A, Brusca S, Patel T, Manasson J, Pamer EG, Littman DR, Abramson SB (2015) Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol 67:128–139 Schmidt E, Zillikens D (2013) Pemphigoid diseases. Lancet 381:320–332 Schmidt E, Della Torre R, Borradori L (2011) Clinical features and practical diagnosis of bullous pemphigoid. Dermatol Clin 29:427–438. viii–ix Schmidt E, Della Torre R, Borradori L (2012) Clinical features and practical diagnosis of bullous pemphigoid. Immunol Allergy Clin North Am 32:217–232. V

328

F. A. P. Zeng and D. F. Murrell

Schmidt E, Spindler V, Eming R, Amagai M, Antonicelli F, Baines JF, Belheouane M, Bernard P, Borradori L, Caproni M, Di Zenzo G, Grando S, Harman K, Jonkman MF, Koga H, Ludwig RJ, Kowalczyk AP, Muller EJ, Nishie W, Pas H, Payne AS, Sadik CD, Seppanen A, Setterfield J, Shimizu H, Sinha AA, Sprecher E, Sticherling M, Ujiie H, Zillikens D, Hertl M, Waschke J (2017) Meeting report of the pathogenesis of pemphigus and pemphigoid meeting in Munich, September 2016. J Invest Dermatol 137:1199–1203 Scully C, Carrozzo M, Gandolfo S, Puiatti P, Monteil R (1999) Update on mucous membrane pemphigoid: a heterogeneous immune-mediated subepithelial blistering entity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88:56–68 Seidman JS, Eichenfield DZ, Orme CM (2019) Dupilumab for bullous pemphigoid with intractable pruritus. Dermatol Online J 25. 13030/qt25q9w6r9 Shih YC, Wang B, Yuan H, Zheng J, Pan M (2020) Role of BP230 autoantibodies in bullous pemphigoid. J Dermatol 47:317–326 Shindo Y, Ito R, Kobayashi D, Ando M, Ichikawa M, Shiraki A, Goto Y, Fukui Y, Iwaki M, Okumura J, Yamaguchi I, Yagi T, Tanikawa Y, Sugino Y, Shindoh J, Ogasawara T, Nomura F, Saka H, Yamamoto M, Taniguchi H, Suzuki R, Saito H, Kawamura T, Hasegawa Y (2013) Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia. Am J Respir Crit Care Med 188:985–995 Shuster S, Black MM, Mcvitie E (1975) The influence of age and sex on skin thickness, skin collagen and density. Br J Dermatol 93:639–643 Stulberg DL, Penrod MA, Blatny RA (2002) Common bacterial skin infections. Am Fam Physician 66:119–124 Sullivan A, Nord CE (2002) Probiotics in human infections. J Antimicrob Chemother 50:625–627 Suthanthiran M, Schwartz JE, Ding R, Abecassis M, Dadhania D, Samstein B, Knechtle SJ, Friedewald J, Becker YT, Sharma VK, Williams NM, Chang CS, Hoang C, Muthukumar T, August P, Keslar KS, Fairchild RL, Hricik DE, Heeger PS, Han L, Liu J, Riggs M, Ikle DN, Bridges ND, Shaked A, Clinical Trials In Organ Transplantation 04 Study, I (2013) Urinary-cell mRNA profile and acute cellular rejection in kidney allografts. N Engl J Med 369:20–31 Szczesiul JM, Shermock KM, Murtaza UI, Siberry GK (2007) No decrease in clindamycin susceptibility despite increased use of clindamycin for pediatric community-associated methicillin-resistant staphylococcus aureus skin infections. Pediatr Infect Dis J 26:852–854 Tamaki K, Furuya T, Kubota Y, Uno A, Shimada S (1991) Seborrheic pemphigoid and polymorphic pemphigoid. J Am Acad Dermatol 25:568–570 Tay YK, Cheong WK (1993) An unusual case of localised pemphigoid. Ann Acad Med Singap 22: 937–938 Theilade E, Wright WH, Jensen SB, Loe H (1966) Experimental gingivitis in man. II. A longitudinal clinical and bacteriological investigation. J Periodontal Res 1:1–13 Timmerman CP, Mattsson E, Martinez-Martinez L, De Graaf L, Van Strijp JA, Verbrugh HA, Verhoef J, Fleer A (1993) Induction of release of tumor necrosis factor from human monocytes by staphylococci and staphylococcal peptidoglycans. Infect Immun 61:4167–4172 Tricamo MB, Rees TD, Hallmon WW, Wright JM, Cueva MA, Plemons JM (2006) Periodontal status in patients with gingival mucous membrane pemphigoid. J Periodontol 77:398–405 Tsuruta D, Nishikawa T, Yamagami J, Hashimoto T (2012) Unilateral bullous pemphigoid without erythema and eosinophil infiltration in a hemiplegic patient. J Dermatol 39:787–789 Tveten Y, Jenkins A, Kristiansen BE (2002) A fusidic acid-resistant clone of Staphylococcus aureus associated with impetigo bullosa is spreading in Norway. J Antimicrob Chemother 50: 873–876 Ueda Y, Nashiro K, Seki Y, Otsuka F, Tamaki K, Ishibashi Y (1989) Pemphigoid vegetans. Br J Dermatol 120:449–453 Ujiie H, Sasaoka T, Izumi K, Nishie W, Shinkuma S, Natsuga K, Nakamura H, Shibaki A, Shimizu H (2014) Bullous pemphigoid autoantibodies directly induce blister formation without complement activation. J Immunol 193:4415–4428

13

Microorganisms in Pathogenesis and Management of Bullous Pemphigoid

329

Vaillant L, Bernard P, Joly P, Prost C, Labeille B, Bedane C, Arbeille B, Thomine E, Bertrand P, Lok C, Roujeau JC (1998) Evaluation of clinical criteria for diagnosis of bullous pemphigoid. French Bullous Study Group. Arch Dermatol 134:1075–1080 Venning VA, Taghipour K, Mohd Mustapa MF, Highet AS, Kirtschig G (2012) British association of dermatologists' guidelines for the management of bullous pemphigoid 2012. Br J Dermatol 167:1200–1214 Vogelzang A, Guerrini MM, Minato N, Fagarasan S (2018) Microbiota - an amplifier of autoimmunity. Curr Opin Immunol 55:15–21 Volz T, Kaesler S, Draing C, Hartung T, Rocken M, Skabytska Y, Biedermann T (2018) Induction of IL-10-balanced immune profiles following exposure to LTA from staphylococcus epidermidis. Exp Dermatol 27:318–326 Wade WG (2013) The oral microbiome in health and disease. Pharmacol Res 69:137–143 Waller JM, Maibach HI (2005) Age and skin structure and function, a quantitative approach (I): blood flow, pH, thickness, and ultrasound echogenicity. Skin Res Technol 11:221–235 Wanke I, Steffen H, Christ C, Krismer B, Gotz F, Peschel A, Schaller M, Schittek B (2011) Skin commensals amplify the innate immune response to pathogens by activation of distinct signaling pathways. J Invest Dermatol 131:382–390 Wessman LL, Andersen LK, Davis MDP (2018) Incidence of diseases primarily affecting the skin by age group: population-based epidemiologic study in Olmsted County, Minnesota, and comparison with age-specific incidence rates worldwide. Int J Dermatol 57:1021–1034 Wilhelm KP, Cua AB, Maibach HI (1991) Skin aging. Effect on transepidermal water loss, stratum corneum hydration, skin surface pH, and casual sebum content. Arch Dermatol 127:1806–1809 Williams DM (1990) Vesiculo-bullous mucocutaneous disease: benign mucous membrane and bullous pemphigoid. J Oral Pathol Med 19:16–23 Winkelmann RK, Su WP (1979) Pemphigoid vegetans. Arch Dermatol 115:446–448 Wong CH, Yam AK, Tan AB, Song C (2008) Approach to debridement in necrotizing fasciitis. Am J Surg 196:E19–E24 Woodhead M, Blasi F, Ewig S, Garau J, Huchon G, Ieven M, Ortqvist A, Schaberg T, Torres A, Van Der Heijden G, Read R, Verheij TJ, Joint Taskforce Of The European Respiratory, S., European Society For Clinical, M. & Infectious, D (2011) Guidelines for the management of adult lower respiratory tract infections--full version. Clin Microbiol Infect 17(Suppl 6):E1–E59 Wright EK, Kamm MA, Teo SM, Inouye M, Wagner J, Kirkwood CD (2015) Recent advances in characterizing the gastrointestinal microbiome in Crohn's disease: a systematic review. Inflamm Bowel Dis 21:1219–1228 Wysocki AB (2002) Evaluating and managing open skin wounds: colonization versus infection. AACN Clin Issues 13:382–397 Xia W, Quan T, Hammerberg C, Voorhees JJ, Fisher GJ (2015) A mouse model of skin aging: fragmentation of dermal collagen fibrils and reduced fibroblast spreading due to expression of human matrix metalloproteinase-1. J Dermatol Sci 78:79–82 Xu J, Saunders CW, Hu P, Grant RA, Boekhout T, Kuramae EE, Kronstad JW, Deangelis YM, Reeder NL, Johnstone KR, Leland M, Fieno AM, Begley WM, Sun Y, Lacey MP, Chaudhary T, Keough T, Chu L, Sears R, Yuan B, Dawson TL Jr (2007) Dandruff-associated Malassezia genomes reveal convergent and divergent virulence traits shared with plant and human fungal pathogens. Proc Natl Acad Sci U S A 104:18730–18735 Yamamoto C, Tamai K, Nakano H, Matsuzaki Y, Kaneko T, Sawamura D (2008) Vitamin D3 inhibits expression of pemphigus vulgaris antigen desmoglein 3: implication of a partial mechanism in the pharmacological effect of vitamin D3 on skin diseases. Mol Med Rep 1: 581–583 Yancey KB, Egan CA (2000) Pemphigoid: clinical, histologic, Immunopathologic, and therapeutic considerations. JAMA 284:350–356

330

F. A. P. Zeng and D. F. Murrell

Yayli S, Pelivani N, Beltraminelli H, Wirthmuller U, Beleznay Z, Horn M, Borradori L (2011) Detection of linear IgE deposits in bullous pemphigoid and mucous membrane pemphigoid: a useful clue for diagnosis. Br J Dermatol 165:1133–1137 Yoshioka M, Fukuishi N, Iriguchi S, Ohsaki K, Yamanobe H, Inukai A, Kurihara D, Imajo N, Yasui Y, Matsui N, Tsujita T, Ishii A, Seya T, Takahama M, Akagi M (2007) Lipoteichoic acid downregulates fcepsilonRI expression on human mast cells through toll-like receptor 2. J Allergy Clin Immunol 120:452–461 Zeeuwen PL, Kleerebezem M, Timmerman HM, Schalkwijk J (2013) Microbiome and skin diseases. Curr Opin Allergy Clin Immunol 13:514–520 Zinder R, Cooley R, Vlad LG, Molnar JA (2019) Vitamin A and wound healing. Nutr Clin Pract 34: 839–849

Part IV Microorganisms in Pathogenesis & Management of Autoimmune Thyroid Diseases

Microorganisms in Pathogenesis and Management of Graves’ Disease

14

Silvia Martina Ferrari, Fabrizio Guarneri, Poupak Fallahi, Alessandro Antonelli, and Salvatore Benvenga

Abstract

Graves’ disease (GD) is an organ-specific autoimmune disorder associated with serum antithyroid-stimulating hormone receptor autoantibodies, and it is the most frequent cause of hyperthyroidism in Western countries. The not entirely known GD risk factors are comprised of genetic predisposition and interactions between endogenous and environmental factors. Several papers evaluated whether infectious agents may trigger GD development, with discordant results. It is S. M. Ferrari (*) Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy e-mail: [email protected] F. Guarneri Department of Clinical and Experimental Medicine-Dermatology, University of Messina, Messina, Italy P. Fallahi Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy e-mail: [email protected] A. Antonelli Department of Surgical, Medical and Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy e-mail: [email protected] S. Benvenga Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy Master Program on Childhood, Adolescent and Women’s Endocrine Health, University of Messina, Messina, Italy Interdepartmental Program of Molecular and Clinical Endocrinology and Women’s Endocrine Health, Azienda Ospedaliera Universitaria Policlinico ‘G. Martino’, Messina, Italy # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_14

333

334

S. M. Ferrari et al.

recognized that Helicobacter pylori and hepatitis C virus (HCV) are the most important microorganisms associated with thyroid autoimmunity and those with more reported information. It has been suggested that HCV is able to enter thyroid cells stimulating the release of Th1 chemokines (CXCL10, CXCL11, and CXCL9) and other cytokines (interleukin-8, etc.) that recruit Th1 lymphocytes into the gland, favoring the onset and reiteration of the autoimmune inflammation. This could lead to the appearance of serum thyroid autoantibodies and hypothyroidism. To date, no guidelines exist in this field given that there are still some unanswered questions, with this gap precluding clinicians from the best management of GD patients. Further research is needed to identify new GD risk factors and to reduce its occurrence and improve its management. Keywords

Graves’ disease · Graves’ ophthalmopathy · Chemokines · Cytokines · Anti-TSHR autoantibodies · TgAb · TPOAb · Infective agents · Hepatitis C virus · Helicobacter pylori

14.1

Introduction

Graves’ disease (GD) is an organ-specific autoimmune disorder due to overstimulation of the thyroid by serum antithyroid-stimulating hormone receptor (TSH-R) stimulating autoantibodies, and it is the most frequent cause of hyperthyroidism in Western countries (yearly incidence ~20/100,000 persons) (Antonelli et al. 2015; Smith and Hegedüs 2016). GD is one of the principal autoimmune thyroid disorders (AITD), which are linked to the failure of immune tolerance against thyroid antigens (Romagnani 1998; McLachlan and Rapoport 2014). It is characterized by increased TSH-R-driven synthesis and secretion of thyroid hormones and by the appearance of circulating antithyroid antibodies (ATA) and of autoreactive lymphocytes in the thyroid (Furszyfer et al. 1972). TSH-R, thyroglobulin (Tg), and thyroid peroxidase (TPO) have unusual properties (“immunogenicity”) contributing to the breakdown of tolerance (McLachlan and Rapoport 2014). The specific section of this chapter devoted to microorganisms cannot be understood completely without some introductory explanations on the epidemiology, clinical picture, and pathogenesis of GD.

14.2

Epidemiology

GD is more prevalent in females, particularly those between 30 and 60 years of age, with a risk of 3%, compared to 0.5% for men (Smith and Hegedüs 2016). A study conducted in Minnesota reported an age-related incidence in participants with 20–40 years of age (Furszyfer et al. 1972). A French study reported 73.3% of

14

Microorganisms in Pathogenesis and Management of Graves’ Disease

335

cases with GD among 1572 hyperthyroid patients (Goichot et al. 2016). In Sweden, the risk of GD is 1.7%, with a mean age of ~48 years at diagnosis (AbrahamNordling et al. 2011). Furthermore, the frequency of GD is higher in Asia and lower in sub-Saharan Africa (McGrogan et al. 2008; Shapira et al. 2010). An elevated risk of thyroid cancer, particularly the tall cell variant of papillary thyroid cancer, has been observed in GD patients with thyroid nodules (Antonelli et al. 2008a; MacFarland et al. 2018; Spinelli et al. 2004).

14.3

Clinical Manifestations

GD clinical manifestations are linked to hyperthyroidism and to the autoimmune process. Since thyroid hormones target various body systems, symptoms and signs associated with GD are multiple, significantly influencing the general health. Common symptoms include heat sensitivity and increased sweating (with the skin being, therefore, warm and moist), weight loss even in the face of hyperphagia, tremor, insomnia, irritability and anxiety, palpitations, fatigue, increase of thyroid volume (goiter), modifications in menstrual cycles, reduced libido, erectile dysfunction, frequent bowel movements, and others (Vaidya and Pearce 2014; Antonelli et al. 2020a). A study conducted in >3000 patients with thyrotoxicosis showed that more than a half of them with an age >61 years had less than three classic thyrotoxicosis symptoms (Boelaert et al. 2010); atrial fibrillation was the most frequently associated one. Among 500,000 adult patients followed up for more than 8 years, an incidence of 13% was reported for atrial fibrillation in those with thyrotoxicosis aged >65 years (Selmer et al. 2012). Thyrotoxicosis may be triggered by hard physical activity, high carbohydrate load, alcohol, or infections, and it may rarely be associated with thyrotoxic periodic paralysis (Chang et al. 2013). Another triggering factor of autoimmune hyperthyroidism is stress (see below for more details) (Vita et al. 2015). Rarely, thyrotoxicosis is very severe and even life-threatening, a condition known as thyroid storm (Vaidya and Pearce 2014). Thyroid storm can be precipitated by various events, such as infection, surgery, a poor compliance to the treatment, and trauma (Vaidya and Pearce 2014). Thyroid storm is linked to an altered liver function, features of cardiac failure, tachycardia, deranged mental state, fever, and agitation (Akamizu et al. 2012). An autoimmune manifestation of GD, which occurs with a frequency of ~1–5%, is pretibial myxedema, also called thyroid dermopathy or Graves’ dermopathy (Menconi et al. 2014). It is characterized by a waxy, discolored induration of the skin on the anterior aspect of the lower legs, until the dorsum of the feet, or by a non-localized, non-pitting edema of the skin in the same areas (Burch and Cooper 2015). It can also reach the higher-up trunk and upper extremities (including the face, ears, neck, back, and chest) in more advanced cases. Acropachy is comparable to the clubbing of toes or fingers, and it is observed only in patients with dermopathy (Smith and Hegedüs 2016).

336

S. M. Ferrari et al.

Graves’ ophthalmopathy (GO), another autoimmune manifestation, occurs in up to 50% of GD patients. Patients can have no ocular symptoms or be symptomatic and disturbed by the appearance of their eyes. Common ocular symptoms include an exaggerated tearing (often aggravated by bright lights, wind, or cold air), the perception of a foreign object in the eye, retroocular pain, diplopia, veiling of sight, color vision desaturation, and sometimes loss of vision. The characteristic signs of Graves’ orbitopathy are periorbital edema, proptosis (or exophthalmos), and tearing. The exophthalmos is often asymmetric, and the feeling of pressure behind the eyeballs can also be present. Periorbital edema can accompany and mask the proptosis. Conjunctival inflammation and ulceration can occur from overexposure in more severe cases (Davies and Burch 2019). The Clinical Activity Score is based on the classical signs of acute inflammation (redness, pain, swelling, and altered function), and it was suggested as a clinical classification to distinguish between the active and quiescent stages of the disease. It permits to evaluate both the severity and evolution of the disease. Encephalopathy can also be associated with AITD, a relatively rare steroidresponsive encephalopathy reported both in patients with Hashimoto’s thyroiditis (HT) and GD (Cantón et al. 2000). In ~20% of GD patients, an association with another autoimmune disease has been shown. In an Italian study (Ferrari et al. 2019a), 3209 GD patients (984 of whom had GO) were evaluated prospectively for the prevalence of other autoimmune diseases. They were compared with three age- and sex-matched control groups of similar iodine intake: 1069 healthy subjects, 1069 patients with autoimmune thyroiditis (AT), and 1069 patients with multinodular goiter (MNG). This study showed that another associated autoimmune disease was present in 16.7% of GD patients: vitiligo (2.6%), chronic autoimmune gastritis (2.4%), Sjogren disease (0.8%), celiac disease (1.1%), polymyalgia rheumatica (1.3%), sarcoidosis and systemic lupus erythematosus (6 years old, acute anterior uveitis, AS, enthesitis-associated arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, acute anterior uveitis, or one of these diseases in first-degree relative (i.e., parents, siblings) (Lin et al. 2009). Unfortunately, the etiology of this disease is not yet fully understood, although hereditary predisposition and environmental factors are known to play significant roles in its pathogenesis. It is also important to note the child’s condition before the disease (due to the high incidence of infectious diseases in the anamnesis) and possible signs of connective tissue dysplasia (e.g., increased joint mobility, hernia, mitral valve prolapse). Other precipitating factors in the development of disease among adolescents include ankylosing arthritis, physical and mental overload, trauma, hypothermia, and vaccinations (Prelog et al. 2008).

424

Z. Mukhatayev et al.

17.1.1.4 Ankylosing Spondylitis Ankylosing spondylitis (AS) is a systemic inflammatory disease in which the spine is predominantly affected (Zhu et al. 2019a). This involves a pathological process in the spine that causes the fusion of individual vertebrae (i.e., ankylosis), eventually leading to limitation of mobility. At the same time, ossification of the ligaments surrounding the spine occurs. As a result, the spine can completely lose its flexibility and turn into a solid bone (Mcveigh and Cairns 2006). Bekhterev (1892) described the main clinical manifestations of this disease and proposed its isolation as a nosological form (Kesselring 2011). Strumpell demonstrated that the basis of the disease is a chronic ankylosing inflammatory process in the spine and sacroiliac joints (Strümpell 1897). Subsequently, Marie (1898) described the rhizomelic form of the disease (Weber 1931). The pathological process involves the sacroiliac joints, spine and peripheral joints, intervertebral discs, vertebral bodies, and spinal ligaments at their points of attachment to the vertebral body (enthesopathy). The sacroiliac joint is the first to be affected, followed by the intervertebral and costovertebral joints, in which chronic inflammation of the synovial membrane initially develops at the onset of the disease. This is histologically similar to synovitis in rheumatoid arthritis (RA) (Khan and Van Der Linden 2019). As a result, progressive destruction of the articular cartilage develops with ankylosing of the iliosacral joint and small joints of the spine, along with erosion of the subchondral bone. Extraarticular sclerosis is also observed in the bone. Later on, similar changes occur in the pubic symphysis (Zhu et al. 2019a). 17.1.1.5 Arthritis Related to Inflammatory Bowel Diseases Ulcerative colitis is a chronic inflammatory process of unknown etiology that develops in the mucosa and submucosa, predominantly of the colon (Arvikar and Fisher 2011). Regional granulomatous ileitis is a chronic, possibly viral, bowel disease that affects all layers of the intestinal wall (transmural lesion) and sometimes spreads to the mesentery and regional lymph nodes. This affects both the small and large intestines, but it is most often localized in the terminal section of the small intestines (regional, terminal ileitis). These diseases can be accompanied by damage to the peripheral joints, the spine, or both (Orchard 2012). The clinical manifestations of the articular syndrome in both processes are of the same type. Arthritis (i.e., inflammation) and arthralgia (i.e., pain without inflammation) are the two types of joint problems that can occur. In 60–70% of cases, the large joints are affected in patients with peripheral arthritis. Compared with other types of arthritis, this is not erosive or deforming, and no long-term joint damage is expected (Orchard 2012). The pathogenesis of the intestinal process and joint damage has not yet been fully established, but it is believed to involve toxic, immune, and autoimmune mechanisms, among others (Zhang and Li 2014). 17.1.1.6 Undifferentiated Spondyloarthritis (uSpA) Undifferentiated SpA (uSpA) is a nonspecific mono- or polyarthropathy that lacks the clinical, serological, and radiological features that suggest a specific diagnosis (Zeidler et al. 1992). This often turns out to be an early presentation of a more

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

425

well-known form of arthritis. Most people with undifferentiated spondyloarthritis have one or more of the following symptoms: inflammatory back pain, unilateral or alternating buttock pain, enthesitis, peripheral arthritis, arthritis of the small joints, swollen fingers or toes, heel pain, fatigue, and iritis (Kataria and Brent 2004). The concept of uSpA is currently used to describe a clinical setting in which the classical features of SpA are not fully present (Lamot et al. 2015).

17.1.2 Socioeconomic Impact The quality of life of patients with SpAs is significantly impacted by the pain and fatigue caused by the nature of their disease (Hewlett et al. 2005). These also exert a considerable psychological impact, specifically in terms of anxiety and depression (Dickens et al. 2002). The features of such chronic diseases can negatively impact patients’ social life, including their personal relationships with family members and friends (Minnock et al. 2003). In addition, having a chronic disease impairs their working capacity. Furthermore, SpAs can negatively impact productivity, especially during the prime of patients’ working lives. Thus, it is important to spread awareness of these diseases. Patients should be empowered to seek appropriate care so as to receive a timely diagnosis and appropriate therapy (Ramonda et al. 2016).

17.2

Pathophysiology of SpA

17.2.1 The Genetic Basis of SpA 17.2.1.1 HLA-B*27 The association between SpA development and HLA-B*27 was first discovered in 1973 (Schlosstein et al. 1973; Caffrey and James 1973). The strength of association varies and is dependent on the specific SpA. HLA-B*27, a major histocompatibility complex (MHC) class I molecule, is considered the primary genetic risk factor for the development of AS, which is the prototype of SpA. Indeed, AS is present in up to 90% of SpA patients (Hammer et al. 1990; Brown et al. 1997). The risk of AS in monozygotic twins is as high as 63%. First-degree relatives have an 8% risk. Second- and third-degree relatives experience a 1 and 0.7% risk, respectively (Brown et al. 2000). However, the small sample sizes producing these data introduce a significant limitation (Díaz-Peña et al. 2020). Another study using singlenucleotide polymorphisms’ (SNPs) data from independent cases and controls approximated AS heritability at 39.9 and 7.4% for RA (Cortes et al. 2013; Ellinghaus et al. 2016). Molecular typing results determined the HLA-B*27 subtypes highly associated with SpA. The differences between subtypes are located in exons 2 and 3, leading to amino acid substitutions of the peptide-binding cleft (Díaz-Peña et al. 2020). The most abundant HLA subtypes in SpA are HLA-B*2705 (the most prevalent in Caucasian and American Indian populations and worldwide) (Reveille and Maganti 2009), HLA-B*2704 (Asian population), HLA-B*2702

426

Z. Mukhatayev et al.

(Mediterranean population), HLA-B*2703, and HLA-B*2707 (Middle and Southeast Asian populations) (Reveille and Maganti 2009). Interestingly, two additional HLA-B*27 subtypes, HLA-B*2706 and HLA-B*2709, have not been associated with SpA at all (López-Larrea et al. 1995; Paladini et al. 2005).

17.2.1.2 Non-HLA B27 MHC Genes The presence of the HLA-B*27 gene contributes to only 20% of SpA genetic risk (De Koning et al. 2018). The other genes contributing to the development of SpA were identified by genome-wide association studies (GWAS) (Dougados and Baeten 2011). Approximately, 7% of the genetic predisposition to SpA comes from nonMHC genes (Ellinghaus et al. 2016). The known non-HLA-B*27 genes include endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) and ERAP2, genes involved in the IL-17/IL-23 pathway such as the interleukin 23 receptor (IL23R) (Burton et al. 2007), and two gene deserts on chromosomes 21q22 and 2p15 (Reveille et al. 2010a). Furthermore, many MHC-I and MHC-II loci may contribute to the advancement of AS. For example, the HLA-A, HLA-B*40, HLA-B*60, HLA-DRB1, HLADQA1, and HLA-DPB1 genes have been found to promote AS development by interacting with natural killer (NK) cells and T cells participating in antigen presentation and inflammation progression (Zhu et al. 2019b). 17.2.1.3 IL-17/IL-23 Pathways The IL-17/IL-23 pathways are believed to contribute immensely to the development of autoimmune conditions. IL-23 is a pro-inflammatory cytokine expressed by antigen-presenting cells (APCs) such as macrophages and dendritic cells. IL-23 stimulates the differential expansion of T helper 17 (Th17) cells (Tan et al. 2009). One proposed disease mechanism implicates IL-23 maintaining the pathogenic phenotype of Th17 cells via the Blimp-1 (Prdm1) transcription factor (Jain et al. 2016). Downstream targets of IL-23 signaling pathways such as tyrosine kinase 2 (TYK2) and signal transducer and activator of transcription 3 (STAT3) have known polymorphisms that also increase the susceptibility to AS (Davidson et al. 2011). IL-23-activated Th17 cells are usually located in the lamina propria of the intestine. Exposure to specific antigens, particularly from bacterial origins, can induce Th17 cell instability leading to their transition into regulatory T cells (Tregs) (Gagliani et al. 2015). Moreover, Treg cell accumulation in the bowel might be promoted by IL-23 cytokines (Fasching et al. 2017; Garcia-Montoya et al. 2018b). Th17 cells play a crucial role in inflammation (Mcgeachy et al. 2009) via the pro-inflammatory cytokine, IL-17 (Yago et al. 2017). IL-17 is known for its enhanced effects on osteoclasts and various effects on bone metabolism (Pedersen and Maksymowych 2019a). Significantly, the inhibition of IL-17 reduced joint inflammation and suppressed bone erosion in murine arthritis models (Lubberts et al. 2001; Koenders et al. 2005). 17.2.1.4 ERAP1/ERAP2 Polymorphism in endoplasmic reticulum aminopeptidase (ERAP)1 and ERAP2 genes combined with the presence of HLA-B*27 brings the genetic risk of disease

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

427

development to 70% (Burton et al. 2007). In fact, ERAP1/ERAP2 genes are recognized as the second most significant risk factors for AS, after HLA-B*27 (Tsui et al. 2010). One study confirmed that HLA-B*27-positive patients show an association between ERAP1 and AS, suggesting an epistatic interaction between these genes (Vitulano et al. 2017). ERAP1 polymorphisms have also been linked to HLA-B*27-negative and HLA-B*40-positive cases of AS (Kanaseki et al. 2006). Interestingly, ERAP2 SNPs have been associated with both HLA-B*27-negative and HLA-B*27-positive AS cases (Zhu et al. 2019b). Genetically, the ERAP1 and ERAP2 genes are located at chromosome 5q15 (Kanaseki et al. 2006). Five SNPs of ERAP1 and two SNPs of ERAP2 increased the risk of SpA development. ERAP1 polymorphisms such as rs30187, rs27044, rs174820, rs2287987, and rs10050860 and ERAP2 SNPs rs2549782 and rs2248374 interfered with the trimming function of aminopeptidases leading to SpA development (Vitulano et al. 2017).

17.2.2 Main Mechanistic Hypotheses Underlying SpA Pathogenesis The exact pathogenesis of SpA has yet to be fully elucidated. Many theories have been proposed to explain the contribution and interaction of genetic and environmental factors in disease pathogenesis, including the arthritogenic peptide hypothesis, the protein misfolding hypothesis, the HLA-B*27 homodimer formation hypothesis, and the altered antigen processing hypothesis (Fig. 17.1).

17.2.2.1 Arthritogenic Peptide Hypothesis One of the oldest and major hypotheses explaining the relationship between the HLA-B*27 and SpA is the “arthritogenic peptide hypothesis,” also known as molecular mimicry hypothesis (Cusick et al. 2012; Rosenbaum and Asquith 2016). This hypothesis considers that there are certain immunodominant arthritis-causing HLA-B*27-specific antigenic peptides, which are shared between arthritis-causing bacteria and autoantigens, resulting in cross-reactivity and HLA-B*27-restricted cytotoxic T cell response and corresponding autoimmune response in joints or other affected tissues (Khan 2013; Reveille 2019a; Oldstone 1989; Grandon et al. 2019; Pedersen and Maksymowych 2019b; Garcia-Montoya et al. 2018a). Thus, when some HLA-B*27-positive individuals get infected with arthritis-causing pathogens, HLA-B*27-restricted cytotoxic T cells get activated in the joints and initiate the autoimmune response (Reveille 2019a; Pedersen and Maksymowych 2019b; Sharip and Kunz 2020). Much evidence is concordant with this hypothesis. Peptides from the HLA-B*27 allele have sequence homology with peptides from enterobacteria and Chlamydia. It has been previously shown that Chlamydia may induce autoreactive cytotoxic T lymphocytes with specificity for HLA-B*27 (Popov et al. 2002). In patients who developed ReA, after being infected with Salmonella or Chlamydia pathogens, HLA-B*27-restricted CD8+ T cell Salmonella- or Chlamydia-specific responses have been found (Bowness 2015; Appel et al. 2004). Many studies on HLA-B*27 alleles and their differential association with SpA pathogenesis have greatly supported the arthritogenic peptide hypothesis. For

428

Z. Mukhatayev et al.

Fig. 17.1 The hypothesis of the pathogenetic role of HLA-B*2705 molecules in spondyloarthritis. (1) Arthritogenic peptides are demonstrated by properly folded HLA-B*27, which can be identified by autoreactive CD8+ T cells, causing inflammation. (2) Misfolded HLA-B*27 chains and binding of BiP result in ER stress and activation of UPR and in turn the increased production of IL-23 and other pro-inflammatory cytokines. (3) Cell surface HLA homodimers interact with CD4+ T cells through innate immune receptors, such as KIR-3DL2, facilitating cell-mediated autoimmune responses. (4) Altered ERAP1 activity can lead to changes in peptide processing, with pathological consequences. ER, endoplasmic reticulum; ERAP1, ER aminopeptidase 1; KIR-3DL2, killer immunoglobulin-like receptor; and UPR, unfolded protein response. Adapted from Sharip and Kunz (2020)

example, some allelic variants, such as HLA-B*2705, HLA-B*2702, and HLA-B*2704, are strongly linked with the disease, whereas other alleles, including HLA-B*2706 and HLA-B*2709, were not, or only weakly, correlated with disease pathogenesis (Syrbe and Sieper 2020a). HLA-B*27 can react with antigens of gram-negative microorganisms. For example, Klebsiella bacteria have antigens that are molecularly homologous to HLAB*27 or other self-antigens and have immunological cross-reactivity with them. The HLA-B*27.1 antigen (residues 72–77) and Klebsiella pneumoniae nitrogenase (residues 188–193) share six similar amino acids (De Vries et al. 1992). The Pul-D secretion protein “DRDE” sequence (residues 596–599) of Klebsiella pullulanase enzyme is similar to the “DRED” motif (residues 74–77) of HLAB*27 (Fielder et al. 1995). Antigenic extracts of five gut-inhabited bacterial agents, including Klebsiella, Enterobacter, Salmonella, Shigella, and Yersinia microbes, reacted positively with antibodies from a rabbit immunized with HLA-B*27-positive lymphocytes, implying the presence of shared cross-reactive antigens (Welsh

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

429

et al. 1980). Klebsiella can cause the host to develop various types of cross-reactive antibodies, each of which will attack a different portion of the body, particularly those with strong HLA-B*27 antigen expression (Rashid et al. 2013; Cauli et al. 2012). Furthermore, Klebsiella pullulanase A and collagens (types I, III, and IV) have molecular similarities, explaining why pathogenic lesions are seen in the spine (Fielder et al. 1995). As a result, anti-Klebsiella antibodies may act as autoantibodies against HLA-B*27 and spinal collagens, implying that AS is an autoimmune illness.

17.2.2.2 The Unfolded Protein Response The unfolded protein response (UPR) is another hypothesis considering the role of HLA-B*27 in disease pathogenesis. This hypothesis suggests that compared to other MHC, HLA-B*27 molecules tend to fold slowly or even misfold in the endoplasmic reticulum (ER), resulting in the accumulation of misfolded HLA-B*27. This accumulation of misfolded forms of HLA-B*27 results in ER stress and induces UPR, which seeks to restore the cell to its normal state (Schittenhelm et al. 2015; Mear et al. 1999; Kenna et al. 2015). UPR affects cytokine production on multiple levels, from stimulating surface receptors to directly activating pro-inflammatory pathways (Smith 2018). Moreover, UPR destabilizes the normal immune system and leads to the production of inflammatory cytokines, such as IL-1, IL-23, and INF-β that are involved in the pathogenesis of AS and activate the IL-17/IL-23 signaling pathway (Ambarus et al. 2018; Delay et al. 2009; Colbert 2000). HLA-B*27 misfolding activates NF-kβ, resulting in the increased production of pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6 (Sharip and Kunz 2020). In accordance with the UPR hypothesis, HLA-B*27 misfolding and UPR have been found in the gut and synovial joints of patients with SpA and transgenic rat models of AS (Ebringer 1983). Despite the clear link between the accumulation of misfolded HLA-B*27 and the production of pro-inflammatory cytokines, the role of misfolded HLA-B*27 and ER stress in the SpA pathogenesis is not completely understood and remains to be discovered (Sharip and Kunz 2020). 17.2.2.3 HLA-B*27 Homodimer Formation The HLA-B*27 homodimer formation hypothesis suggests that free HLA-B*27 heavy chains can homodimerize without the β2 microglobulin domain. Cysteine disulfide bonds form homodimers at Cys 67 (Zhu et al. 2019b). Newly assembled homodimers abnormally interact with leukocyte immunoglobulin-like receptors (LILR) and killer cell immunoglobulin-like receptor 3DL2 (KIR-3DL2) (Giles et al. 2012). This interaction promotes inflammation by activating the IL-17/IL-23 signaling pathway (Wong-Baeza et al. 2013). KIR-3DL2 and LILR are highly expressed on the cell surface of both CD4+ T cells and NK cells (Garcia-Montoya et al. 2018a). Interestingly, the KIR-3DL2 receptor interacts with HLA-B*27 homodimers with much higher affinity than with HLA-B*27 heterodimers (Zhu et al. 2019b). This higher affinity stimulates differentiation and survival of KIR-3DL2 expressing CD4+ T cells and NK cells in SpA patients (Chan et al. 2005; Wong-Baeza et al. 2013), which upregulates IL-17, TNF-α, and INF-γ cytokine expression (Bowness et al. 2011). Overall, the interaction between KIR-

430

Z. Mukhatayev et al.

3DL2, LILR receptors, and HLA-B*27 homodimers drives inflammation by promoting T cell and NK cell survival and involves the differentiation of LILR+ APCs (Reveille 2019b; Syrbe and Sieper 2020b). These findings help define the role of HLA-B*27 homodimers in auto-inflammation associated with SpA pathogenesis.

17.2.2.4 Abnormal Antigen Processing by ERAP1 and ERAP2 ERAP1 and ERAP2 aminopeptidases are zinc metalloproteinases located in the ER (Rock et al. 2016). ERAP1 trims peptides down to 8–10-mer peptides at the N-terminus leaving suitable anchor residues for antigen presentation by MHC class I molecules, particularly HLA-B*27 on the surface of NK or CD8+ T cells (Kanaseki et al. 2006; López De Castro 2018). ERAP1 can also proteolytically cleave several surface cytokine receptors such as TNFR1, IL-6Rα, and IL-1R2, interfering with their capacity to conduct cell signals and reduce pro-inflammatory processes (Zhu et al. 2019b). However, one study demonstrated that cytokine receptor cleavage does not play a central role in developing SpA (Reveille 2012). ERAP2 is known for its affinity for shorter peptides (7–8 mers). Its capacity to cleave these shorter peptides will not apply to MHC class I presentation (Sharip and Kunz 2020). The levels of ERAP2 are much lower in ER compared to ERAP1 and might not be present at all in 25% of individuals possessing exact ERAP2 SNPs (Andrés et al. 2010). Alterations of ERAP1/ERAP2 can affect appropriate peptide amounts by interfering with HLA-B*27 folding speed, further elevating ER stress and the development of AS (Reveille 2014). Disease-associated ERAP1 alleles are loss of function (LoF), demonstrating that abnormal processing of peptides and presentation are the keys to developing SpA (Sharip and Kunz 2020). ERAP1 LoF polymorphisms alter the expression of HLA-B*27 heavy chains, folding, and dimerization in T and NK cells (Dashti et al. 2018). This effectively diminishes cell surface levels of HLA-B*27 homodimers [54], resulting in the alteration of the MHC class I peptidome (Li et al. 2019). ERAP1/ERAP2 activity disruption causes altered immunodominance and changes activation of NK and T cells, leading to distorted innate and adaptive immune responses (Sharip and Kunz 2020).

17.3

The Microbiome in SpA

The conventional explanation for the onset of autoimmune conditions, including SpA, has been based on a combination of genetic predisposition and environmental factors triggering immunological deregulation, and several hypotheses and models have been proposed to describe these interactions (described in part 2 of this chapter). However, none of these hypotheses explains SpA pathogenesis completely. Recent research has discovered another key contributor to the disease etiopathogenesis – the human microbiome. The intestinal or gut microbiome contains the largest population of total bacteria in the human body. In the healthy gut, the microbiome involves nine bacterial divisions (Bäckhed et al. 2005; Eckburg et al. 2005), where Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria account for 98% of all 16S rRNA sequences (Hattori and Taylor 2009). Researchers

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

431

currently debate that the intestinal microbiome can be comprised of unique clusters or “enterotypes,” differing in composition and having distinct functions. These enterotypes are divided into three groups. Enterotype 1 is dominated by the Bacteroidetes genus, enterotype 2 by Prevotella, and enterotype 3 by Ruminococcus (Arumugam et al. 2011). The definitive role of microbiome diversity and the significance of named classification types in disease pathogenesis remain unknown. Nevertheless, tremendous numbers of recent publications provide valuable insights and create new avenues of research in many diseases implicating the microbiome.

17.3.1 Role of the Gut Microbiome in Reactive Arthritis Many studies report the onset of ReA after 1–3 weeks of a gut or genitourinary tract infection (Carter and Hudson 2009). Post-dysentery ReA has been linked to Salmonella spp., Shigella spp., Campylobacter spp., and Yersinia spp. bacteria, whereas post-veneral ReA has been linked to Chlamydia spp. bacteria (Table 17.2) (Paget 2012). Synovial fluid cultures in ReA are generally negative for these pathogenic microorganisms, in contrast to septic arthritis, indicating an autoimmune origin, with HLA-B*27 thought to be a predisposing factor (Carter and Hudson 2009; Paget 2012). One hypothesis for the etiology of ReA suggests that infection with a particular bacterium causes increased intestinal permeability. Evidently, weeks after the initial infection, studies show that synovial fluid from ReA patients, which was traditionally considered to be sterile, includes bacterial components such as bacterial DNA, antigenic proteins, and lipopolysaccharides (Siala et al. 2009; Merilahti-Palo et al. 1991; Granfors et al. 1990). These permit luminal antigens to spread to other parts of the body and interact with the host’s immune system, resulting in inflammation and synovitis (Martínez-González et al. 1994). Importantly, even after the host is rid of infection, these antigens persist and cause autoantigen tolerance to break down. This may occur by disrupting signals between the expected physiological response and the normal microbiome, causing the immune system to react to antigens similar to the host (Albert and Inman 1999; Table 17.2 List of pathogenic microorganisms associated with SpA SpA type Reactive arthritis

Ankylosing spondylitis Psoriatic arthritis Arthritis related to inflammatory bowel diseases

Associated microorganism Post-dysentery: Salmonella spp., Shigella spp., Campylobacter spp., and Yersinia spp. Post-veneral: Chlamydia spp. Bacteroides, Enterococcus, Staphylococcus, Veillonella, and Klebsiella Firmicutes and Proteobacteria Bacteroides vulgaris

References Paget (2012)

Sinkorová et al. (2008), Rashid and Ebringer (2007) Gao et al. (2008) Rath et al. (1999)

432

Z. Mukhatayev et al.

Foxman et al. 2008). Several investigations have demonstrated that typical enteric organisms, notably gram-negative bacteria associated with ReA, have hypervariable area sequence homology with HLA-B*27 (Lahesmaa et al. 1993; Scofield et al. 1993). Furthermore, after Salmonella spp. infection, certain SNPs of Toll-like receptor-2 (TLR-2), an essential protein in the pathogen recognition response, are linked to ReA (Tsui et al. 2008). Taken together, neither a persistent live pathogen nor an intact organism appears to be required for inflammation following infection (Paget 2012). The molecular mimicry concept, although fascinating, largely relies on circumstantial data (Albert and Inman 1999).

17.3.2 Role of the Gut Microbiome in Ankylosing Spondylitis In AS, the intestinal microbiome plays a significant role in disease pathogenesis, confirmed by many animal studies. In germ-free environments, HLA-B*27/humanß2m transgenic rats do not develop SpA-like symptoms (Taurog et al. 1994). A similar result was observed using an ankylosing enthesopathy mouse model (Reháková et al. 2000). However, after recolonization with a mixture of Bacteroides, Enterococcus, Staphylococcus, and Veillonella species, animals exhibited progressive enthesitis and ankylosis of the tarsal joints and ankle (Table 17.2). Interestingly, colonization with Lactobacillus species does not result in arthritic conditions for these animal models (Sinkorová et al. 2008). Furthermore, repeated injection of lipopolysaccharide (LPS) to susceptible mice reduced the incidence of ankylosing enthesopathy and was linked to greater levels of interleukin-6 (IL-6) and interleukin10 (IL-10) in the blood (Capkova et al. 2012). In contrast, systemic injection with microbial ß-1,3-glucan (curdlan) of autoimmune-prone SKG mice, which carry a mutation in the ZAP-70 gene (Sakaguchi et al. 2003), triggered the development of a Th17- and IL-23-dependent disease recapitulating human SpA, with enthesitis, dactylitis, peripheral and axial arthritis, psoriasiform lesions, ileitis, and uveitis (Sakaguchi et al. 2003; Ruutu et al. 2012). Ablation of IL-17- or IL-23-dependent cell signaling through gene knockouts or neutralizing antibodies further showed that SKG arthritis severity, enthesitis severity, and ileitis severity were all IL-23-dependent (Ruutu et al. 2012; Benham et al. 2014), whereas enthesitis was specifically dependent on IL-17 and IL-22 pathways (Benham et al. 2014). These and other studies by the authors suggest that in response to systemic β-1,3-glucan administration, intestinal IL-23 induces the deregulation of the local mucosa associated with the disruption of the mucus barrier and the production of cytokines, ultimately leading to SpA development, including IL-17-/IL-22-dependent enthesitis. These studies further highlight the potential of targeting IL-23 signaling as a promising therapeutic avenue for the treatment of SpA. To further dissect the interplay between host genetic background, the local microbial and mucosal regulatory environment, and IL-23-dependent pathways in the development of SpA, the same group of investigators then compared the response of SKG mice to curdlan under a variety of conditions: Toll-like receptor 4 (TLR-4)-deficient SKG mice, wild-type BALB/c mice raised in germ-free or

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

433

specific pathogen-free conditions, and mice recolonized with modified Schaedler flora, a restricted bacterial consortium SKG mice to curdlan. Although the inflammatory response was measurable in all cases following curdlan exposure (regardless of SKG allele presence or microbiome diversity), the incidence and severity of arthritis and ileitis in SKG mice were dependent on the diversity of the host microbiome. Accordingly, disease incidence and severity positively correlated with microbiome diversity (Rehaume et al. 2014). These findings, thus, support the notion that the intestinal microbiome induces an initial IL-23-dependent proinflammatory reaction in the lamina propria in the SKG animal model. This is then accompanied by an inflammatory response in the form of enthesitis, arthritis, and axial osteoproliferation. Importantly, SKG animal studies also suggest that IL-23 and HLA-B*27 provide independent genetic contributions to SpA development (Benham et al. 2014; Rehaume et al. 2014). Many studies report the impact of gut microbiome composition on AS pathogenesis. A few years ago, an initiative was taken to correlate intestinal colonization with Klebsiella to the development of AS (Table 17.2) (Rashid and Ebringer 2007). However, the results were difficult to reproduce in the laboratory, and the findings are still disputed (Beukelman et al. 1990). Stebbings et al. investigated the fecal microbiota of 15 AS patients and 15 control participants using denaturing gradient gel electrophoresis but observed no changes between the two groups (Stebbings et al. 2002). Lin et al. compared the cecal microbiome of HLA-B*27/human-ß2m transgenic rats with wild-type Lewis rats using two different methods: metagenomic profiling using BRISK (biome representational in silico karyotyping) and 16S rRNA sequencing. When comparing transgenic to wild-type animals, the BRISK analysis indicated a more significant proportion of Bacteroides vulgatus, while the 16S rRNA analysis revealed a greater prevalence of Paraprevotella and a decreased incidence of an unknown Rikenellaceae species (Lin et al. 2014). These data indicate that HLA-B*27 is linked to changes in the cecal microbiota. Using 16S rRNA highthroughput sequencing, Costello et al. evaluated the microbial makeup of the distal ileum in human AS patients. When compared with healthy controls (Costello et al. 2015), AS individuals exhibited a higher proportion of the Lachnospiraceae, Veillonellaceae, Prevotellaceae, Porphyromonadaceae, and Bacteroidaceae families. They also showed a reduced frequency of the Ruminococcaceae and Rikenellaceae families. Remarkably, the Lachnospiraceae, Ruminococcaceae, and Prevotellaceae families were discovered to be overrepresented in dextran sodium sulfate (DSS)treated mice, an experimental model for IBD (Nagalingam et al. 2011; Elinav et al. 2011).

17.3.3 Role of the Gut Microbiome in Psoriatic Arthritis The microbiome also contributes to the pathogenesis of PsA. Many studies have evaluated the skin microbiome in PsA. Results showed that the psoriatic plaques exhibited a substantially greater number of bacteria belonging to the Firmicutes phylum, whereas Propionibacterium spp. were underrepresented compared to

434

Z. Mukhatayev et al.

healthy controls (Gao et al. 2008). Others have reported that Firmicutes was the most common phylum in both healthy and psoriasis patients, but levels were more abundant in healthy volunteers. Furthermore, the phylum Proteobacteria was overrepresented in psoriasis patients (Table 17.2), while Propionibacterium and Staphylococci spp. were underrepresented (Fahlén et al. 2012). Since PsA develops in roughly a third of individuals initially diagnosed with psoriasis (Christophers et al. 2010), the skin microbiome may provide important insight into the etiology of PsA (Castelino et al. 2014). The gut microbiota of psoriasis and PsA patients were compared to healthy controls in recent studies. While both the psoriasis and PsA groups had lower Coprococcus genus levels than healthy controls, the PsA group had considerably lower levels of the Akkermansia and Ruminococcus genera, indicating a pattern of diversity loss that might be linked to illness progression (Scher et al. 2015). Interestingly, these genera have been linked to IBD, with Ruminococcus and Akkermansia having a lower abundance in ulcerative colitis and Crohn’s disease (Png et al. 2010). Researchers discovered that in PsA patients, gut dysbiosis is associated with increased levels of secreted (sIgA) and reduced levels of receptor activator of nuclear factor kappa-B ligand (RANKL) in the intestinal mucosa. It is possible that these precursors indicate a gut barrier rupture caused by microbiome changes or that they can contribute to propagating inflammation to distant joints and entheses (Scher et al. 2015). In either case, these findings demand additional investigation to facilitate the understanding of PsA etiology.

17.3.4 Role of the Gut Microbiome in Arthritis Related to Inflammatory Bowel Diseases The latest GWAS have identified a genetic linkage between IBD and SpA concomitance (Lees et al. 2011), as well as implicating IL23R as a susceptibility gene for Crohn’s disease (Brand 2009), AS (Reveille et al. 2010b), and psoriasis (Nair et al. 2009), though, the pathogenesis of arthritis related to IBD remains elusive. Decades have passed since the microbiome-induced SpA-like arthritis was observed in the HLA-B*27/human-ß2m transgenic rat model (Taurog et al. 1994). In these rats, Bacteroides vulgaris preferentially induced colitis (Rath et al. 1999) (Table 17.2), whereas Lactobacillus rhamnosus GG prevented its relapse (Dieleman et al. 2003). Apart from the microbial impact, genetic predisposition, such as CARD15 gene polymorphisms, can also be associated with the development of Crohn’s disease and intestinal inflammation in SpA patients (Laukens et al. 2005). The CARD15 gene codes for an intracellular protein that serves as a pattern recognition receptor for bacterial compounds and activates the NF-kβ pathway. It is produced by various intestinal cells (dendritic, monocyte, paneth, and epithelial). Thus, aberrant interactions between the gastrointestinal tract and invading microorganisms may lead to arthritis-related IBD in a vulnerable host (Jacques et al. 2010).

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

435

17.3.5 Host-Microbiota Interactions, Metabolites, and Microbial Components The microbiota, a group of microorganisms that reside within the human body, offers critical signals for the immune system’s development and proper function. Many researchers are exploring the developing field of host-microbiota investigations owing to the growing availability of tools that characterize microbial populations. In addition to the microbiome, their metabolites and components are also crucial for immunological homeostasis, and they have a significant impact on the host’s vulnerability to a variety of immune-mediated illnesses and disorders. To date, there are approximately 23,000 protein-coding genes in the human genome, whereas the gut microbiome has about nine million functional genes (Yang et al. 2009), providing a vast amount of metabolites to the human body. Currently, described microbial metabolites include short-chain fatty acids (SCFAs), mediumchain fatty acids (MCFAs), tryptophan catabolites, polyamines, and other proteolytic products. These metabolites are derived from dietary fiber consumption by the gut microbiota. The intestinal bacteria can manufacture new molecules, produce food metabolites that serve as precursors for host enzymes, and even digest host-derived products, indicating that the host and the microbiota can communicate in both directions. Determined by the availability of substrates and the presence of various microorganisms, the level of different metabolites varies along the longitude of the gastrointestinal tract (Kaur et al. 2018). These metabolites enable cell-specific responses to microbial-derived metabolites to be potentiated by functional and spatial gradients. For example, supplementing SCFAs, which include acetate, propionate, and butyrate, to wild-type mice for just 2 weeks might result in a rise in the composition of fecal Akkermansia, a gram-negative bacterium that is decreased in PsA fecal samples (Scher et al. 2015). Besides, a study involving the HLA-B*27 humanized rat model for SpA showed significant decreases in cecal concentrations of MCFA caproate, heptanoate, and caprate (Asquith et al. 2017). SCFAs can affect host cells through a variety of mechanisms. SCFAs bind to membrane G-protein-coupled receptors such as GPR43, GPR41, and GPR109A, activating downstream signaling pathways like MAPK, NF-, and PI3K (Ulven 2012). By directly inhibiting HDACs, SCFAs can control the cell cycle, impact cellular metabolism, and alter the transcriptome landscape within the cell. Butyrate inhibits HDACs in regulatory T cells (Tregs), causing acetylation of histone H3 in the promoter and conserved noncoding regions of the FoxP3 gene, increasing the production of this essential Treg transcriptional component (Furusawa et al. 2013). Additional research is needed to understand the mechanisms of action of these metabolites and determine whether SCFA or MCFAs may be employed as prebiotics in treating chronic inflammatory disorders such as SpA and its comorbidities in patients. In contrast, patients with AS and PsA have increased blood concentrations of tryptophan when they discontinue using their antirheumatic medications for a week, and their levels are significantly lowered when they begin taking anti-inflammatory drugs (Aylward and Maddock 1974). These findings are consistent with a case study

436

Z. Mukhatayev et al.

wherein a PsA patient showed substantial improvements in both skin and joint conditions after reducing tryptophan intake (Auckland 1969), indicating the importance of tryptophan deficiency in blocking T cell activation (Mellor and Munn 2003). Most of these studies might benefit from a reinvestigation using sophisticated mass spectrometry and metabolomic technologies to understand better the function of tryptophan and its downstream metabolites in immune-mediated illnesses. Moreover, metabolomic investigations on HLA-B*27 transgenic rats’ small intestinal samples demonstrated an increase in spermidine (polyamine) levels compared to healthy animals (Asquith et al. 2017). Nevertheless, the amounts of spermidine and its potential consequences in SpA patients have yet to be identified. Sulfate-reducing bacteria can contribute to the conversion of SO42 molecules to H2S. Stebbings et al. found a high prevalence of sulfate-reducing microbes in the feces of AS patients and a concomitant increase in H2S molecules in the gut lumen of AS patients compared to healthy individuals (Stebbings et al. 2002). In small intestinal samples of SpA rat models, p-cresol sulfate levels were significantly higher than controls (Asquith et al. 2017). Further studies are needed to reveal the functional properties of this inflammatory metabolite. As a growing number of microbial metabolites are associated with immune-mediated disorders, it is critical to understand how these metabolites work so that feasible diagnostic and therapeutic intervention techniques may be developed.

17.4

Management of SpA

17.4.1 Current Treatment Avenues for SpA Over the last decades, the treatment of SpA has significantly progressed. Given the heterogeneity of disease manifestations among the subtypes of SpA, various treatment approaches need to be considered (Davis Jr. and Mease 2008). Based on the main site of the body that is affected, SpA may be characterized as either axial or peripheral. Peripheral SpA refers to disease with predominantly peripheral features of enthesitis, arthritis, and dactylitis, whereas axial SpA mainly involves inflammation of the axial skeleton (Jones et al. 2018). Axial SpA is a predominant type of SpA, which affects patients with AS. Therefore, this section discusses the treatment recommendations mainly relevant for axial SpA. Management recommendations for axial SpA have been developed by the Assessment of SpondyloArthritis International Society (ASAS) in conjunction with the European League Against Rheumatism (EULAR) (Van Der Heijde et al. 2017b). The current treatment recommendations include a combination of pharmacological and non-pharmacological treatment options (Zochling et al. 2006) (Table 17.1). Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line therapy for alleviating inflammation, back pain, and spine stiffness (Van Der Heijde et al. 2017b). NSAIDs, including traditional nonselective NSAIDs and selective cyclooxygenase-2 inhibitors (Rudwaleit et al. 2009), can efficiently alleviate symptoms and

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

437

decrease C-reactive protein levels during acute inflammation (Benhamou et al. 2010). Other NSAIDs, such as diclofenac, ibuprofen, celecoxib, and etoricoxib, are also highly effective in reducing back pain and morning stiffness (Braun et al. 2011a; Ward et al. 2016). Around 70–80% of AS patients reported a substantial relief from back pain and stiffness under treatment with NSAIDs (Song et al. 2008). Interestingly, continuous intake of a fixed dose of NSAIDs was found to be more effective in delaying radiographic changes than on-demand usage of NSAIDs (Wanders et al. 2005; Reveille 2019a; Poddubnyy et al. 2012). However, it is estimated that around two-thirds of patients fail to respond to NSAIDs (Toussirot 2019); such patients should be provided with other therapeutic options. One of the major concerns with NSAIDs is its safety profile, especially in the gastrointestinal tract and kidney, as well as in the cardiovascular system (Toussirot 2019). Longterm administration of NSAIDs has been associated with gastrointestinal, cardiovascular, and renal side effects (Dubash et al. 2018). Thus, during the use of NSAIDs, the benefit-risk ratio must be estimated due to various side effects. In particular, the cardiovascular safety of long-term NSAID intake should be carefully examined (Toussirot 2011). For instance, treatment with cyclooxygenase-2 and nonselective NSAIDs (e.g., naproxen and indomethacin) has been associated with an increased risk for cardiovascular complications (Mukherjee et al. 2001). Serious adverse effects occur in approximately 1% of patients per year (Song et al. 2008). Therefore, treatment with NSAID might not be suitable for patients who do not efficiently respond to it and for patients who are unable to tolerate its side effects (Davis Jr. and Mease 2008). Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) have also been proposed as first-line treatment. Depending on the SpA subtypes, patients who do not respond to or could not tolerate NSAIDs may be considered as candidates for DMARDs (Davis Jr. and Mease 2008). The three most commonly used agents in this class are methotrexate, sulfasalazine, and leflunomide. These drugs are mostly recommended for patients with peripheral manifestations. The efficiency of both methotrexate and leflunomide has been demonstrated in PsA and peripheral SpA, but neither is effective for axial SpA (Sieper and Poddubnyy 2016). A study examining the efficiency of sulfasalazine versus placebo in AS demonstrated that sulfasalazine has beneficial effects, relieves back pain, and improves morning stiffness and erythrocyte sedimentation rate (ESR) (Braun et al. 2006). However, when comparing sulfasalazine and TNF-α inhibitors in axial SpA and AS patients, it was found that the response rate of sulfasalazine was lower than that of TNF blockers but higher than that of placebo (Braun et al. 2011b; Huang and Huang 2012). On the other hand, the use of methotrexate in patients with AS has resulted in modest beneficial effects in the peripheral manifestations of disease and a minor improvement in axial involvement (Ostendorf et al. 1998). Non-pharmacological treatment options are also important for the management of SpA, including patient education and regular exercise. Exercise and physical therapy are crucial for maintaining spinal mobility and improving muscle strength in SpA patients (Reimold and Chandran 2014; Van Der Horst-Bruinsma and Nurmohamed 2012). Exercise has always been adopted in SpA treatment to alleviate symptoms

438

Z. Mukhatayev et al.

and ameliorate disease progression (Dubash et al. 2018). In fact, the health status of patients improved after performing physical exercises at least 30 min/day (Reveille 2019a). Since different exercise programs are currently available and not all physical activities are automatically beneficial to SpA patients (Reimold and Chandran 2014), supervised physical therapy is actually more effective than individual home exercise (Dagfinrud et al. 2004). Furthermore, a meta-analysis of six studies revealed that group exercise in the hospital yields better results than home exercise in terms of reducing SpA-associated impairments (Dagfinrud et al. 2004). Multimodal home and group exercises, which consist of breathing, posture, and stretching, result in a significant improvement in disease activity, spinal mobility, and the physical wellbeing of patients (Reimold and Chandran 2014). Thus, better management of SpA requires a successful combination of both non-pharmacological and pharmacological treatments (Huang and Huang 2012).

17.4.2 Emerging Therapeutic Options for SpA Despite the high anti-inflammatory efficiency of currently available treatment options for SpA (i.e., NSAIDs and DMARDs), some patients do not respond to or tolerate these drugs. The lack of understanding of the etiology and disease mechanisms underlying the pathogenesis of SpA hindered the development of efficient therapies for the disease. Since then, substantial progress has been made after gaining a clearer understanding of the etiopathogenic factors involved in SpA, especially with the identification of the role of major inflammatory contributing pathways. This led to the development of cytokine-targeted therapies, such as TNF-α and IL inhibitors (Toussirot 2019, 2011). The introduction of TNF inhibitors has led to a substantial improvement in the treatment of SpA, not only for axial manifestations but also for peripheral arthritis and enthesitis (Van Der Horst-Bruinsma and Nurmohamed 2012). Currently, five TNF-α inhibitors, namely, adalimumab, certolizumab, etanercept, infliximab, and golimumab, have been approved for the treatment of AS in many countries worldwide (Reveille 2019a). These agents differ in their molecular structure and administration route (Bruner et al. 2014). Despite the lack of head-to-head comparison of these TNF-α inhibitors, all of them exhibited comparable efficiency in phase III randomized controlled trials (Ritchlin et al. 2009). They are effective for a wide variety of disease manifestations (Dougados et al. 2010) and for reducing inflammatory features on both laboratory tests (i.e., C-reactive protein levels) and imaging (i.e., axial inflammation detected by MRI) (Toussirot 2019; Braun et al. 2012). Since no single agent has been proven superior to the others, the choice between these agents is based on the patient’s preference with regard to the administration route (i.e., subcutaneous injections versus intravenous administration), the risk of tuberculosis reactivation, and other preferences (Toussirot 2011). TNF-α blockers are more effective in preventing articular damage in the peripheral joints than axial ones (Braun et al. 2011b; Bruner et al. 2014). Because SpA is a chronic disease requiring daily treatment, initiating TNF-α therapy rather than giving continuous NSAID

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

439

treatment could be a better option (Toussirot 2011). Recent studies suggest that early initiation of TNF therapy is associated with reduced radiographic spinal progression (Maas et al. 2017). In line with this, a meta-analysis evaluating five randomized controlled trials in PA revealed that TNF-α blocking agents are better than non-biological treatment modalities in controlling radiographic progression after 24 and 48 weeks of treatment (Goulabchand et al. 2014). TNF-α blockers were also found to have an adequate safety profile (Braun et al. 2015; Toussirot 2011). TNF-α inhibitors have dramatically improved the treatment and care of SpA, but new unfulfilled needs have emerged for up to 40% of patients who do not respond to these agents or have certain contraindications for their use (Toussirot 2017; Sieper 2012). Thus, there is a need to better understand the cellular and molecular mechanisms underlying the disease so as to identify a new pathological pathway that can be a potential target in SpA (Toussirot 2017). A better understanding of the IL-23/Th17 axis in the pathogenesis of SpA has resulted in the development of IL-17A inhibitors and opened new treatment possibilities for patients with axial SpA. Recognizing the importance of the IL-23/ IL-17 axis has resulted in a rapidly expanding repertoire of compounds targeting this axis. For instance, IL-17 signaling has been identified as a key modulator of synovial inflammation and joint destruction in SpA through their actions on synovial cells, osteoblasts, and chondrocytes (Raychaudhuri 2013). IL-17A inhibitors could be an effective and well-tolerated alternative to conventional SpA treatment options (Raychaudhuri and Raychaudhuri 2017). Because of this, different therapeutics targeting IL-23 or IL-17A have been developed, including ustekinumab, secukinumab, ixekizumab, and brodalumab (Leonardi et al. 2008; Yeremenko et al. 2014). These agents have all successfully completed preclinical development programs and are currently undergoing randomized trials (Leonardi et al. 2008, Yeremenko et al. 2014). In this sense, targeting the IL-23/Th17 axis represents a promising approach. Indeed, targeting IL-17A with secukinumab represents the most significant advancement in the treatment of axial SpA (Toussirot 2017). TNF-α and IL-17 inhibitors have exhibited comparable efficiency in the treatment of axial SpA (Torgutalp and Poddubnyy 2018). Moreover, secukinumab and antiTNF agents were found to have roughly similar therapeutic responses (Toussirot 2017; Braun et al. 2011a). Secukinumab is also associated with reduced MRI inflammation, and this improvement has been sustained up to 52 weeks (Toussirot 2017). Moreover, anti-IL-17 agents might be preferable for patients with a family history of multiple sclerosis, a high risk of tuberculosis, or a severe heart failure (Toussirot 2019). Over the last decade, SpA treatment options have undergone a radical change from symptomatic treatment with NSAIDs supplemented with physical therapy and exercise to targeted biological treatments. In addition, treatment options have broadened with the development of anti-IL-17 drugs and other biologics (Sieper and Poddubnyy 2016). The advancement of cytokine-targeting therapies revolutionized the field and opened new avenues for development. Emerging treatment options are now available, providing beneficial therapeutic options in patients with axial SpA

440

Z. Mukhatayev et al.

(Toussirot 2017). In the following sections, these new, emerging treatment options will be discussed. Janus kinases (JAKs) affect intracellular signaling via the activation of signal transducer and activator of transcription, which play an essential role in numerous inflammatory pathways (Schwartz et al. 2016). Therefore, JAKs are potential targets for SpA treatment. Currently, several JAK inhibitors (i.e., tofacitinib and filgotinib) are under investigation for axial SpA (Braun et al. 2015). JAK inhibitors are small molecules that are orally available (Toussirot 2017). Both tofacitinib and filgotinib demonstrated positive results in phase II studies with AS patients (Coates et al. 2015; Ramiro et al. 2014), but confirmation in phase III studies is needed. Moreover, another study has demonstrated that tofacitinib was associated with reduced MRI inflammation (Van Der Heijde et al. 2017a). Since JAK inhibitors interfere with proinflammatory signaling pathways, this could potentially lead to reduced production of cytokines and ameliorate inflammation; therefore, JAK inhibitors are very promising agents for SpA, but more clinical studies are needed (Van Den Bosch and Deodhar 2014). Apremilast is an orally administrated small molecule that targets phosphodiesterase 4 (PDE4). Apremilast inhibits the activation of pro-inflammatory cytokines and activates anti-inflammatory mediators (Dubash et al. 2018). The inhibition of PDE4 induces an increase in intracellular cyclic adenosine monophosphate and blocks the production of pro-inflammatory cytokines, including TNF-α (Schafer 2012; Toussirot 2017). Apremilast has been approved for the treatment of psoriasis and PsA (Toussirot 2017). Treatment with apremilast resulted in a reduction in cytokine levels, including interferon-γ, TNFα, IL-12, and IL-23. Recently, large double-blind and randomized multicenter studies demonstrated that apremilast is effective in the treatment of psoriasis, PsA, and AS, with a significantly higher number of patients treated with apremilast achieving endpoints compared with baseline (Schett et al. 2012). Taken together, this small molecule seems to be effective for treating psoriasis and PsA, but more studies are needed prior to initiate the treatment for SpA and AS patients (Toussirot 2017) (Table 17.3).

17.4.3 Intestinal Microbiome Strategies The strong association between gut inflammation and SpA suggests a potential therapeutic approach to the medication of diet or intestinal microbiome. Alteration of the gut microbiome and amelioration of disease manifestations using prebiotics and probiotics have gained considerable interest. Prebiotics and probiotics can contribute to the maintenance of healthy gut composition and therefore play an important role in the overall health of the gastrointestinal tract (Quigley 2012). Prebiotics are plant-based fibers that may enhance the activity of beneficial gut bacteria, thereby promoting host health (Smith et al. 2020). On the other hand, probiotics are live microorganisms that are administered in reasonable amounts for the benefit of host organism; these could alter the existing gut microbiota as well as the innate and adaptive immune response. Studies on HLA-B*27 transgenic rats

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

441

Table 17.3 List of available and emerging treatment options for SpA

Targets Drugs Conventional therapy NSAIDs Cyclooxygenase2 Naproxen

DMARDs

TNFα

Current status/ clinical trial name (phase) Approved Approved

Indomethacin

Approved

Diclofenac Sulfasalazine

Approved Approved

Methotrexate

Approved

Leflunomide

Approved

Adalimumab

Approved

Certolizumab

Approved

Infliximab

Approved

Golimumab

Approved

Etanercept

Approved

Emerging treatment options IL-17A Secukinumab

Ixekizumab

Bimekizumab

NCT02696031 (III)

NCT02757352 (III) COAST-X (III) NCT02963506 (II) NCT03215277 (II)

References Rudwaleit et al. (2009), Reveille (2019a), Toussirot (2011) Rudwaleit et al. (2009), Reveille (2019a), Toussirot (2011), Sieper and Poddubnyy (2016) Rudwaleit et al. (2009), Reveille (2019a), Toussirot (2011) Rudwaleit et al. (2009) Torgutalp and Poddubnyy (2018), Toussirot (2011), Reveille (2019a) Torgutalp and Poddubnyy (2018), Toussirot (2011), Reveille (2019a) Torgutalp and Poddubnyy (2018), Toussirot (2011), Reveille (2019a) Torgutalp and Poddubnyy (2018), Toussirot (2011), Reveille (2019a), Bruner et al. (2014), Jones et al. (2018), Braun et al. (2015) Torgutalp and Poddubnyy (2018), Toussirot (2011), Reveille (2019a), Bruner et al. (2014), Jones et al. (2018), Braun et al. (2015) Torgutalp and Poddubnyy (2018), Toussirot (2011), Reveille (2019a), Bruner et al. (2014), Jones et al. (2018), Braun et al. (2015) Torgutalp and Poddubnyy (2018), Toussirot (2011), Reveille (2019a), Bruner et al. (2014), Jones et al. (2018), Braun et al. (2015) Torgutalp and Poddubnyy (2018), Reveille (2019a), Bruner et al. (2014), Jones et al. (2018), Braun et al. (2015) Sieper and Poddubnyy (2016), Torgutalp and Poddubnyy (2018), Yeremenko et al. (2014), Braun et al. (2011a), Bruner et al. (2014), Toussirot (2017) Torgutalp and Poddubnyy (2018), Yeremenko et al. (2014), Jones et al. (2018) Torgutalp and Poddubnyy (2018), Yeremenko et al. (2014), Jones et al. (2018) (continued)

442

Z. Mukhatayev et al.

Table 17.3 (continued)

Targets

Drugs Brodalumab

IL-12/IL23

Ustekinumab

PDE4 inhibitor

Apremilast

JAK

Tofacitinib

Upadacitinib

Filgotinib

Current status/ clinical trial name (phase) NCT02985983 (III) NCT02429882 (III) NCT02437162 (III) NCT02438787 (III) NCT01583374 (III) POSTURE (III) NCT01786668 (II) NCT03502616 (III) NCT03178487 (III) NCT03117270 (II) TORTUGA (II)

References Torgutalp and Poddubnyy (2018), Yeremenko et al. (2014), Jones et al. (2018) Torgutalp and Poddubnyy (2018), Yeremenko et al. (2014), Jones et al. (2018) Torgutalp and Poddubnyy (2018), Bruner et al. (2014), Braun et al. (2015) Braun et al. (2015), Torgutalp and Poddubnyy (2018), Jones et al. (2018), Poddubnyy and Sieper (2019) Braun et al. (2015), Torgutalp and Poddubnyy (2018), Jones et al. (2018), Poddubnyy and Sieper (2019) Braun et al. (2015), Torgutalp and Poddubnyy (2018), Jones et al. (2018), Poddubnyy and Sieper (2019)

treated with prebiotic compounds inulin and oligofructose demonstrated that prebiotic treatment significantly decreased inflammatory cytokines, such as IL-1β, and increased the levels of TGF-β by increasing the abundance of Lactobacillus and Bifidobacterium species (Hoentjen et al. 2005). Several initial studies on the use of probiotics in SpA have also been conducted (Reimold and Chandran 2014). The administration of Lactobacillus acidophilus and Lactobacillus salivarius daily for 4 weeks to 18 patients resulted in significant improvements in disease manifestations (Altan et al. 2006). In HLA-B*27 transgenic rats, combination treatment with probiotics and prebiotics resulted in an increase in microbial diversity and a reduction of colitis. These studies show promise for prebiotic and probiotic supplements as therapy for various SpAs by renewing and restoring host gut microbiota (Gill and Rosenbaum 2020). Nevertheless, due to the huge diversity of probiotic organisms and treatment approaches, more studies are needed to make reliable conclusions.

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

17.5

443

Association Between SpA and Susceptibility to SARS-COV-2 Infection and Outcome

The immune reaction triggered by SARS-CoV-2 infection can lead to a massive inflammatory response with a “cytokine storm” with often fatal consequences (Song et al. 2020; Hu et al. 2021). Divergences in the activation of cytokine signaling networks might contribute to individual COVID-19 pathophysiology and drive the varied clinical manifestations (Le Bert et al. 2020; Ren et al. 2021). Autoimmune and auto-inflammatory diseases by their nature might affect susceptibility to SARSCoV-2 and influence infection course and outcome as immunomodulatory treatment might be associated with an increased risk for viral infections of the respiratory tract, including COVID-19. SpA is characterized by the secretion of pro-inflammatory cytokines, such as TNF-α, INF-γ, IL-12, IL-23, and IL-17. Many of these cytokines also play a crucial role in the disease course and severity of COVID-19 (Song et al. 2020; Hu et al. 2021; Jahaj et al. 2021). Indeed, some of the treatments used in clinical care of SpA, such as antimalarial drugs, glucocorticoids, IL-6 inhibitors, and TNF-α inhibitors, have also been proposed as potential treatments for patients with severe COVID-19 (Hu et al. 2021; Atzeni et al. 2021), thus raising the possibility that the immunomodulatory treatment of SpA patients might have a positive influence on the course of COVID-19. To date, limited data exist regarding the course and mortality of COVID-19 in SpA patients and how immunomodulatory drug treatment might influence the course of COVID-19. While several case studies (Duret et al. 2020; Coskun Benlidayi et al. 2020) and retrospective or longitudinal studies (Roux et al. 2020; Hasseli et al. 2021b; Raiker et al. 2021; Rosenbaum et al. 2022; Schulze-Koops et al. 2021) have been published, caution in interpreting the available data is warranted, because studies generally suffer from low sample sizes, particularly a low number of severe courses, and may have limited patient matching (age, gender, comorbidities, disease activity, or treatment). Nevertheless, there is a trend indicating that SpA confers some protection against a severe COVID-19 outcome. A gender- and age-matched study by Hasseli et al. evaluated the differences in outcome of SARS-CoV-2 infection in patients affected with rheumatoid arthritis (RA) or SpA. One hundred four RA patients and 104 SpA (40% AS patients and 54% PsA patients, 6% with enteropathic arthritis) patients were investigated. The study revealed that patients affected with either RA or SpA had an increased risk of COVID-19 infection compared to the general population (Hasseli et al. 2021a). The infection risk in both patient cohorts depended on disease activity and the presence of comorbidities on one hand and on the type and dosage of immunomodulatory treatment on the other hand. Interestingly, the SpA patient cohort had a significantly lower rate of hospitalization (16%) compared to the RA patient cohort (30%), and a lower percentage of hospitalized SpA patients required oxygen treatment (10%) compared to RA patients (18%). Thus, SpA might be associated with an increased risk for SARS-CoV-2 infection, but a lower risk for development of a severe course of COVID-19. Whether this is due to the nature of SpA or due to receiving immunomodulatory treatment remains an open question. The results by Hasseli

444

Z. Mukhatayev et al.

et al. were largely confirmed by a recent retrospective multicenter study examining the outcomes of 9766axial SpA (ax-SpA) patients with COVID-19 (Raiker et al. 2021). Patients in this study were predominantly classified as having non-radiographic SpA (nr-SpA) with a smaller cohort of patients having AS (8842 nr-SpA and 924 AS). When compared to matched control patients with COVID-19 but without inflammatory arthritis, patients with ax-SpA were at lower risk for mortality and morbidity including hospitalization and severe COVID-19 disease course (measured as a composite of mortality and mechanical ventilation) (Raiker et al. 2021). There was no difference in COVID-19 outcomes detected between AS and other subtypes in this study, although rates of hospitalization were higher in AS patients and AS was also associated with a higher risk for venous thromboembolism (Raiker et al. 2021). Prior treatment with tumor necrosis factor inhibitors did not influence COVID-19 outcome (Raiker et al. 2021). These results contrast with findings reported in initial studies in which data were obtained through surveys (Rosenbaum et al. 2022; Costantino et al. 2021). In addition, while treatment with anti-TNF was not associated with a higher rate of severe COVID-19 disease, the risk for patients with other treatments, for example, rituximab or sulfasalazine, may differ (Schulze-Koops et al. 2021) (Strangfeld et al. 2021; Rosenbaum et al. 2021b; Schäfer et al. 2021). Additional studies will be required to determine how immunosuppressive and/or immunomodulating agents such as biological disease-modifying antirheumatic drugs affect the rate and the outcome of severe SARS-CoV-2 infections of patients with SpA. Likewise, additional studies will be required to determine whether genetic factors that contribute to SpA development also influence COVID-19 disease predisposition and outcome. The observed lower hospitalization rate of SpA patients with COVID19 compared to patients affected with COVID-19 only (Hasseli et al. 2021a; Raiker et al. 2021) might indicate a protective effect as a result of spondyloarthritis. HLAB*27 status emerges as a likely candidate because evidence suggests that HLA-B*27 confers some protection against HIV (Hendel et al. 1999), hepatitis C (Fitzmaurice et al. 2015), and possibly influenza (Boon et al. 2004). However, a survey specifically investigating a link between HLA-B27 status in patients with SpA and SARS-CoV-2 infection found no statistically significant association (Rosenbaum et al. 2021a). While a limitation of this study was the relatively small number of patients with confirmed COVID-19 positivity, the results are in accordance with previous findings that HLA-B*27 status does not protect against severe acute respiratory syndrome caused by other coronaviruses (Arnaud and Devilliers 2021; Yuan et al. 2014). Therefore, investigation of other SpA-linked HLA alleles, as well as ERAP1/ERAP2 alleles, will be required when assessing COVID-19 outcomes of SpA patients given the central role these alleles play in the activation and regulation of the immune response. Of future interest will also be the role of the gut microbiome in COVID-19 patients in general and in SpA patients specifically. Accumulating evidence suggests that COVID-19 broadly affects the composition of the gut bacterial microbiome, mycobiome, and virome (Yeoh et al. 2021; Zuo et al. 2021, 2020a, b). Notably, gut dysbiosis may be involved in COVID-19 severity possibly via modulating host

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

445

immune responses (Yeoh et al. 2021, Zuo et al. 2021, 2020a, b). These studies highlight the need to further understand whether and how gut microorganisms are involved in inflammation and COVID-19 susceptibility and disease course in SpA patients.

17.6

Conclusion

Several significant clinical and pathological challenges in spondyloarthritis remain unresolved, including the impact of the microbiome in the disease pathogenesis. The immune system and the microbiome are engaged in a series of complex interactions that are impacted by several environmental factors, and they interact both locally and across considerable distances within the body. Thus, uncovering the fundamental role of the microbiome in shaping the host’s immune system has increasingly been recognized as an essential part of host-microbiota interaction. Microbiota-produced metabolites and their cellular and molecular parts are becoming more widely recognized as an essential component of the disease’s pathophysiology, with significant implications for immunological function and dysfunction. Bacterial metabolites are produced due to interactions between microorganisms and hosts, and there is an increasing recognition that this co-metabolism has a significant impact on human health and illness. These findings prove that mammals are holobionts that rely on both host and microbial genomes to operate appropriately. Novel microbial metabolites and components that are related to immune system function will potentially be discovered and might be predicted using meta-omic and emerging computational tools. Acknowledgments This work was supported by the Collaborative Research Program Grant #021220CRP1722 awarded to JK, AK, and BA.

References Albert LJ, Inman RD (1999) Molecular mimicry and autoimmunity. N Engl J Med 341:2068–2074 Altan L, Bingol U, Aslan M, Yurtkuran M (2006) The effect of balneotherapy on patients with ankylosing spondylitis. Scand J Rheumatol 35:283–289 Ambarus CA, Yeremenko N, Baeten DL (2018) Altered cytokine expression by macrophages from HLA-B27-positive spondyloarthritis patients without evidence of endoplasmic reticulum stress. Rheumatol Adv Pract 2:rky014 Andrés AM, Dennis MY, Kretzschmar WW, Cannons JL, Lee-Lin S-Q, Hurle B, Program NCS, Schwartzberg PL, Williamson SH, Bustamante CD (2010) Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation. PLoS Genet 6:e1001157 Appel H, Kuon W, Kuhne M, Wu P, Kuhlmann S, Kollnberger S, Thiel A, Bowness P, Sieper J (2004) Use of HLA-B27 tetramers to identify low-frequency antigen-specific T cells in chlamydia-triggered reactive arthritis. Arthritis Res Ther 6:R521–R534

446

Z. Mukhatayev et al.

Arévalo M, Gratacós Masmitjà J, Moreno M, Calvet J, Orellana C, Ruiz D, Castro C, Carreto P, Larrosa M, Collantes E, Font P (2018) Influence of HLA-B27 on the ankylosing spondylitis phenotype: results from the REGISPONSER database. Arthritis Res Ther 20:221 Arnaud L, Devilliers H (2021) Correspondence on ‘Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry’ [published online ahead of print, 2021 Feb 18]. Ann Rheum Dis; annrheumdis-2021-220037. https://doi.org/10.1136/annrheumdis-2021-220037 Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto J-M, Bertalan M, Borruel N, Casellas F, Fernandez L, Gautier L, Hansen T, Hattori M, Hayashi T, Kleerebezem M, Kurokawa K, Leclerc M, Levenez F, Manichanh C, Nielsen HB, Nielsen T, Pons N, Poulain J, Qin J, Sicheritz-Ponten T, Tims S, Torrents D, Ugarte E, Zoetendal EG, Wang J, Guarner F, Pedersen O, De Vos WM, Brunak S, Doré J, Antolín M, Artiguenave F, Blottiere HM, Almeida M, Brechot C, Cara C, Chervaux C, Cultrone A, Delorme C, Denariaz G, Dervyn R, Foerstner KU, Friss C, Van De Guchte M, Guedon E, Haimet F, Huber W, Van Hylckama-Vlieg J, Jamet A, Juste C, Kaci G, Knol J, Kristiansen K, Lakhdari O, Layec S, Le Roux K, Maguin E, Mérieux A, Melo Minardi R, M'rini C, Muller J, Oozeer R, Parkhill J, Renault P, Rescigno M, Sanchez N, Sunagawa S, Torrejon A, Turner K, Vandemeulebrouck G, Varela E, Winogradsky Y, Zeller G, Weissenbach J, Ehrlich SD, Bork P, Meta HITC (2011) Enterotypes of the human gut microbiome. Nature 473:174–180 Arvikar SL, Fisher MC (2011) Inflammatory bowel disease associated arthropathy. Curr Rev Musculoskelet Med 4:123–131 Asquith M, Davin S, Stauffer P, Michell C, Janowitz C, Lin P, Ensign-Lewis J, Kinchen JM, Koop DR, Rosenbaum JT (2017) Intestinal metabolites are profoundly altered in the context of HLA-B27 expression and functionally modulate disease in a rat model of spondyloarthritis. Arthritis Rheumatol 69:1984–1995 Atzeni F, Masala IF, Rodriguez-Carrio J, Rios-Garces R, Gerratana E, La Corte L, Giallanza M, Nucera V, Riva A, Espinosa G, Cervera R (2021) The rheumatology drugs for COVID-19 management: which and when? J Clin Med 10:783 Auckland G (1969) Psoriasis and arthritis: treatment with low tryptophan diet. Br J Dermatol 81: 388–389 Aylward M, Maddock J (1974) Proceedings: plasma L-tryptophan concentrations in chronic rheumatic diseases and the effects of some antirheumatic drugs on the binding of the aminoacid to plasma proteins in vivo and in vitro. Rheumatol Rehabil 13:62–74 Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI (2005) Host-bacterial mutualism in the human intestine. Science 307:1915–1920 Benham H, Rehaume LM, Hasnain SZ, Velasco J, Baillet AC, Ruutu M, Kikly K, Wang R, Tseng HW, Thomas GP, Brown MA, Strutton G, Mcguckin MA, Thomas R (2014) Interleukin-23 mediates the intestinal response to microbial β-1,3-glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis Rheumatol 66:1755–1767 Benhamou M, Gossec L, Dougados M (2010) Clinical relevance of C-reactive protein in ankylosing spondylitis and evaluation of the NSAIDS/Coxibs' treatment effect on C-reactive protein. Rheumatology (Oxford) 49:536–541 Beukelman CJ, Quarles Van Ufford HC, Van Bree FP, Aerts PC, Nieuwenhoff C, Reerink G, Van Leeuwen A, Van Dijk H (1990) Trial and error in producing ankylosing-spondylitis-selective antisera according to Andrew Geczy. Scand J Rheumatol Suppl 87:74–79. Discussion 79–80 Boon AC, De Mutsert G, Fouchier RA, Sintnicolaas K, Osterhaus AD, Rimmelzwaan GF (2004) Preferential HLA usage in the influenza virus-specific CTL response. J Immunol 172:4435– 4443 Bowness P (2015) HLA-B27. Annu Rev Immunol 33:29–48 Bowness P, Ridley A, Shaw J, Chan AT, Wong-Baeza I, Fleming M, Cummings F, Mcmichael A, Kollnberger S (2011) Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J Immunol 186:2672–2680

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

447

Brand S (2009) Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. Gut 58:1152– 1167 Braun J, Zochling J, Baraliakos X, Baraliakos X, Alten R, Alten R, Burmester G, Burmester G, Grasedyck K, Grasedyck K, Brandt J, Brandt J, Haibel H, Haibel H, Hammer M, Hammer M, Krause A, Krause A, Mielke F, Mielke F, Tony HP, Tony HP, Ebner W, Ebner W, Gömör B, Gömör B, Hermann J, Hermann J, Zeidler H, Zeidler H, Beck E, Beck E, Baumgaertner M, Baumgaertner M, Sieper J, Sieper J (2006) Efficacy of sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis: a multicentre randomised controlled trial. Ann Rheum Dis 65(9):1147–1153 Braun J, Van Den Berg R, Baraliakos X, Boehm H, Burgos-Vargas R, Collantes-Estevez E, Dagfinrud H, Dijkmans B, Dougados M, Emery P, Geher P, Hammoudeh M, Inman RD, Jongkees M, Khan MA, Kiltz U, Kvien T, Leirisalo-Repo M, Maksymowych WP, Olivieri I, Pavelka K, Sieper J, Stanislawska-Biernat E, Wendling D, Ozgocmen S, Van Drogen C, Van Royen B, Van Der Heijde D (2011a) 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 70:896–904 Braun J, Van Der Horst-Bruinsma IE, Huang F, Burgos-Vargas R, Vlahos B, Koenig AS, Freundlich B (2011b) Clinical efficacy and safety of etanercept versus sulfasalazine in patients with ankylosing spondylitis: a randomized, double-blind trial. Arthritis Rheum 63:1543–1551 Braun J, Baraliakos X, Hermann K-GA, Van Der Heijde D, Inman RD, Deodhar AA, Baratelle A, Xu S, Xu W, Hsu B (2012) Golimumab reduces spinal inflammation in ankylosing spondylitis: MRI results of the randomised, placebo- controlled GO-RAISE study. Ann Rheum Dis 71:878 Braun J, Kiltz U, Heldmann F, Baraliakos X (2015) Emerging drugs for the treatment of axial and peripheral spondyloarthritis. Expert Opin Emerg Drugs 20:1–14 Brown MA, Kennedy LG, Macgregor AJ, Darke C, Duncan E, Shatford JL, Taylor A, Calin A, Wordsworth P (1997) Susceptibility to ankylosing spondylitis in twins the role of genes, HLA, and the environment. Arthritis Rheum 40:1823–1828 Brown M, Laval S, Brophy S, Calin A (2000) Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 59:883–886 Bruner V, Atteno M, Spano A, Scarpa R, Peluso R (2014) Biological therapies for Spondyloarthritis. Ther Adv Musculoskelet Dis 6:92–101 Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, Mccarthy MI, Ouwehand WH, Samani NJ (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39:1329–1337 Busse K, Liao W (2010) Which psoriasis patients develop psoriatic arthritis? Psoriasis Forum 16: 17–25 Caffrey MF, James D (1973) Human lymphocyte antigen association in ankylosing spondylitis. Nature 242:121–121 Capkova J, Hrncir T, Kubatova A, Tlaskalova-Hogenova H (2012) Lipopolysaccharide treatment suppresses spontaneously developing ankylosing enthesopathy in B10.BR male mice: the potential role of interleukin-10. BMC Musculoskelet Disord 13:110 Carter JD, Hudson AP (2009) Reactive arthritis: clinical aspects and medical management. Rheum Dis Clin 35:21–44 Castelino M, Eyre S, Upton M, Ho P, Barton A (2014) The bacterial skin microbiome in psoriatic arthritis, an unexplored link in pathogenesis: challenges and opportunities offered by recent technological advances. Rheumatology (Oxford) 53:777–784 Cauli A, Dessole G, Vacca A, Vacca A, Porru G, Porru G, Cappai L, Cappai L, Piga M, Piga M, Bitti PP, Bitti PP, Fiorillo MT, Fiorillo MT, Sorrentino R, Sorrentino R, Carcassi C, Carcassi C, Mathieu A, Mathieu A (2012) Susceptibility to ankylosing spondylitis but not disease outcome is influenced by the level of HLA-B27 expression, which shows moderate variability over time. Scand J Rheumatol 41(3):214–218

448

Z. Mukhatayev et al.

Chan A, Kollnberger S, Wedderburn L, Bowness P (2005) Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondyloarthritis. Arthritis Rheum 52:3586–3595 Christophers E, Barker JN, Griffiths CE, Daudén E, Milligan G, Molta C, Sato R, Boggs R (2010) The risk of psoriatic arthritis remains constant following initial diagnosis of psoriasis among patients seen in European Dermatology Clinics. J Eur Acad Dermatol Venereol 24:548–554 Coates LC, Moverley AR, Mcparland L, Brown S, Navarro-Coy N, O'Dwyer JL, Meads DM, Emery P, Conaghan PG, Helliwell PS (2015) Effect of tight control of inflammation in early psoriatic arthritis (TICOPA): A UK multicentre, open-label, randomised controlled trial. Lancet 386:2489–2498 Colbert RA (2000) HLA-B27 Misfolding: a solution to the spondyloarthropathy conundrum? Mol Med Today 6:224–230 Colbert RA (2010) Classification of juvenile spondyloarthritis: enthesitis-related arthritis and beyond. Nat Rev Rheumatol 6:477–485 Colmegna I, Cuchacovich R, Espinoza LR (2004) HLA-B27-associated reactive arthritis: pathogenetic and clinical considerations. Clin Microbiol Rev 17:348–369 Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T, Leo P, Cremin K, Pryce K, Harris J, Lee S (2013) Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 45:730–738 Coskun Benlidayi I, Kurtaran B, Tirasci E, Guzel R (2020) Coronavirus disease 2019 (COVID-19) in a patient with ankylosing spondylitis treated with secukinumab: a case-based review. Rheumatol Int 40:1707–1716 Costantino F, Bahier L, Tarancon LC, Leboime A, Vidal F, Bessalah L, Breban M, D'Agostino MA (2021) COVID-19 in French patients with chronic inflammatory rheumatic diseases: clinical features, risk factors and treatment adherence. Joint Bone Spine 88:105095 Costello ME, Ciccia F, Willner D, Warrington N, Robinson PC, Gardiner B, Marshall M, Kenna TJ, Triolo G, Brown MA (2015) Brief report: intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol 67:686–691 Cusick MF, Libbey JE, Fujinami RS (2012) Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol 42:102–111 Dagfinrud H, Hagen KB, Kvien TK (2004) Physiotherapy interventions for ankylosing spondylitis. Cochrane Database Syst Rev, Issue 4. Art. No.: CD002822. https://doi.org/10.1002/14651858. CD002822.pub2. Accessed 12 May 2022 Dashti N, Mahmoudi M, Aslani S, Jamshidi A (2018) HLA-B*27 subtypes and their implications in the pathogenesis of ankylosing spondylitis. Gene 670:15–21 Davidson SI, Liu Y, Danoy PA, Wu X, Thomas GP, Jiang L, Sun L, Wang N, Han J, Han H (2011) Association of STAT3 and TNFRSF1A with ankylosing spondylitis in Han Chinese. Ann Rheum Dis 70:289–292 Davis JC Jr, Mease PJ (2008) Insights into the pathology and treatment of spondyloarthritis: from the bench to the clinic. Semin Arthritis Rheum 38(2):83–100 De Koning A, Schoones JW, Van Der Heijde D, Van Gaalen FA (2018) Pathophysiology of axial spondyloarthritis: consensus and controversies. Eur J Clin Investig 48:E12913 De Vries DD, Dekker-Saeys AJ, Gyodi E, Bohm U, Ivanyi P (1992) Absence of autoantibodies to peptides shared by HLA-B27.5 and Klebsiella pneumoniae nitrogenase in serum samples from HLA-B27 positive patients with ankylosing spondylitis and Reiter's syndrome. Ann Rheum Dis 51:783–789 Delay ML, Turner MJ, Klenk EI, Smith JA, Sowders DP, Colbert RA (2009) HLA-B27 Misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheum 60:2633–2643 Díaz-Peña R, Castro-Santos P, Durán J, Santiago C, Lucia A (2020) The genetics of spondyloarthritis. J Pers Med 10:151 Dickens C, Mcgowan L, Clark-Carter D, Creed F (2002) Depression in rheumatoid arthritis: a systematic review of the literature with meta-analysis. Psychosom Med 64:52–60

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

449

Dieleman LA, Goerres MS, Arends A, Sprengers D, Torrice C, Hoentjen F, Grenther WB, Sartor RB (2003) Lactobacillus GG prevents recurrence of colitis in HLA-B27 transgenic rats after antibiotic treatment. Gut 52:370–376 Dougados M, Baeten D (2011) Spondyloarthritis. Lancet 377:2127–2137 Dougados M, Combe B, Braun J, Landewé R, Sibilia J, Cantagrel A, Feydy A, Heijde D, Leblanc V, Logeart I (2010) A randomised, multicentre, double-blind, placebocontrolled trial of etanercept in adults with refractory heel enthesitis in spondyloarthritis: the heel trial. Ann Rheum Dis 69:1430–1435 Dubash S, Mcgonagle D, Marzo-Ortega H (2018) New advances in the understanding and treatment of axial spondyloarthritis: from chance to choice. Ther Adv Chronic Dis 9:77–87 Duret PM, Sebbag E, Mallick A, Gravier S, Spielmann L, Messer L (2020) Recovery from COVID19 in a patient with spondyloarthritis treated with TNF-alpha inhibitor etanercept. Ann Rheum Dis 79:1251–1252 Ebringer A (1983) The cross-tolerance hypothesis, HLA-B27 and ankylosing-spondylitis. Br J Rheumatol 22:53–66 Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA (2005) Diversity of the human intestinal microbial flora. Science 308:1635–1638 Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI, Flavell RA (2011) NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:745–757 Ellinghaus D, Jostins L, Spain SL, Cortes A, Bethune J, Han B, Park YR, Raychaudhuri S, Pouget JG, Hübenthal M (2016) Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet 48:510–518 Fahlén A, Engstrand L, Baker BS, Powles A, Fry L (2012) Comparison of bacterial microbiota in skin biopsies from normal and psoriatic skin. Arch Dermatol Res 304:15–22 Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J (2017) Therapeutic potential of targeting the Th17/Treg axis in autoimmune disorders. Molecules 22:134 Fielder M, Pirt SJ, Tarpey I, Wilson C, Cunningham P, Ettelaie C, Binder A, Bansal S, Ebringer A (1995) Molecular mimicry and ankylosing spondylitis: possible role of a novel sequence in pullulanase of Klebsiella pneumoniae. FEBS Lett 369:243–248 Fitzmaurice K, Hurst J, Dring M, Rauch A, Mclaren PJ, Gunthard HF, Gardiner C, Klenerman P, Irish HCVRC, Swiss HIVCS (2015) Additive effects of HLA alleles and innate immune genes determine viral outcome in HCV infection. Gut 64:813–819 Foxman B, Goldberg D, Murdock C, Xi C, Gilsdorf JR (2008) Conceptualizing human microbiota: from multicelled organ to ecological community. Interdiscip Perspect Infect Dis 2008:613979 Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H (2013) Commensal microbederived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:446–450 Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, De Zoete MR, Licona-Limón P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S, Flavell RA (2015) Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523: 221–225 Gao Z, Tseng CH, Strober BE, Pei Z, Blaser MJ (2008) Substantial alterations of the cutaneous bacterial biota in psoriatic lesions. PLoS One 3:E2719 Garcia Ferrer HR, Azan A, Iraheta I, Von Feldt J, Espinoza LR, Manasson J, Scher JU, Garcia Kutzbach A, Ogdie A (2018) Potential risk factors for reactive arthritis and persistence of symptoms at 2 years: a case-control study with longitudinal follow-up. Clin Rheumatol 37:415– 422 Garcia-Montoya L, Gul H, Emery P (2018a) Recent advances in ankylosing spondylitis: understanding the disease and. Management F1000res:7

450

Z. Mukhatayev et al.

Garcia-Montoya L, Gul H, Emery P (2018b) Recent advances in ankylosing spondylitis: understanding the disease and management. F1000Research, 7, F1000 Faculty Rev-1512. https://doi. org/10.12688/f1000research.14956.1 Giles J, Shaw J, Piper C, Wong-Baeza I, Mchugh K, Ridley A, Li D, Lenart I, Antoniou AN, Digleria K (2012) HLA-B27 homodimers and free H chains are stronger ligands for leukocyte Ig-like receptor B2 than classical HLA class I. J Immunol 188:6184–6193 Gill T, Rosenbaum JT (2020) Putative pathobionts in HLA-B27-associated spondyloarthropathy. Front Immunol 11:586494 Gladman DD (2009) Psoriatic arthritis. Dermatol Ther 22:40–55 Goulabchand R, Mouterde G, Barnetche T, Lukas C, Morel J, Combe B (2014) Effect of tumour necrosis factor blockers on radiographic progression of psoriatic arthritis: a systematic review and meta-analysis of randomised controlled trials. Ann Rheum Dis 73:414 Grandon B, Rincheval-Arnold A, Jah N, Corsi JM, Araujo LM, Glatigny S, Prevost E, Roche D, Chiocchia G, Guenal I, Gaumer S, Breban M (2019) HLA-B27 alters BMP/TGFbeta signalling in drosophila, revealing putative pathogenic mechanism for spondyloarthritis. Ann Rheum Dis 78:1653–1662 Granfors K, Jalkanen S, Lindberg AA, Mäki-Ikola O, Von Essen R, Lahesmaa-Rantala R, Isomäki H, Saario R, Arnold WJ, Toivanen A (1990) Salmonella lipopolysaccharide in synovial cells from patients with reactive arthritis. Lancet 335:685–688 Hamdulay SS, Glynne SJ, Keat A (2006) When is arthritis reactive? Postgrad Med J 82:446–453 Hammer RE, Maika SD, Richardson JA, Tang J-P, Taurog JD (1990) Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human β2m: an animal model of HLA-B27associated human disorders. Cell 63:1099–1112 Hasseli R, Muller-Ladner U, Keil F, Broll M, Dormann A, Frabel C, Hermann W, Heinmuller CJ, Hoyer BF, Loffler F, Ozden F, Pfeiffer U, Saech J, Schneidereit T, Schlesinger A, Schwarting A, Specker C, Stapfer G, Steinmuller M, Storck-Muller K, Strunk J, Thiele A, Triantafyllias K, Vagedes D, Wassenberg S, Wilden E, Zeglam S, Schmeiser T (2021a) The influence of the SARS-CoV-2 lockdown on patients with inflammatory rheumatic diseases on their adherence to immunomodulatory medication: a cross sectional study over 3 months in Germany. Rheumatology (Oxford) 60:SI51–SI58 Hasseli R, Pfeil A, Hoyer BF, Krause A, Lorenz HM, Richter JG, Schmeiser T, Voll RE, SchulzeKoops H, Specker C, Muller-Ladner U (2021b) Do patients with rheumatoid arthritis show a different course of COVID-19 compared to patients with spondyloarthritis? Clin Exp Rheumatol 39:639–647 Hattori M, Taylor TD (2009) The human intestinal microbiome: a new frontier of human biology. DNA Res 16:1–12 Hawkes JE, Chan TC, Krueger JG (2017) Psoriasis pathogenesis and the development of novel targeted immune therapies. J Allergy Clin Immunol 140:645–653 Hendel H, Caillat-Zucman S, Lebuanec H, Carrington M, O'Brien S, Andrieu JM, Schachter F, Zagury D, Rappaport J, Winkler C, Nelson GW, Zagury JF (1999) New class I and ii HLA alleles strongly associated with opposite patterns of progression to Aids. J Immunol 162:6942– 6946 Hewlett S, Cockshott Z, Byron M, Kitchen K, Tipler S, Pope D, Hehir M (2005) Patients' perceptions of fatigue in rheumatoid arthritis: overwhelming, uncontrollable, ignored. Arthritis Rheum 53:697–702 Hoentjen F, Welling G, Harmsen H, Zhang X, Snart J, Tannock G, Lien K, Churchill T, Lupicki M, Dieleman L (2005) Reduction of colitis by prebiotics in HLA-B27 transgenic rats is associated with microflora changes and immunomodulation. Inflamm Bowel Dis 11:977–985 Hu B, Huang S, Yin L (2021) The cytokine storm and COVID-19. J Med Virol 93:250–256 Huang Z, Huang F (2012) Update on the management of Spondyloarthritis in Asian countries. Curr Rheumatol Rev 8:39–44 Jacques P, Elewaut D, Mielants H (2010) Interactions between gut inflammation and arthritis/ spondylitis. Curr Opin Rheumatol 22:368–374

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

451

Jahaj E, Vassiliou AG, Keskinidou C, Gallos P, Vrettou CS, Tsipilis S, Mastora Z, Orfanos SE, Dimopoulou I, Kotanidou A (2021) Evaluating the role of the Interleukin-23/17 Axis in critically ill COVID-19 patients. J Pers Med 11:891 Jain R, Chen Y, Kanno Y, Joyce-Shaikh B, Vahedi G, Hirahara K, Blumenschein WM, Sukumar S, Haines CJ, Sadekova S (2016) Interleukin-23-induced transcription factor Blimp-1 promotes pathogenicity of T helper 17 cells. Immunity 44:131–142 Jones A, Ciurtin C, Ismajli M, Leandro M, Sengupta R, Machado PM (2018) Biologics for treating axial spondyloarthritis. Expert Opin Biol Ther 18:641–652 Kanaseki T, Blanchard N, Hammer GE, Gonzalez F, Shastri N (2006) Eraap synergizes with MHC class I molecules to make the final cut in the antigenic peptide precursors in the endoplasmic reticulum. Immunity 25:795–806 Kanda N, Hoashi T, Saeki H (2020) Nutrition and psoriasis. Int J Mol Sci 21:5405 Kataria RK, Brent LH (2004) Spondyloarthropathies. Am Fam Physician 69:2853–2860 Kaur A, Tuncil YE, Sikaroodi M, Gillevet P, Patterson JA, Keshavarzian A, Hamaker BR (2018) Alterations in the amounts of microbial metabolites in different regions of the mouse large intestine using variably fermentable fibres. Bioact Carbohydr Diet Fibre 13:7–13 Kenna TJ, Robinson PC, Haroon N (2015) Endoplasmic reticulum aminopeptidases in the pathogenesis of ankylosing spondylitis. Rheumatology 54:1549–1556 Kesselring J (2011) Vladimirmikhailovic Bekhterev (1857–1927): strange circumstances surrounding the death of the great Russian neurologist. Eur Neurol 66:14–17 Khan MA (2013) Polymorphism of HLA-B27: 105 subtypes currently known. Curr Rheumatol Rep 15:362 Khan MA, Van Der Linden S (2019) Axial spondyloarthritis: a better name for an old disease: a step toward uniform reporting. ACR Open Rheumatol 1:336–339 Koenders MI, Lubberts E, Oppers-Walgreen B, Van Den Bersselaar L, Helsen MM, Di Padova FE, Boots AM, Gram H, Joosten LA, Van Den Berg WB (2005) Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1. Am J Pathol 167:141–149 Lahesmaa R, Skurnik M, Toivanen P (1993) Molecular mimicry: any role in the pathogenesis of spondyloarthropathies? Immunol Res 12:193 Lamot L, Vidović M, Perica M, Bukovac LT, Harjacek M (2015) Pathogenesis of undifferentiated spondyloarthritis. Reumatizam 62:20–26 Laukens D, Peeters H, Marichal D, Vander Cruyssen B, Mielants H, Elewaut D, Demetter P, Cuvelier C, Van Den Berghe M, Rottiers P, Veys EM, Remaut E, Steidler L, De Keyser F, De Vos M (2005) CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn's disease. Ann Rheum Dis 64:930–935 Le Bert N, Tan AT, Kunasegaran K, Tham CYL, Hafezi M, Chia A, Chng MHY, Lin M, Tan N, Linster M, Chia WN, Chen MI, Wang LF, Ooi EE, Kalimuddin S, Tambyah PA, Low JG, Tan YJ, Bertoletti A (2020) SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 584:457–462 Lees CW, Barrett JC, Parkes M, Satsangi J (2011) New IBD genetics: common pathways with other diseases. Gut 60:1739–1753 Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB, Investigators PS (2008) Efficacy and safety of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (phoenix 1). Lancet 371:1665–1674 Li L, Batliwala M, Bouvier M (2019) ERAP1 enzyme-mediated trimming and structural analyses of MHC I-bound precursor peptides yield novel insights into antigen processing and presentation. J Biol Chem 294:18534–18544 Lin YC, Liang TH, Chen WS, Lin HY (2009) Differences between juvenile-onset ankylosing spondylitis and adult-onset ankylosing spondylitis. J Chin Med Assoc 72:573–580 Lin P, Bach M, Asquith M, Lee AY, Akileswaran L, Stauffer P, Davin S, Pan Y, Cambronne ED, Dorris M, Debelius JW, Lauber CL, Ackermann G, Baeza YV, Gill T, Knight R, Colbert RA,

452

Z. Mukhatayev et al.

Taurog JD, Van Gelder RN, Rosenbaum JT (2014) HLA-B27 and human β2-microglobulin affect the gut microbiota of transgenic rats. PLoS One 9:e105684 López De Castro JA (2018) How ERAP1 and ERAP2 shape the Peptidomes of disease-associated MHC-I proteins. Front Immunol 9:2463 López-Larrea C, Sujirachato K, Mehra NK, Chiewsilp P, Isarangkura D, Kanga U, Domínguez O, Coto E, Pena M, Setien F (1995) HLA-B27 subtypes in Asian patients with ankylosing spondylitis evidence for new associations. Tissue Antigens 45:169–176 Lubberts E, Joosten LA, Oppers B, Van Den Bersselaar L, Coenen-De Roo CJ, Kolls JK, Schwarzenberger P, Van De Loo FA, Van Den Berg WB (2001) IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J Immunol 167:1004–1013 Maas F, Arends S, Wink FR, Bos R, Bootsma H, Brouwer E, Spoorenberg A (2017) Ankylosing spondylitis patients at risk of poor radiographic outcome show diminishing spinal radiographic progression during long-term treatment with TNF-α inhibitors. PLoS One 12:E0177231 Martínez-González O, Cantero-Hinojosa J, Paule-Sastre P, Gómez-Magán JC, Salvatierra-Ríos D (1994) Intestinal permeability in patients with ankylosing spondylitis and their healthy relatives. Br J Rheumatol 33:644–647 Mcgeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, Mcclanahan TK, O'shea JJ, Cua DJ (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17–producing effector T helper cells in vivo. Nat Immunol 10:314–324 Mcveigh CM, Cairns AP (2006) Diagnosis and management of ankylosing spondylitis. BMJ 333: 581–585 Mear JP, Schreiber KL, Munz C, Zhu XM, Stevanovic S, Rammensee HG, Rowland-Jones SL, Colbert RA (1999) Misfolding of HLA-B27 as A result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol 163:6665–6670 Mellor AL, Munn DH (2003) Tryptophan catabolism and regulation of adaptive immunity. J Immunol 170:5809–5813 Merilahti-Palo R, Söderström KO, Lahesmaa-Rantala R, Granfors K, Toivanen A (1991) Bacterial antigens in synovial biopsy specimens in yersinia triggered reactive arthritis. Ann Rheum Dis 50:87 Minnock P, Fitzgerald O, Bresnihan B (2003) Quality of life, social support, and knowledge of disease in women with rheumatoid arthritis. Arthritis Rheum 49:221–227 Moll JM, Wright V (1973) Psoriatic arthritis. Semin Arthritis Rheum 3:55–78 Mukherjee D, Nissen SE, Topol EJ (2001) Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954–959 Nagalingam NA, Kao JY, Young VB (2011) Microbial ecology of the murine gut associated with the development of dextran sodium sulfate-induced colitis. Inflamm Bowel Dis 17:917–926 Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng BJ, Ruether A, Schreiber S, Weichenthal M, Gladman D, Rahman P, Schrodi SJ, Prahalad S, Guthery SL, Fischer J, Liao W, Kwok PY, Menter A, Lathrop GM, Wise CA, Begovich AB, Voorhees JJ, Elder JT, Krueger GG, Bowcock AM, Abecasis GR (2009) Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 41:199–204 Ocampo DV, Gladman D (2019) Psoriatic arthritis. F1000Research, 8, F1000 Faculty Rev-1665. https://doi.org/10.12688/f1000research.19144.1 Oldstone MBA (1989) Molecular mimicry as a mechanism for the cause and as a probe uncovering etiologic agent(S) of autoimmune-disease. Curr Top Microbiol Immunol 145:127–135 Orchard TR (2012) Management of arthritis in patients with inflammatory bowel disease. Gastroenterol Hepatol (N Y) 8:327–329 Ostendorf B, Specker C, Schneider M (1998) Methotrexate lacks efficacy in the treatment of severe ankylosing spondylitis compared with rheumatoid and psoriatic arthritis. J Clin Rheumatol 4: 129–136 Paget SA (2012) The microbiome, autoimmunity, and arthritis: cause and effect: an historical perspective. Trans Am Clin Climatol Assoc 123:257–266

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

453

Paladini F, Taccari E, Fiorillo MT, Cauli A, Passiu G, Mathieu A, Punzi L, Lapadula G, Scarpa R, Sorrentino R (2005) Distribution of HLA–B27 subtypes in sardinia and continental Italy and their association with spondylarthropathies. Arthritis Rheum 52:3319–3321 Pedersen SJ, Maksymowych WP (2019a) The pathogenesis of ankylosing spondylitis: an update. Curr Rheumatol Rep 21:1–10 Pedersen SJ, Maksymowych WP (2019b) The pathogenesis of ankylosing spondylitis: an update. Curr Rheumatol Rep 21:58 Png CW, Lindén SK, Gilshenan KS, Zoetendal EG, Mcsweeney CS, Sly LI, Mcguckin MA, Florin TH (2010) Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol 105:2420–2428 Poddubnyy D, Sieper J (2019) Current unmet needs in spondyloarthritis. Curr Rheumatol Rep 21: 43 Poddubnyy D, Rudwaleit M, Haibel H, Listing J, Marker-Hermann E, Zeidler H, Braun J, Sieper J (2012) Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German spondyloarthritis inception cohort. Ann Rheum Dis 71:1616–1622 Popov I, Cruz CSD, Barber BH, Chiu B, Inman RD (2002) Breakdown of CTL tolerance to self HLA-B*2705 induced by exposure to Chlamydia trachomatis. J Immunol 169:4033 Prelog M, Schwarzenbrunner N, Sailer-Höck M, Kern H, Klein-Franke A, Ausserlechner MJ, Koppelstaetter C, Brunner A, Duftner C, Dejaco C, Strasak AM, Müller T, Zimmerhackl LB, Brunner J (2008) Premature aging of the immune system in children with juvenile idiopathic arthritis. Arthritis Rheum 58:2153–2162 Quigley EM (2012) Prebiotics and probiotics: their role in the management of gastrointestinal disorders in adults. Nutr Clin Pract 27(2):195–200. https://doi.org/10.1177/0884533611423926 Raiker R, Pakhchanian H, Kavadichanda C, Gupta L, Kardes S, Ahmed S (2021) Axial spondyloarthritis may protect against poor outcomes in COVID-19: propensity score matched analysis of 9766 patients from a nationwide multi-centric research network. Clin Rheumatol 41(3):721–730 Ramiro S, Van Der Heijde D, Van Tubergen A, Stolwijk C, Dougados M, Van Den Bosch F, Landewe R (2014) Higher disease activity leads to more structural damage in the spine in ankylosing spondylitis: 12-year longitudinal data from the OASIS cohort. Ann Rheum Dis 73: 1455–1461 Ramonda R, Marchesoni A, Carletto A, Bianchi G, Cutolo M, Ferraccioli G, Fusaro E, De Vita S, Galeazzi M, Gerli R, Matucci-Cerinic M, Minisola G, Montecucco C, Pellerito R, Salaffi F, Paolazzi G, Sarzi-Puttini P, Scarpa R, Bagnato G, Triolo G, Valesini G, Punzi L, Olivieri I (2016) Patient-reported impact of spondyloarthritis on work disability and working life: the ATLANTIS survey. Arthritis Res Ther 18:78 Rashid T, Ebringer A (2007) Ankylosing spondylitis is linked to klebsiella--the evidence. Clin Rheumatol 26:858–864 Rashid T, Wilson C, Ebringer A, Ebringer A (2013) The link between ankylosing spondylitis, Crohn's disease, klebsiella, and starch consumption. Clin Dev Immunol 2013:872632 Rath HC, Wilson KH, Sartor RB (1999) Differential induction of colitis and gastritis in HLA-B27 transgenic rats selectively colonized with Bacteroides vulgatus or Escherichia coli. Infect Immun 67:2969–2974 Raychaudhuri SP (2013) Role of IL-17 in psoriasis and psoriatic arthritis. Clin Rev Allergy Immunol 44:183–193 Raychaudhuri SP, Raychaudhuri SK (2017) Mechanistic rationales for targeting interleukin-17A in spondyloarthritis. Arthritis Res Ther 19:51 Reháková Z, Capková J, Stĕpánková R, Sinkora J, Louzecká A, Ivanyi P, Weinreich S (2000) Germ-free mice do not develop ankylosing enthesopathy, a spontaneous joint disease. Hum Immunol 61:555–558 Rehaume LM, Mondot S, Aguirre De Cárcer D, Velasco J, Benham H, Hasnain SZ, Bowman J, Ruutu M, Hansbro PM, Mcguckin MA, Morrison M, Thomas R (2014) ZAP-70 genotype

454

Z. Mukhatayev et al.

disrupts the relationship between microbiota and host, leading to spondyloarthritis and ileitis in SKG mice. Arthritis Rheumatol 66:2780–2792 Reimold AM, Chandran V (2014) Nonpharmacologic therapies in spondyloarthritis. Best Pract Res Clin Rheumatol 28:779–792 Ren X, Wen W, Fan X, Hou W, Su B, Cai P, Li J, Liu Y, Tang F, Zhang F, Yang Y, He J, Ma W, He J, Wang P, Cao Q, Chen F, Chen Y, Cheng X, Deng G, Deng X, Ding W, Feng Y, Gan R, Guo C, Guo W, He S, Jiang C, Liang J, Li YM, Lin J, Ling Y, Liu H, Liu J, Liu N, Liu SQ, Luo M, Ma Q, Song Q, Sun W, Wang G, Wang F, Wang Y, Wen X, Wu Q, Xu G, Xie X, Xiong X, Xing X, Xu H, Yin C, Yu D, Yu K, Yuan J, Zhang B, Zhang P, Zhang T, Zhao J, Zhao P, Zhou J, Zhou W, Zhong S, Zhong X, Zhang S, Zhu L, Zhu P, Zou B, Zou J, Zuo Z, Bai F, Huang X, Zhou P, Jiang Q, Huang Z, Bei JX, Wei L, Bian XW, Liu X, Cheng T, Li X, Zhao P, Wang FS, Wang H, Su B, Zhang Z, Qu K, Wang X, Chen J, Jin R, Zhang Z (2021) COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas. Cell 184: 5838 Reveille JD (2012) Genetics of spondyloarthritis--beyond the MHC. Nat Rev Rheumatol 8:296– 304 Reveille JD (2014) An update on the contribution of the MHC to AS susceptibility. Clin Rheumatol 33:749–757 Reveille JD (2019a) 57-Spondyloarthritis. In: Rich RR, Fleisher TA, Shearer WT, Schroeder HW, Frew AJ, Weyand CM (eds) Clinical immunology, 5th edn. Content Repository Only. Elsevier, London, pp 769–787 Reveille JD (2019b) Spondyloarthritis. In: Clinical Immunology. Elsevier, Amsterdam Reveille JD, Arnett FC (2005) Spondyloarthritis: update on pathogenesis and management. Am J Med 118:592–603 Reveille JD, Maganti RM (2009) Subtypes of HLA-B27: history and implications in the pathogenesis of ankylosing spondylitis. In: Molecular Mechanisms of Spondyloarthropathies. Springer, New York, pp 159–176 Reveille JD, Sims A-M, Danoy P, Evans DM, Leo P, Pointon JJ, Jin R, Zhou X, Bradbury LA, Appleton LH (2010a) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42:123 Reveille JD, Sims AM, Danoy P, Evans DM, Leo P, Pointon JJ, Jin R, Zhou X, Bradbury LA, Appleton LH, Davis JC, Diekman L, Doan T, Dowling A, Duan R, Duncan EL, Farrar C, Hadler J, Harvey D, Karaderi T, Mogg R, Pomeroy E, Pryce K, Taylor J, Savage L, Deloukas P, Kumanduri V, Peltonen L, Ring SM, Whittaker P, Glazov E, Thomas GP, Maksymowych WP, Inman RD, Ward MM, Stone MA, Weisman MH, Wordsworth BP, Brown MA (2010b) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42:123–127 Ritchlin CT, Kavanaugh A, Gladman DD, Mease PJ, Helliwell P, Boehncke WH, De Vlam K, Fiorentino D, Fitzgerald O, Gottlieb AB, Mchugh NJ, Nash P, Qureshi AA, Soriano ER, Taylor WJ, Group For, R., Assessment Of, P. & Psoriatic, A (2009) Treatment recommendations for psoriatic arthritis. Ann Rheum Dis 68:1387–1394 Rock KL, Reits E, Neefjes J (2016) Present yourself! By MHC class I and MHC class II molecules. Trends Immunol 37:724–737 Rosenbaum JT, Asquith MJ (2016) The microbiome: a revolution in treatment for rheumatic diseases? Curr Rheumatol Rep 18:62 Rosenbaum JT, Hamilton H, Weisman MH, Reveille JD, Winthrop KL, Choi D (2021a) The effect of HLA-B27 on susceptibility and severity of COVID-19. J Rheumatol 48:621–622 Rosenbaum JT, Weisman MH, Shafer C, Aslanyan E, Howard RA, Ogle K, Hamilton H, Reveille JD, Winthrop KL, Choi D (2021b) Correspondence on ‘Factors associated with COVID-19related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry’. Annals of the rheumatic diseases, annrheumdis2021-220588. Advance online publication. https://doi.org/10.1136/annrheumdis-2021-220588 Online ahead of print

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

455

Rosenbaum JT, Weisman MH, Hamilton H, Shafer C, Aslanyan E, Howard RA, Ogle K, Reveille JD, Winthrop KL, Choi D (2022) The interplay between COVID-19 and Spondyloarthritis or its treatment. J Rheumatol 49(2):225–229. https://doi.org/10.3899/jrheum.210742 Roux CH, Brocq O, Gerald F, Pradier C, Bailly L (2020) Clinical impact of COVID-19 on a French population of spondyloarthritis patients. Clin Rheumatol 39:3185–3187 Rudwaleit M, Landewe R, Van Der Heijde D, Listing J, Brandt J, Braun J, Burgos-Vargas R, Collantes-Estevez E, Davis J, Dijkmans B, Dougados M, Emery P, Van Der Horst-Bruinsma IE, Inman R, Khan MA, Leirisalo-Repo M, Van Der Linden S, Maksymowych WP, Mielants H, Olivieri I, Sturrock R, De Vlam K, Sieper J (2009) The development of assessment of spondyloarthritis international society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal. Ann Rheum Dis 68:770–776 Ruutu M, Thomas G, Steck R, Degli-Esposti MA, Zinkernagel MS, Alexander K, Velasco J, Strutton G, Tran A, Benham H, Rehaume L, Wilson RJ, Kikly K, Davies J, Pettit AR, Brown MA, Mcguckin MA, Thomas R (2012) β-glucan triggers spondyloarthritis and Crohn's diseaselike ileitis in SKG mice. Arthritis Rheum 64:2211–2222 Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, Sakihama T, Matsutani T, Negishi I, Nakatsuru S, Sakaguchi S (2003) Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426:454–460 Schafer P (2012) Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol 83:1583–1590 Schäfer M, Strangfeld A, Hyrich KL, Carmona L, Gianfrancesco M, Lawson-Tovey S, Mateus EF, Gossec L, Robinson PC, Yazdany J, Machado PM (2021) Response to: ‘Correspondence on ‘Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician reported registry” by Mulhearn et al. Annals of the rheumatic diseases, annrheumdis-2021-220134. Advance online publication. https://doi.org/10.1136/annrheumdis-2021-220134 Online published ahead of print Scher JU, Ubeda C, Artacho A, Attur M, Isaac S, Reddy SM, Marmon S, Neimann A, Brusca S, Patel T, Manasson J, Pamer EG, Littman DR, Abramson SB (2015) Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol 67:128–139 Schett G, Wollenhaupt J, Papp K, Joos R, Rodrigues JF, Vessey AR, Hu C, Stevens R, De Vlam KL (2012) Oral apremilast in the treatment of active psoriatic arthritis: results of a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 64:3156–3167 Schittenhelm RB, Sian TC, Wilmann PG, Dudek NL, Purcell AW (2015) Revisiting the arthritogenic peptide theory: quantitative not qualitative changes in the peptide repertoire of HLA-B27 allotypes. Arthritis Rheumatol 67:702–713 Schlosstein L, Terasaki PI, Bluestone R, Pearson CM (1973) High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 288:704–706 Schulze-Koops H, Krueger K, Vallbracht I, Hasseli R, Skapenko A (2021) Increased risk for severe COVID-19 in patients with inflammatory rheumatic diseases treated with rituximab. Ann Rheum Dis 80:E67 Schwartz DM, Bonelli M, Gadina M, O'shea JJ (2016) Type I/II cytokines, jaks, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol 12:25–36 Scofield RH, Warren WL, Koelsch G, Harley JB (1993) A hypothesis for the HLA-B27 immune dysregulation in spondyloarthropathy: contributions from enteric organisms, B27 structure, peptides bound by B27, and convergent evolution. Proc Natl Acad Sci U S A 90:9330–9334 Sharip A, Kunz J (2020) Understanding the pathogenesis of spondyloarthritis. Biomolecules 10: 1461 Siala M, Gdoura R, Fourati H, Rihl M, Jaulhac B, Younes M, Sibilia J, Baklouti S, Bargaoui N, Sellami S, Sghir A, Hammami A (2009) Broad-range PCR, cloning and sequencing of the full 16s rRNA gene for detection of bacterial DNA in synovial fluid samples of Tunisian patients with reactive and undifferentiated arthritis. Arthritis Res Ther 11:R102

456

Z. Mukhatayev et al.

Sieper J (2012) Developments in therapies for Spondyloarthritis. Nat Rev Rheumatol 8:280–287 Sieper J, Poddubnyy D (2016) New evidence on the management of spondyloarthritis. Nat Rev Rheumatol 12:282–295 Sinkorová Z, Capková J, Niederlová J, Stepánková R, Sinkora J (2008) Commensal intestinal bacterial strains trigger ankylosing enthesopathy of the ankle in inbred B10.BR (H-2(K)) male mice. Hum Immunol 69:845–850 Smith JA (2018) Regulation of cytokine production by the unfolded protein response; implications for infection and autoimmunity. Front Immunol 9:422 Smith NM, Maloney NG, Shaw S, Horgan GW, Fyfe C, Martin JC, Suter A, Scott KP, Johnstone AM (2020) Daily fermented whey consumption alters the fecal short-chain fatty acid profile in healthy adults. Front Nutr 7:165 Song IH, Poddubnyy DA, Rudwaleit M, Sieper J (2008) Benefits and risks of ankylosing spondylitis treatment with nonsteroidal antiinflammatory drugs. Arthritis Rheum 58:929–938 Song P, Li W, Xie J, Hou Y, You C (2020) Cytokine storm induced by SARS-CoV-2. Clin Chim Acta 509:280–287 Stebbings S, Munro K, Simon MA, Tannock G, Highton J, Harmsen H, Welling G, Seksik P, Dore J, Grame G, Tilsala-Timisjarvi A (2002) Comparison of the faecal microflora of patients with ankylosing spondylitis and controls using molecular methods of analysis. Rheumatology (Oxford) 41:1395–1401 Strangfeld A, Schafer M, Gianfrancesco MA, Lawson-Tovey S, Liew JW, Ljung L, Mateus EF, Richez C, Santos MJ, Schmajuk G, Scire CA, Sirotich E, Sparks JA, Sufka P, Thomas T, Trupin L, Wallace ZS, Al-Adely S, Bachiller-Corral J, Bhana S, Cacoub P, Carmona L, Costello R, Costello W, Gossec L, Grainger R, Hachulla E, Hasseli R, Hausmann JS, Hyrich KL, Izadi Z, Jacobsohn L, Katz P, Kearsley-Fleet L, Robinson PC, Yazdany J, Machado PM, Alliance C-GR (2021) Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis 80:930–942 Strümpell A (1897) Bemerkung Über Die Chronische Ankylosirende Entzündung Der Wirbelsäule Und Der Hüftgelenke. Dtsch Z Nervenheilkd 11:338–342 Syrbe U, Sieper J (2020a) Chapter 36—Spondyloarthritides. In: Rose NR, Mackay IR (eds) The autoimmune diseases, 6th edn. Academic Press Syrbe U, Sieper J (2020b) Spondyloarthritides. In: The Autoimmune Diseases. Elsevier, Amsterdam Tan ZY, Bealgey KW, Fang Y, Gong YM, Bao S (2009) Interleukin-23: immunological roles and clinical implications. Int J Biochem Cell Biol 41:733–735 Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernández-Sueiro JL, Balish E, Hammer RE (1994) The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 180:2359–2364 Torgutalp M, Poddubnyy D (2018) Emerging treatment options for spondyloarthritis. Best Pract Res Clin Rheumatol 32:472–484 Toussirot E (2011) Current therapeutics for spondyloarthritis. Expert Opin Pharmacother 12:2469– 2477 Toussirot E (2017) New treatment options and emerging drugs for axial spondyloarthritis: biological and targeted synthetic agents. Expert Opin Pharmacother 18(3):275–282 Toussirot E (2019) Pharmacological management of axial spondyloarthritis in adults. Expert Opin Pharmacother 20:1483–1491 Townes JM, Deodhar AA, Laine ES, Smith K, Krug HE, Barkhuizen A, Thompson ME, Cieslak PR, Sobel J (2008) Reactive arthritis following culture-confirmed infections with bacterial enteric pathogens in Minnesota and Oregon: a population-based study. Ann Rheum Dis 67: 1689–1696 Tsui FW, Xi N, Rohekar S, Riarh R, Bilotta R, Tsui HW, Inman RD (2008) Toll-like receptor 2 variants are associated with acute reactive arthritis. Arthritis Rheum 58:3436–3438

17

Microorganisms in the Pathogenesis and Management of Spondyloarthritis

457

Tsui FW, Haroon N, Reveille JD, Rahman P, Chiu B, Tsui HW, Inman RD (2010) Association of an ERAP1 ERAP2 haplotype with familial ankylosing spondylitis. Ann Rheum Dis 69:733–736 Ulven T (2012) Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front Endocrinol (Lausanne) 3:111 Van Den Bosch F, Deodhar A (2014) Treatment of spondyloarthritis beyond TNF-alpha blockade. Best Pract Res Clin Rheumatol 28:819–827 Van Der Heijde D, Deodhar A, Wei JC, Drescher E, Fleishaker D, Hendrikx T, Li D, Menon S, Kanik KS (2017a) Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study. Ann Rheum Dis 76:1340–1347 Van Der Heijde D, Ramiro S, Landewe R, Baraliakos X, Van Den Bosch F, Sepriano A, Regel A, Ciurea A, Dagfinrud H, Dougados M, Van Gaalen F, Geher P, Van Der Horst-Bruinsma I, Inman RD, Jongkees M, Kiltz U, Kvien TK, Machado PM, Marzo-Ortega H, Molto A, NavarroCompan V, Ozgocmen S, Pimentel-Santos FM, Reveille J, Rudwaleit M, Sieper J, SampaioBarros P, Wiek D, Braun J (2017b) 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis 76:978–991 Van Der Horst-Bruinsma IE, Nurmohamed MT (2012) Management and evaluation of extraarticular manifestations in spondyloarthritis. Ther Adv Musculoskelet Dis 4:413–422 Vitulano C, Tedeschi V, Paladini F, Sorrentino R, Fiorillo M (2017) The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis. Clin Exp Immunol 190:281–290 Wanders A, Heijde DVD, Landewé R, Béhier J-M, Calin A, Olivieri I, Zeidler H, Dougados M (2005) Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum 52:1756–1765 Ward MM, Deodhar A, Akl EA, Lui A, Ermann J, Gensler LS, Smith JA, Borenstein D, Hiratzka J, Weiss PF, Inman RD, Majithia V, Haroon N, Maksymowych WP, Joyce J, Clark BM, Colbert RA, Figgie MP, Hallegua DS, Prete PE, Rosenbaum JT, Stebulis JA, Van Den Bosch F, Yu DT, Miller AS, Reveille JD, Caplan L (2016) American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol 68(2):282–298 Weber FP (1931) “Spondylose Rhizomélique” (Pierre Marie). Proc R Soc Med 24:521–523 Welsh J, Avakian H, Cowling P, Ebringer A, Wooley P, Panayi G, Ebringer R (1980) Ankylosing spondylitis, HLA-B27 and Klebsiella. I. Cross-reactivity studies with rabbit antisera. Br J Exp Pathol 61:85–91 WHO Food Safety Programme & Food and Agriculture Organization of the United Nations (2002) Risk assessments for salmonella in eggs and broiler chickens: interpretative summary. World Health Organization. https://apps.who.int/iris/handle/10665/42618 Wong-Baeza I, Ridley A, Shaw J, Hatano H, Rysnik O, Mchugh K, Piper C, Brackenbridge S, Fernandes R, Chan A (2013) KIR3DL2 binds to HLA-B27 dimers and free H chains more strongly than other HLA class I and promotes the expansion of T cells in ankylosing spondylitis. J Immunol 190:3216–3224 Wu IB, Schwartz RA (2008) Reiter's syndrome: the classic triad and more. J Am Acad Dermatol 59: 113–121 Yago T, Nanke Y, Kawamoto M, Kobashigawa T, Yamanaka H, Kotake S (2017) IL-23 and Th17 disease in inflammatory arthritis. J Clin Med 6:81 Yang X, Xie L, Li Y, Wei C (2009) More than 9,000,000 unique genes in human gut bacterial community: estimating gene numbers inside a human body. PLoS One 4:e6074 Yeoh YK, Zuo T, Lui GC, Zhang F, Liu Q, Li AY, Chung AC, Cheung CP, Tso EY, Fung KS, Chan V, Ling L, Joynt G, Hui DS, Chow KM, Ng SSS, Li TC, Ng RW, Yip TC, Wong GL, Chan FK, Wong CK, Chan PK, Ng SC (2021) Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut 70:698–706 Yeremenko N, Paramarta JE, Baeten D (2014) The interleukin-23/interleukin-17 immune axis as a promising new target in the treatment of spondyloarthritis. Curr Opin Rheumatol 26(4):361–370

458

Z. Mukhatayev et al.

Yuan FF, Velickovic Z, Ashton LJ, Dyer WB, Geczy AF, Dunckley H, Lynch GW, Sullivan JS (2014) Influence of HLA gene polymorphisms on susceptibility and outcome post infection with the SARS-CoV virus. Virol Sin 29:128–130 Zeidler H, Mau W, Khan MA (1992) Undifferentiated spondyloarthropathies. Rheum Dis Clin N Am 18:187–202 Zhang YZ, Li YY (2014) Inflammatory bowel disease: pathogenesis. World J Gastroenterol 20:91– 99 Zhu W, He X, Cheng K, Zhang L, Chen D, Wang X, Qiu G, Cao X, Weng X (2019a) Ankylosing spondylitis: etiology, pathogenesis, and treatments. Bone Res 7:22 Zhu W, He X, Cheng K, Zhang L, Chen D, Wang X, Qiu G, Cao X, Weng X (2019b) Ankylosing spondylitis: etiology, pathogenesis, and treatments. Bone Res 7:1–16 Zochling J, Van Der Heijde D, Burgos-Vargas R, Collantes E, Davis JC Jr, Dijkmans B, Dougados M, Geher P, Inman RD, Khan MA, Kvien TK, Leirisalo-Repo M, Olivieri I, Pavelka K, Sieper J, Stucki G, Sturrock RD, Van Der Linden S, Wendling D, Bohm H, Van Royen BJ, Braun J, Group, A. I. A. I. W. & European League Against, R (2006) ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 65:442–452 Zuo T, Zhan H, Zhang F, Liu Q, Tso EYK, Lui GCY, Chen N, Li A, Lu W, Chan FKL, Chan PKS, Ng SC (2020a) Alterations in fecal fungal microbiome of patients with COVID-19 during time of hospitalization until discharge. Gastroenterology 159:1302–1310.e5 Zuo T, Zhang F, Lui GCY, Yeoh YK, Li AYL, Zhan H, Wan Y, Chung ACK, Cheung CP, Chen N, Lai CKC, Chen Z, Tso EYK, Fung KSC, Chan V, Ling L, Joynt G, Hui DSC, Chan FKL, Chan PKS, Ng SC (2020b) Alterations in gut microbiota of patients with COVID-19 during time of hospitalization. Gastroenterology 159:944–955.e8 Zuo T, Liu Q, Zhang F, Yeoh YK, Wan Y, Zhan H, Lui GCY, Chen Z, Li AYL, Cheung CP, Chen N, Lv W, Ng RWY, Tso EYK, Fung KSC, Chan V, Ling L, Joynt G, Hui DSC, Chan FKL, Chan PKS, Ng SC (2021) Temporal landscape of human gut RNA and DNA virome in SARS-CoV-2 infection and severity. Microbiome 9:91

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

18

Aigul Sharip, Zhussipbek Mukhatayev, Darya Chunikhina, Madina Baglanova, Dimitri Poddighe, Bayan Ainabekova, Almagul Kushugulova, and Jeannette Kunz

Abstract

Ankylosing spondylitis (AS) is a chronic systemic auto-inflammatory disease that mainly affects sacroiliac joints and the axial skeleton. AS shows the highest genetic association to human leukocyte antigen B27 (HLA-B*27) among the SpA family of diseases. While this link has been discovered many decades ago, the etiopathology of AS and the pathogenic role of HLA-B*27 in disease development remain to be fully elucidated. Increasing evidence supports the hypothesis that HLA-B*27-dependent diseases, such as, have an underlying microbial pathogenesis. This chapter discusses the causal mechanisms underlying disease pathogenesis in animal models and patient studies including the role of pathobionts in contributing toward HLA-B*27-associated AS. The chapter further discusses the current therapeutic approaches and the various emerging approaches of therapeutic modalities including prebiotics/probiotics, diet, targeted antibiotics, and microbial metabolites. As our understanding of the complex host-microbe interactions in AS improves, this may spur the

A. Sharip · Z. Mukhatayev · D. Chunikhina · D. Poddighe · J. Kunz (*) Department of Biomedical Sciences, Nazarbayev University School of Medicine, Nur-Sultan, Republic of Kazakhstan e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected] M. Baglanova · B. Ainabekova Department of Internal Medicine with the Course of Gastroenterology, Endocrinology and Pulmonology, NJSC Astana Medical University, Nur-Sultan, Republic of Kazakhstan A. Kushugulova Laboratory of Human Microbiome and Longevity, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, Nur-Sultan, Republic of Kazakhstan e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_18

459

460

A. Sharip et al.

development of new therapeutic avenues for AS and other HLA-B*27-associated diseases using approaches that target gut microbiota composition and function. Keywords

Ankylosing spondylitis · Spondyloarthropathy · HLA-B27 · Microbiome · Dysbiosis · Probiotic · ERAP1 · ERAP2 · Interleukin-23

18.1

Introduction

Ankylosing spondylitis (AS) is the most frequent clinical subtype of a group of chronic inflammatory diseases known as “spondyloarthropathies” (SpA). AS is a progressive and debilitating disease, primarily affecting the sacroiliac and spinal joints and the related tendons and ligaments (Yang et al. 2016; Dakwar et al. 2008). Indeed, the usual manifestations of AS are persistent back pain and stiffness; however, as the disease progresses, the chronic inflammation can lead to fibrosis and calcification, which may result in the fusion of the spine (“bamboo spine”) and loss of spine flexibility at the final stage (Sieper et al. 2002; Zhu et al. 2019). In addition, some extra-articular manifestations can occur, such as acute anterior uveitis and inflammatory bowel disease (IBD) (Molto and Nikiphorou 2018). AS is a multifactorial autoimmune disease where multiple genetic and environmental factors contribute in a complex and variable way to disease initiation and progression (Stone et al. 2003; Coşkun et al. 2014; Solmaz et al. 2016). Despite intense efforts, its underlying pathogenesis remains enigmatic. AS is characterized by a strong genetic background where HLA-B*27 is a major risk factor. The association between HLA-B*27 and AS was discovered almost 50 years ago, linking the susceptibility of a rheumatic disease to these particular genes in the major histocompatibility complex (Schlosstein et al. 1973; Brewerton et al. 1973). However, the exact etiology of AS is not completely established, despite the progress in understanding the pathogenesis of autoimmune diseases (Zhu et al. 2019). The overall contribution of HLA-B*27 to AS inheritance is estimated to be 20–30%, indicating that other genetic factors are involved in disease initiation and progression. Indeed, most of HLA-B*27-positive individuals (around 80%) do not develop AS (Alan et al. 2006), and several other MHC genes have been associated with AS. Despite the strong genetic background in AS, environmental factors are also implicated in initiating and promoting the disease, including infectious agents. Bacteria are suggested to be potential triggers in the etiopathogenesis of AS, as it happens with reactive arthritis (ReA) (Sieper et al. 2002). Bacterial genomes and proteins have been found in the synovial fluids of affected joints in ReA patients, and specific T-cells of bacteria have been described in the blood and synovial fluids of the affected individuals. Microbial infection acts as a triggering factor of a host’s innate immune system and the development of AS (Gaston et al. 1989).

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

461

18.1.1 Epidemiology The overall prevalence of AS is 0.1–1.4% in the general population (Yang et al. 2016; Dakwar et al. 2008). The prevalence of AS varies according to ethnicity. AS is more common in the northern European populations and the least common in Mediterranean and sub-Saharan populations. The highest AS prevalence (approximately 2.5%) is reported among Eskimo populations in Alaska (Boyer et al. 1994). There is a close correlation between the observed frequency of HLA-B*27 and the prevalence of AS in specific populations (Zhu et al. 2019; Sieper et al. 2002). Populations with higher frequencies of HLA-B*27 tend to have more AS cases. Overall, the prevalence of AS is 5–6% among HLA-B*27-positive individuals (Reveille and Weisman 2013). Besides, a positive family history for AS significantly and further increases the risk of developing AS (8.2% in first-degree relatives), which can be up to 16 times higher than that described in the general population (Van Der Linden et al. 1984b; Brown et al. 2000). AS primarily affects young people: indeed, the peak of incidence is described in the second and third decades of life. The onset of AS occurs 30 years of age in approximately 80% of cases, whereas only 5% experience the first symptoms 45 years of age (Braun and Sieper 2006). AS is diagnosed more commonly in male (male to female ratio is approximately 2:1) (Braun and Sieper 2006). However, in some populations, the percentage of males among patients affected with AS can be 65–80% (Dougados et al. 1999; Zink et al. 2000). Interestingly, gender can even affect some clinical aspects and disease patterns: the axial skeleton (spine) and pelvis are primarily affected in men, whereas the involvement of peripheral joints (knees, wrists, and hips) is observed more frequently in women (Kaipiainen-Seppanen et al. 1997; Calin 2006).

18.1.2 Clinical Overview 18.1.2.1 Symptoms Symptoms include diffuse low back pain, buttock discomfort, limited spinal mobility, hip pain, and shoulder pain, which are the most common symptoms complained by AS patients. At any stage of the disease, asymmetric arthritis of peripheral joints, primarily in the lower limbs, could cause additional symptoms. Moreover, several extra-articular manifestations can occur. Among those, acute anterior uveitis (Dakwar et al. 2008) is the most common one: it may manifest with unilateral ocular discomfort, photophobia, and increased lachrymation. Loss of spinal mobility, including limited flexion and extension of the lumbar spine, and reduction of lumbar lordosis are the main findings emerging from the physical examination of AS patients (Sieper et al. 2002). Spine mobility is frequently reduced symmetrically in both the anterior and lateral movements. The Schober’s test, used to determine whether there is any decrease in lumbar spinal motion, is helpful for the evaluation of mobility and is used as a screening approach for AS

462

A. Sharip et al.

(Viitanen et al. 1995). Local tenderness can occur, indicating that the inflammatory process also involves the insertion of ligaments into bones (entheses) (Calin 2006).

18.1.2.2 Diagnosis and Classification The diagnosis of AS is based on clinical features, laboratory examinations, and physical and radiological findings. Currently, the most widely used diagnostic classification for AS is the modified New York (mNY) criteria proposed in 1984 (Dakwar et al. 2008; Van Der Linden et al. 1984a). Sacroiliitis is the hallmark of AS, and the severity of sacroiliitis can be graded radiographically in four stages. Based on the mNY criteria, the diagnosis of AS can be made if at least one clinical criterion (inflammatory back pain, alternating buttock pain, and morning stiffness) is associated with at least one confirmed radiological change (including the limitation in lumbar spinal motion and unilateral or bilateral sacroiliitis) (Zhu et al. 2019; Akgul and Ozgocmen 2011). Furthermore, other classification systems for the diagnosis of AS are Amor criteria and European Spondyloarthropathy Study Group (ESSG) criteria (Zhu et al. 2019). Although no laboratory test is diagnostic for AS, some findings are supportive. Indeed, the inflammatory parameters are often increased: C-reactive protein (CRP) is raised in 50–70% of patients with acute disease (Braun and Sieper 2007), and the erythrocyte sedimentation rate (ESR) is elevated in 50% of patients. Total serum IgA can be elevated sometimes, and some plasmatic enzymes (e.g., creatinine phosphokinase and alkaline phosphatase) can be slightly altered. As mentioned, HLA-B*27 testing can strongly support the diagnosis of AS, especially if the clinical picture is not completely clear. However, HLA-B*27 positivity may not negate a diagnosis for AS when clinical and radiological findings are obvious. The presence of radiographic sacroiliitis is the most important radiological finding in support of AS diagnosis (Van Der Linden et al. 1984a). Syndesmophytes and ankylosis are the most characteristic features that are visible on conventional radiographs after months to many years of disease. Osteoporosis (Karberg et al. 2005) and related pathological fractures (Cooper et al. 1994) and hyperkyphosis (predominantly seen in male patients) (Vosse et al. 2006) represent additional radiological aspects that can appear during the disease course. CT and MRI have been used to evaluate the sacroiliac joints and facilitate diagnosis (Calin 2006; Braun and Sieper 2007). Overall, achieving an appropriate diagnosis of AS before the appearance of irreversible damage can be challenging, and unfortunately, a diagnostic delay of several years is not uncommon (Sieper et al. 2002).

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

18.2

463

Pathogenesis of AS

18.2.1 Genetic Predisposition to AS Since its discovery, HLA-B*27 constitutes the main genetic risk factor for AS, providing an important landmark in spondyloarthritis research (Schlosstein et al. 1973). Indeed, 90–95% of AS patients are HLA-B*27 positive, whereas only 1–2% of the general population is HLA-B*27 positive (Zhu et al. 2019; Alan et al. 2006). The individual genetic background is a crucial contributor to AS pathogenesis, which has been confirmed by family studies. The positive family history for AS significantly (approximately 15–20%) increases the risk of developing AS, especially in the first-degree relatives (Reveille 2011; Brown 2010). Twin studies have demonstrated the high concordance rate of AS between monozygotic twins (63%) and dizygotic twins (23%) (Brown et al. 2000). Molecular typing analyses have shown that several allelic variants of HLA-B*27 exist that differ in few amino acid residues. The difference in amino acid sequence of these HLA-B*27 forms can alter protein conformation, which may lead to alternative peptide presentation (Bowness 2015). The most common form of HLA-B*27 among White Europeans is B*2705. An increased risk for AS was associated with the following HLA-B*27 allelic variants, B*2702, B*2703, B*2704, B*2705, and B*2710, in various populations and ethnicities; conversely, others (e.g., B*2706 and B*2709) were not associated with AS (Syrbe and Sieper 2020). The overall contribution of HLA-B*27 to AS inheritance is estimated to be 20–30%, indicating that other genetic factors contribute to disease initiation and progression. Indeed, most of HLA-B*27-positive individuals (around 80%) never develop AS (Alan et al. 2006). Genome-wide association studies have proposed >40 genetic regions that may influence disease pathogenesis (Cortes et al. 2013). Besides HLA-B*27, several other MHC genes have been associated with AS, such as HLA-B*60 (Wei et al. 2015), HLA-B*7 (Khan et al. 1978), HLA-B*16, and HLA-B*35. Moreover, these genes have been also associated with HLA-B*27negative AS in different ethnic groups (Zhu et al. 2019). In addition, several non-MHC (major histocompatibility complex) genes were implicated in AS development. In particular, an association between AS and genetic variations in the endoplasmic reticulum (ER) aminopeptidases 1 and 2 (ERAP1 and ERAP2) was reported. The main function of ERAP1 and ERAP2 is to trim peptides for the optimal length that enable them to bind to HLA class 1 molecules, including HLA-B*27. The variants included in disease-associated ERAP1 and ERAP2 can increase the risk of AS only in the context of HLA-B*27 (Evans et al. 2011a), suggesting that these genetic polymorphisms alter the interaction of HLA-B*27 with peptides. The IL-23/IL-17 axis is thought to be critically involved in the development of autoimmunity. These two cytokines are functionally linked, since IL-23 signaling is responsible for orchestrating the differentiation and expansion of Th17 cells, which are major drivers of inflammatory processes by secreting cytokine IL-17A (Mcgeachy et al. 2009). Some polymorphisms in the IL23R gene have been linked

464

A. Sharip et al.

to several autoimmune diseases, including AS (Burton et al. 2007b), IBD (Duerr et al. 2006), and psoriasis (Nair et al. 2009), which indeed can be concomitant in some patients. Other polymorphisms associated with increased susceptibility to AS are found in genes implicated in the downstream cascade of the IL-23R signaling pathway, including the signal transducer and activator of transcription 3 (STAT3) and tyrosine kinase 2 (TYK2) (Cho et al. 2006; Davidson et al. 2011). Particularly, EOMES, RUNX3, and TBX21 are genes participating in T-cell proliferation and survival (Cortes et al. 2013), and others (e.g., CARD9) are implicated in the innate immune response (Pointon et al. 2010).

18.2.2 The Role of Microorganisms in the Pathogenesis of AS While AS has a strong genetic background, environmental factors have also been implicated in initiating and promoting the disease, including infectious agents. Bacteria are suggested to be potential triggers in the etiopathogenesis of AS, as it happens with reactive arthritis (ReA) (Sieper et al. 2002). Bacterial genomes and proteins have been detected in the synovial fluids of affected joints in ReA patients, and specific T-cells of bacteria have been described in the blood and synovial fluids of the affected individuals. Microbial infection is thought to act as a triggering factor of a host’s innate immune response that when aberrantly regulated may lead to the development of AS (Gaston et al. 1989). In recent years, many studies have suggested that several pathogens might be involved in AS etiopathogenesis. Klebsiella pneumoniae was the first to be speculated as potentially involved in AS pathogenesis, since some patients’ stool had an increased presence of this bacterium. Initially, this species was hypothesized to deliver an antigen that resembles a molecule coded by the HLA-B*27 gene (Ebringer et al. 1978). However, further studies showed no correlation between the fecal carriage of Klebsiella pneumoniae and disease activity (Zhang et al. 2018). Other pathogens that have been associated with AS development are Lachnospiraceae, Prevotellaceae, Rikenellaceae, Porphyromonadaceae, and Bacteroidaceae (Costello et al. 2015). In contrast, the Rosenbaum Group has reported the potential involvement of non-gut bacteria, such as Porphyromonas gingivalis and Prevotella intermedia, as their high antibody titer was found in patients with SpA (Rosenbaum and Asquith 2016a). Along these lines, chronic periodontitis has been associated with severe spinal dysmobility in AS (Kang et al. 2015). A case-control study has reported conflicting results (Bautista-Molano et al. 2017), suggesting that more studies are necessary to understand the link between these pathogens and AS fully. HLA-B*27 transgenic rats have not developed SpA-like features in a germ-free environment, indicating the importance of the gut microbiome in disease pathogenesis (Alan et al. 2006). Moreover, the fact that ReA is caused by genitourinary infections, Chlamydia trachomatis, or other gram-negative enterobacteria, such as Salmonella, Campylobacter, and Shigella, provides solid evidence that bacterial infections could be

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

465

Table 18.1 List of microorganisms potentially involved in the pathogenesis of AS and ReA Pathogens Referencess Ankylosing spondylitis-associated enteric pathogens Klebsiella pneumonia Ebringer et al. (1978) Lachnospiraceae Rosenbaum and Asquith (2016a) Prevotellaceae Rosenbaum and Asquith (2016a) Rikenellaceae Rosenbaum and Asquith (2016a) Porphyromonadaceae Rosenbaum and Asquith (2016a) Bacteroidaceae Rosenbaum and Asquith (2016a) Porphyromonas gingivalis Rosenbaum and Asquith (2016a) Prevotella intermedia Rosenbaum and Asquith (2016a) Arthritis-associated enteric pathogens Campylobacter van der Linden and van der Heijde (2000) Chlamydia Appel et al. (2004) Shigella van der Linden and van der Heijde (2000) Yersinia Granfors et al. (1989b) Salmonella Antoniou et al. (2019) Brucella Redford et al. (2019)

important for other SpA diseases as well (Granfors et al. 1989a). Of note, infections with enteric pathogens in most cases do not contribute to the development of ReA. According to Ajene and colleagues, the ReA incidence for Salmonella, Campylobacter, and Shigella varied from 0.1 to 29%, 0 to 16%, and 0 to 12%, respectively (Ajene et al. 2013). Given the variety of pathogens linked to ReA, disease etiology is expected to include host-microbe interactions, as evidenced by the presence of bacteria or their products in the joint, followed by a local immune response. Taken together, further investigation is warranted to explore the role of the pathogens listed in Table 18.1 and understand their involvement in the AS and ReA fully.

18.2.3 Gut Dysbiosis in AS Disturbance of the intestinal flora can lead to many diseases, including diabetes, obesity, chronic kidney disease, and IBD (Burcelin 2016; Paun and Danska 2016; Sampaio-Maia et al. 2016; Jostins et al. 2012). Many studies support the notion that gut dysbiosis also plays a critical role in AS pathophysiology (Costello et al. 2015, 2013; Rosenbaum and Davey 2011). AS is significantly associated with IBD (Mitulescu et al. 2016; Ebringer et al. 2007), and about 70% of patients with AS have subclinical gut inflammation, indicating that the two diseases may be similar entities with a common origin, that is, gut dysbiosis (Costello et al. 2015, Ciccia et al. 2016, Yang et al. 2016). According to a recent study, AS patients have shown a higher abundance of five bacterial families, Lachnospiraceae, Prevotellaceae, Rikenellaceae, Porphyromonadaceae, and Bacteroidaceae, and a lower abundance

466

A. Sharip et al.

of two bacterial families in the terminal ileum, Ruminococcaceae and Rikenellaceae, than those found in healthy controls (Costello et al. 2015). Among these Klebsiella pneumoniae and Bacteroides vulgatus are two bacteria that play a major role in AS pathogenesis (Rath et al. 1999). However, rather than infection, the number of bacteria usually entails a causative immunological response. According to several studies, Klebsiella pneumoniae has been shown to have a great role in the disease pathophysiology. When the disease is in an active inflammatory state, AS is closely linked to the presence of Klebsiella pneumoniae in feces (Ebringer et al. 1978). In HLA-B*27-positive patients, the presence of fecal Klebsiella aerogenes has also been reported to be related to peripheral synovitis (Eastmond et al. 1980). Furthermore, antibodies to K. pneumoniae have been discovered to be linked to intestinal inflammation in patients with the axial form of AS (Tani et al. 1997). Recent studies in patients with AS have observed a decrease in the bacterial diversity of Bifidobacterium and an increase in the number of Bacteroides, C. coccoides, C. leptum, F. prausnitzii, and E. coli. Significant correlations were also found between HLA-B*27 antigen and Lactobacillus and E. coli levels. Lactobacillus and E. coli levels were reduced in patients who tested positive for the HLA-B*27 antigen (Cardoneanu et al. 2021). A separate pathogenetic role is played by the intestinal mycobiota. A number of studies have found a more pronounced fungal dysbiosis than bacterial. As with other autoimmune pathologies like IBD, the dominance of Ascomycota representatives and their negative correlation with Basidiomycota are shown for AS (Li et al. 2019). And the same pathogenetic role of mycobiota like in Crohn’s disease and sclerosing cholangitis with a decrease in the proportion of Saccharomyces cerevisiae and the growth of more pathogenic intestinal fungi is observed. Dysbiosis of intestinal fungi increases the permeability of the intestinal wall, the role of translocation of mycobiotic antigens is shown, and fungal antigens have the function of stimulating autoimmune uveitis (Berthelot et al. 2021). While the role of the gut microbiome in AS has been the focus of numerous studies, the role of microbiota at other bodily sites is less well characterized. The oral microbiota plays a crucial role in periodontal disease and, consequently, in periodontitis. Periodontitis has also been associated with AS, as patients with AS are more likely to develop periodontitis (Bisanz et al. 2016). When comparing patients with AS to healthy individuals, AS patients had a greater level of antibodies directed at Porphyromonas gingivalis, a periodontal bacterium (Ogrendik 2015). Notably, P. gingivalis has been shown to colonize synovial joints and exacerbate murine collagen-induced arthritis indicating that this species may play a causative role in in arthritis due to its ability to translocate to joints (Chukkapalli et al. 2016).

18.2.4 Increased Intestinal Permeability The intestinal epithelium serves as a physical and biochemical barrier to commensal and pathogenic microorganisms, preserving host-microbe interactions and tissue

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

467

homeostasis (Ciccia et al. 2016). When the tight junctions (connections between epithelial cells) are not functioning properly, increased intestinal permeability ensues, resulting in a leaky gut. Dysbiosis of the intestinal microbiota results in disrupting the mucosal barrier and increasing commensal microbiota penetration, which are crucial for the onset and progression of disease (Tlaskalova-Hogenova et al. 2004; Tian et al. 2016; Morris et al. 2016). Gut permeability has been observed to be increased in AS patients and their firstdegree relatives and experimental animal models, suggesting that gut bacteria are exposed to the body more systemically (Martínez-González et al. 1994). Gut permeability in HLA-B*27 rats was roughly five times higher than that in healthy control rats, increasing with age (Kerr et al. 1999). Intestinal permeability alterations may occur before the onset of intestinal inflammation. If a component of endotoxin, lipopolysaccharide (LPS), enters the bloodstream, a significant systemic inflammatory reaction occurs. According to preliminary research, AS can have high serum levels of LPS and fatty acid-binding protein, both associated with intestinal permeability (Ciccia et al. 2016).

18.2.5 Innate Immunity and Gut Inflammation The innate immune system, or inborn nonspecific immunity, serves as the first line of defense against pathogen invasion in the host body. Intestinal macrophages play a critical role in preserving the intestinal barrier and fighting commensal bacteria during this innate immune response. Macrophage receptors can detect and attack invaders, like bacteria or viruses (Ciccia et al. 2016; Toyonaga et al. 2016; Ochi et al. 2016; Cipriani et al. 2016; Bain and Mowat 2014; Steinert et al. 2016). According to several studies, intestinal macrophage dysfunction may raise the risk of IBD, and bacteria can cause macrophages to specialize into different types with diverse functions. M1 and M2 macrophages are the two types of macrophages (Bystrom et al. 2008): M1 macrophages release more pro-inflammatory cytokines, such as TNF and IL-12, whereas M2 macrophages reduce inflammation in various diseases (Vandooren et al. 2009). In AS and Crohn’s disease (CD) patients with intestinal inflammation, an increase in M1 macrophages was reported. Moreover, M2 macrophages were also shown to be increased in AS patients. Although the amount of M1-polarized macrophages was enhanced in certain AS patients, intestinal inflammation was not significant. This could be attributed to the fact that the significant increase in M2 macrophages could counterbalance the pro-inflammatory M1 macrophages (Ciccia et al. 2014). In another study on peripheral SpA, an increased expression of M2 markers, CD163 and CD 200R, and a decrease in pro-inflammatory mediators derived from M1, including TNF-α and IL-1β, were detected (Vandooren et al. 2009). Furthermore, another article has indicated that the IL-23 level produced by subchondral bone marrow M2 macrophages from AS patients was significantly higher than that in normal control specimens (Appel et al. 2013). Despite these findings, the representations of distinct subsets of macrophages in AS patients are still unknown,

468

A. Sharip et al.

and it is possible that the acute and chronic gut tissue inflammatory states of AS patients represent different pathologic illness conditions. The close relationship between AS and gut inflammation related to IBD also suggests that the gut microbiome might play an important role in AS pathogenesis. The cytokine profiles of AS patients and healthy individuals are different; for example, the percentage of T-cells secreting TNF-α and interferon-γ was significantly decreased in peripheral blood of AS patients (Rudwaleit et al. 2001). Moreover, the gut microbiome of AS patients is significantly different from that of healthy individuals (Costello et al. 2015).

18.2.6 Main Hypotheses Underlying AS Pathogenesis AS is a multifactorial disease with contributions from genetic and environmental factors. The exact pathogenesis of AS has yet to be fully elucidated. Several hypotheses have been proposed to account for the complex interaction between genetic and environmental factors including the arthritogenic peptide hypothesis, the protein misfolding hypothesis, and the roles of HLA-B*27 homodimers and the aminopeptidases ERAP1 and ERAP2. These hypotheses have been discussed in detail in the preceding chapter (Part 2.6, Fig. 18.1) and elsewhere (Sharip and Kunz 2020). However, none of these models can fully explain HLA-B*27-dependent AS pathogenesis. Here, we have summarized each hypothesis and discussed the emerging role of HLA-B*27 in gut dysbiosis as a potential key driver of AS development.

Fig. 18.1 Treatment options for AS

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

469

18.2.6.1 Molecular Mimicry Molecular mimicry or the arthritogenic peptide hypothesis suggests that some arthritis-causing peptide sequences presented by HLA-B*27 are homologous between autoantigens and arthritogenic bacteria (Benjamin and Parham 1992; Garcia-Montoya et al. 2018). These bacterial antigenic peptides stimulate the production of specific antibodies to initiate the host immune response. While this leads to the clearance of bacterial infection, reactive antibodies may also attack homologous self-antigens, causing joint inflammation and damage to other tissues (Rosenbaum and Asquith 2016b). For instance, HLA-B*27-restricted cytotoxic CD8+ T-cell responses were observed in reactive arthritis (ReA) patients after infections with Chlamydia or Salmonella (Bowness 2015). Moreover, after these infections, synovial fluids of ReA patients contained reactivated HLA-B*27-specific CD8+ CTLs (cytotoxic T lymphocytes) (Hermann et al. 1993). Another bacterium, Klebsiella pneumoniae, shares some sequence homology between its nitrogenase enzyme and the human HLA-B*27.5 antigen (De Vries et al. 1992). The K. pneumoniae protein PulD (secretin) has been found to cross-react with myosin and HLA-B*27 (Charalambous et al. 1988). Thus, microorganism antigens may trigger antibacterial antibody production that can cross-react with HLA molecules on chondrocytes, fibroblasts, and immunocytes (Zhu et al. 2019). 18.2.6.2 Unfolded Protein Response The unfolded protein response hypothesis proposes that HLA-B*27 misfolds, due to its biophysical and biochemical characteristics. Notably, at the base of the B pocket of the HLA-B*27 molecule, an unpaired cysteine (Cys-67) causes misfolding of HLA-B*27 heavy chains before complex assembly with β2 microglobulin. This misfolding leads to disulfide bond formation and aberrant heavy chain folding (Dangoria et al. 2002). As a result, misfolded HLA-B*27 molecules congregate in the ER, triggering ER stress. This ultimately results in an unfolded protein response (UPR) and autophagy (Garcia-Montoya et al. 2018; Pedersen and Maksymowych 2019). UPR is an adaptive reaction of the ER aiming to clear the accumulated, unfolded HLA-B*27 protein to normalize cell viability and function (Hetz 2012). The activation of UPR genes leads to an increase in T helper (Th) 17 cells and elevation of IL-17, IL-23, and IFN-γ pro-inflammatory cytokine levels (Pedersen and Maksymowych 2019). The misfolding of HLA-B*27 also leads to activation of the NF-κB pathway, which further activates the production of pro-inflammatory TNF-α, IL-1β, and IL-6 (Sharip and Kunz 2020). Evidence in support of HLA-B*27 misfolding and UPR has been found in synovial and gut tissues of AS transgenic rat models and SpA patients (Ebringer 1983). Nevertheless, how the production of proinflammatory cytokines is linked to misfolded HLA-B*27 and ER stress in patients and how this leads to AS development are not completely understood. 18.2.6.3 Formation of HLA-B*27 Homodimers The third hypothesis of HLA-B*27-associated AS development stems from the capability of HLA-B*27 to form disulfide-bonded homodimers, which is a distinct feature of HLA-B*27. These homodimers are expressed on the cell surface of

470

A. Sharip et al.

various cell types such as natural killer cells, CTLs, and B lymphocytes (Babaie et al. 2018). Moreover, these homodimers promote the upregulation of the IL-17/IL-23 signaling pathways, which have been known to be involved in AS pathogenesis (Kenna et al. 2015). Much evidence supports a contribution of HLA-B*27 homodimer formation to AS pathogenesis (Sharip and Kunz 2020).

18.2.6.4 Abnormal Antigen Processing by ERAP1 and ERAP2 The aminopeptidases, ERAP1 and ERAP2, have the second strongest association with AS among all SpA subtypes contributing between 15 and 25% of the population risk in patients with AS (Evans et al. 2011b; Martin-Esteban et al. 2017; Burton et al. 2007a). ERAP1 and ERAP2 are members of the zinc metallopeptidases that trim peptides at the N-terminal end and optimize peptide length for binding to MHC class I molecules. The strong association of AS with ERAP1 was only detected in HLA-B*27-positive individuals, revealing that abnormal antigen processing for antigen presentation by HLA-B*27 is crucial for AS pathogenesis (Keidel et al. 2013; Dashti et al. 2018). The deregulated aminopeptidase activity leads to an altered immune response, possibly resulting in autoimmunity (Sharip and Kunz 2020). The systematic study of ERAP1 genetic polymorphisms and loss-of-function mutations has further demonstrated that ERAP1 plays a key role in SpA pathogenesis through various mechanisms (Seregin et al. 2013). Thus, the effects conferred by the genetic interaction between ERAP1 and HLA-B*27 in AS remain to be fully defined. 18.2.6.5 HLA-B*27-Dependent Gut Dysbiosis in AS Host genetics, in particular HLA-B*27, also induce global changes in gut composition and affect the overall function of the gut microbiome, including how the gut microbiome shapes the immune response and influences inflammation (Rosenbaum and Davey 2011). Indeed, there is accumulating evidence that HLA-B*27 induce AS through effects on the gut microbiome composition (Rosenbaum and Davey 2011; Rosenbaum et al. 2014). Studies on HLA-B*27 transgenic rats showed that the presence or absence of HLA-B*27 is associated with altered intestinal microbiota (Spor et al. 2011). More recently, it has been shown that expression of HLA-B*27 and hβ2m, as well as the non-disease-associated HLA-B*7 allele, alters gut microbial communities in this animal model, providing compelling evidence that major histocompatibility complex (MHC) class I proteins can shape microbiota (Lin et al. 2014b). Since then, many studies and rodent models have revealed alteration of gut microbial communities in various HLA-B*27-associated disorders (Gill et al. 2018; Costello et al. 2015; Scher et al. 2015). Recent evidence suggests that innate immune activation and Th17 expansion may precede the development of dysbiosis and gut inflammation in HLA-B*27 transgenic rats (Asquith et al. 2016). Subsequent studies attempted to investigate the role of HLA-B*27 in shaping the gut microbiome in human patients. Tito and colleagues have analyzed 27 patients with SpA and 15 healthy controls using 16SrRNA profiling, and they did not observe an association of the gut microbiome with HLA-B*27 carriage (limitation: small sample size especially HC) (Tito et al. 2017). In a Chinese study, Wen and

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

471

colleagues conducted shotgun sequencing of stool samples from 97 AS patients and 114 healthy controls and reported significant dysbiosis in the AS patients (Wen et al. 2017). The authors demonstrated that the intestinal microbiome in AS patients was enriched in Prevotella melaninogenica, Prevotella copri, and Prevotella sp. C561 and diminished in Bacteroides spp. (Wen et al. 2017). A similar study by Costello et al. in the terminal ileum of AS patients found higher abundance of five families of bacteria, including Lachnospiraceae, Ruminococcaceae, Rikenellaceae, Porphyromonadaceae, and Bacteroidaceae, and a decrease in the abundance of Veillonellaceae and Prevotellaceae compared to healthy controls (Costello et al. 2015). Breban et al. conducted 16S rRNA profiling of the stool microbiome to study 87 patients with axial SpA (42 with AS), 69 healthy controls, and 28 RA patients, whereas Zhou et al. performed a metagenomic study on 85 untreated AS patients and 62 healthy controls; both studies provided strong evidence of intestinal dysbiosis in SpA patients (Breban et al. 2017; Zhou et al. 2020). The most striking change observed by Breban et al. was an increased abundance of Ruminococcus gnavus in SpA that was positively correlated with disease activity in patients having a history of inflammatory bowel disease (IBD). The study by Zhou et al., which was conducted in untreated AS patients, revealed several AS-enriched species including Bacteroides coprophilus, Parabacteroides coprophilus, Parabacteroides distasonis, Prevotella copri, Eubacterium siraeum, and Acidaminococcus fermentans (Zhou et al. 2020). A challenge remains to define the precise changes in microbiome composition that are disease-linked. While human studies reproducibly reported on gut dysbiosis in AS patients, no clear disease-specific microbial signature has yet emerged. So far, overlap in microbiome imbalances between different studies seems to exist for Ruminococcus gnavus and Prevotellaceae. Taken together, available studies highlight the need for study standardization. In addition, future study design also needs to take into consideration any potential treatment effects on microbiota composition and abundance. Zhou and colleagues found that treatment of AS, particularly with DMARDs or TNF-α inhibitors, conferred a significant effect on gut microbiota composition leading to a decrease in Prevotellaceae abundance (Zhou et al. 2020). If the presence of HLA-B*27 shapes the microbiome, how could this contribute to AS disease pathogenesis? Multiple mechanisms have been proposed. These may include effects of HLA-B*27 favoring a more inflammatory gut microbiome, increased invasiveness of the gut mucosa in HLA-B*27 carriers, and/or aberrant immunological responses to bacteria in HLA-B*27 carriers (Asquith et al. 2019). For example, a heightened immune response to specific bacteria could result in synovitis, if these specific bacteria escape to the synovium where they could trigger an immune response. Specific bacterial antigens have been detected in the joint in reactive arthritis (Merilahti-Palo et al. 1991). The HLA-B*27-induced change in the gut microbiome could also alter gut permeability and allow leakage of multiple bacterial products which could then become arthritogenic. An increase in intestinal permeability has been shown in the HLA-B*27 transgenic rat (Schepens et al. 2009) and in patients with AS (Martinez-Gonzalez et al. 1994; Vaile et al. 1999). Another explanation is that the presence of the HLA-B*27 transgene alters the transcriptional

472

A. Sharip et al.

profiles of the bacteria present in the gut (Rosenbaum et al. 2014). Last, but not least, HLA molecules, either alone or in combination with AS-associated genes, determine gut microbiome composition. However, if HLA-B*27-dependent gut dysbiosis alters gut permeability, which comes first: the change in permeability or the change in the intestinal microbiome? The alteration in the immune response could alter gut permeability and allow the escape of microbial products and/or thereby the alteration in the immune response could affect the microbial population in the gut, and this could result in a change in permeability (Rosenbaum et al. 2014). Importantly, human and rat studies support the hypothesis that HLA-B*27-dependent dysbiosis is a preceding event in AS pathogenesis and may not merely be secondary to disease (Asquith et al. 2017, 2019, 2016). Asquith et al. first showed that HLA-B*27 and HLA-DRB1 have significant effects on human gut microbiota in the absence of any disease (RA or AS) and treatment (Asquith et al. 2019). Therefore, HLA molecules interact with the gut microbiome to cause disease. The outcomes of this study imply that HLA molecules could make important contributions to the heterogeneity of the microbiome, and this can be one of the mechanisms underlying the disease pathogenesis of RA and AS. In addition, several HLA-B*27-dependent metabolic changes including the enrichment of bile acid metabolism, lysine metabolism, fatty acid metabolism, and tryptophan metabolism were reported to occur in HLA-B*27positive individuals (Asquith et al. 2019). Thus, the presence of HLA-B*27 can affect AS disease pathogenesis in multiple ways, including effects on gut microbiome composition and metabolic function.

18.3

Management of AS

The management of patients with AS involves combining pharmacological and non-pharmacological treatments. The main aims of AS therapy are to relieve symptoms, improve spinal flexibility, reduce the long-term complications of the disease, prevent spinal deformity, and harmonize social activities (Zhu et al. 2019). Non-pharmacological therapy consists of patient’s education and physical therapy. Physiotherapy and exercise play an important role in the long-term management of AS (Calin 2006). Pharmacological treatment mainly includes nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), and biologics (Fig. 18.1) (Zhu et al. 2019). Treatment with NSAIDs is proven to reduce inflammatory back pain and leads to short-term functional improvement in some AS patients (Zhu et al. 2019; Ward et al. 2016). Nevertheless, NSAIDs cannot prevent or stop the pathological processes in AS; besides, some of them possess serious side effects. With regard to available biological drugs, the introduction of TNF blockers has been the most significant progress in AS treatment. Clinical trials with these drugs have demonstrated significant amelioration of pain and spinal inflammation, improvement of vertebral function, and reduction of disease activity (Haibel et al.

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

473

2006; Baraliakos et al. 2005; Garcia-Montoya et al. 2018). The use of biological drugs antagonizing interleukin-17A (IL-17A) pathways was reported to be effective in reducing the disease activity of AS patients (Liu et al. 2015; Yago et al. 2017; Garcia-Montoya et al. 2018). Surgical treatment can be considered in AS patients who have already developed vertebral deformities. Corrective osteotomy and stabilization are common surgical procedures and are recommended for patients with severe kyphosis or advanced hip involvement (Zhu et al. 2019). Despite some risks associated with surgery, these procedures can help to control pain and improve digestive and respiratory function (Qian et al. 2017; Lin et al. 2014a).

18.3.1 Pharmacological Treatments 18.3.1.1 Nonsteroidal Anti-inflammatory Drugs NSAIDs are the first-line treatment for AS. They act by inhibiting cyclooxygenase (COX), which is crucial for arachidonic acid conversion into inflammatory prostaglandins (Nakata et al. 2018). Spinal, peripheral joint, and entheseal pain and morning stiffness are alleviated by NSAIDs (Sari et al. 2015). Absent or incomplete response to NSAID therapy indicates a poor prognosis (Braun and Sieper 2007). However, before concluding about NSAID inefficacy in AS patients, at least two NSAIDs should be used for a minimal period of 4 weeks (Daikh and Chen 2014). Up to 80% of AS patients treated with NSAIDs have reported either good or very good symptom resolution along with a significant reduction of the inflammatory parameters (Song et al. 2008; Barkhuizen et al. 2006; Sieper et al. 2008). Moreover, NSAIDs have been the first therapeutic agents that, if used continuously to treat AS, resulted to improve the radiographic alterations and delay the spinal ossification (Daikh and Chen 2014; Song et al. 2008). However, COX-2 selective NSAIDs and nonselective NSAIDs can have cardiovascular, gastrointestinal, renal, liver, skin-related side effects, even though these are described in a small percentage of patients. Indeed, liver enzymes, urinalysis, and blood pressure should be regularly monitored to prevent iatrogenic health issues. Therefore, the risk-benefit ratio of NSAIDs in AS patients needs to be carefully assessed, and the lowest effective dose should be prescribed for the necessary period of time only (Song et al. 2008; Daikh and Chen 2014). 18.3.1.2 TNF Blockers If patients are not responsive to NSAIDs, and/or the use of these drugs needs to be excessively protracted and/or causes side effects, biological therapy, mainly represented by antitumor necrosis factor-alpha (TNF-α) therapy, can be considered (Inman et al. 2008; Song et al. 2008). Extensive research has clearly demonstrated the high efficacy of anti-TNF-α therapy in AS patients, especially if started at early stages (Barkham et al. 2009; Braun et al. 2011; Haibel et al. 2008). No significant differences have been among the available TNF-α inhibitors in the therapeutic effects on rheumatological manifestations; however, adalimumab and infliximab

474

A. Sharip et al.

were more effective against gastrointestinal comorbidities (IBDs) than etanercept (Moon and Kim 2014). Despite the high efficacy, the broad use of anti-TNF-α therapy is limited by the high cost (Baeten et al. 2015; Callhoff et al. 2015). Moreover, medical concerns of using anti-TNF therapy are related to the increased susceptibility to respiratory tract infections and, in detail, tuberculosis; thus, before treatment administration, Mycobacterium tuberculosis screening must be done (Khalessi et al. 2008).

18.3.1.3 Corticosteroids Glucocorticoids (GCs) possess potent anti-inflammatory effect. They ultimately act by reducing the production of several inflammatory mediators, such as chemokines, cytokines, adhesion molecules, and arachidonic acid metabolites. GCs can be administered either orally, intravenously, or locally, according to the clinical situation (Akkoc et al. 2006). GCs can be used in AS patients who are refractory to NSAID therapy, where the clinical situation requires a rapid control of the systemic and articular inflammation. However, they cannot be used for long time, due to the several side effects, including osteoporosis, alteration of the glucose tolerance, and immunosuppression. Actually, AS patients with peripheral arthritis could be effectively treated with local (intra-articular or periarticular) steroids with a significant benefit and without risks of side effects (Sari et al. 2015). Overall, the use of GCs is not advised as standard treatment for axial AS according to the ASAS/EULAR recommendations, except for specific conditions (Braun et al. 2011). 18.3.1.4 Conventional Disease-Modifying Antirheumatic Drugs (cDMARDs) Conventional DMARDs suppress synovial inflammation and prevent structural damage in AS. The most frequently prescribed cDMARDs in AS are sulfasalazine, methotrexate, and leflunomide (Sari et al. 2015). However, cDMARDs are mainly effective on peripheral arthritis, whereas they are not associated with clear benefit on axial arthritis (Song et al. 2008). According to a Cochrane meta-analysis, sulfasalazine can significantly improve peripheral arthritis in AS but has no greater effect than placebo on back pain (Chen and Liu 2005). Methotrexate has not shown any impact on either back pain or peripheral arthritis of AS (Clegg 2006), whereas leflunomide may have some results for treating peripheral manifestations of AS (Haibel et al. 2006). Among documented side effects of DMARDs are liver, mucocutaneous, gastrointestinal, and hematological symptoms (Khalessi et al. 2008).

18.3.2 Surgical Treatment Surgical treatment in AS is considered when radiographic evidence of severe and irreversible damage is established and leads to progressive disability and deterioration of patients’ quality of life. Thoracolumbar kyphosis can develop in about 30% of patients, if AS is not timely and appropriately treated (Kubiak et al. 2005).

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

475

Closing-opening wedge osteotomy and stabilization are advised for patients with severe kyphosis, whereas fusion procedures are implemented in case of segmental instability (Mcveigh and Cairns 2006). These interventions are reported to be effective in controlling progressive deformity, resolving disability, alleviating pain, rehabilitating general balance and horizontal axis of view, and assisting digestive and respiratory functions (He et al. 2017; Qian et al. 2017; Koller et al. 2018). Another serious complication of AS is hip arthritis, affecting about one-third of AS patients (Vander Cruyssen et al. 2010). Total hip arthroplasty (THA) is recommended in patients with disability, persisting pain, and structural damage evidenced by radiography (Mcveigh and Cairns 2006; Feng et al. 2016; Xu et al. 2017).

18.3.3 Future Perspectives on the Management of AS and Novel Treatments: Strategies Targeting the Intestinal Microbiome 18.3.3.1 Pre- and Probiotics Prebiotics consisting of plant-based crude fibers and probiotics comprising beneficial bacterial strains are known to stimulate the activity of gut bacteria and provide health benefits for the host (Hill et al. 2014; Smith et al. 2020). As proven by various studies on HLA-B*27 TG rats, the supplementation with prebiotics, such as oligofructose and inulin, resulted in the expansion of favorable Bifidobacterium and Lactobacillus strains, leading to the elevation of immunomodulatory TGF-β and decline of IL-1β levels (Hoentjen et al. 2005) and reducing colitis disease activity (Hoentjen et al. 2006). The combination of prebiotic and probiotic, namely, inulin, Bifidobacteria, and Lactobacilli, resulted in the attenuation of colitis disease activity and increased microbial spectrum (Schultz et al. 2004). The supplementation with prebiotics and probiotics demonstrates promising results as a future therapeutic approach aimed at restoring and supporting healthy gut microbiota in AS associated with gut inflammation. Moreover, due to associations of AS pathogenesis with bacterial infections, the application of antimicrobial therapies involving antibiotics, especially against Klebsiella, could be effective (Rashid and Ebringer 2007). 18.3.3.2 Diet Diet greatly contributes to the maintenance of gut microbial consortium by supplementing gut bacteria with crucial molecules, which are further processed into metabolic products. A high-fiber diet is known to attenuate inflammatory processes (Duan et al. 2018). The amelioration of colonic inflammation was demonstrated in the HLA-B*27 TG rat model maintained on a fiber-rich diet for 13 weeks (Rodriguez-Cabezas et al. 2003). Fiber-enriched cruciferous vegetables full of indoles have been shown to activate aryl hydrocarbon receptors (AhRs) responsible for the perception of environmental signals. AhRs sustain intraepithelial lymphocytes and innate lymphoid cells (Tilg 2015). Moreover, a low-starch diet limits the nutrients for enterobacterial growth, such as Klebsiella (Alan et al. 2006). In the study of Finegold and colleagues, involving two groups of people on

476

A. Sharip et al.

low-protein/high-starch and high-protein/low-starch diets, the average number of Klebsiella microorganisms was 42-fold higher in the high-starch group. Another important constituent of AS patients’ diet should be short-chain fatty acids (SCFA); not only they suppressed innate immune cells from the vigorous immune response, but also they maintained mucosal homeostasis by nourishing colonocytes (Gill and Rosenbaum 2020). Propionate supplementation of HLA-B*27 TG rats demonstrated inflammation decrease (Gill and Rosenbaum 2020) and uveitis alleviation in the inducible model (Nakamura et al. 2017). Another SCFA, known as butyrate, decreased inflammatory cytokines in macrophages in vitro and in vivo (Chang et al. 2014). Therefore, dietary manipulations such as a high-fiber diet, decrease in starch, and inclusion of SCFA-rich products can significantly contribute to the therapy of AS.

18.4

Conclusion

AS is a disease with significant genetic association to HLA-B*27. Rodent models of AS have uncovered the key role that gut microbiota play in AS pathogenesis and have highlighted a link between HLA-B*27 and gut dysbiosis that likely precedes the development of AS symptoms. Recent findings confirm gut dysbiosis with decreased bacterial diversity in AS patients and indicate that the intestinal microbiome in patients with AS is characterized by an inflammatory status induced by the increase in some, potentially pro-inflammatory, bacterial species and a reduction of potentially anti-inflammatory or protective species. Studies also show that the composition of the intestinal microbiome is influenced by numerous factors, including, among others, genetic background, inflammatory markers, and treatment. Therefore, the intestinal microbiome could be considered a “biomarker” for inflammation in patients and could be used as a diagnostic or prognostic tool to aid in earlier diagnosis or to predict the therapeutic response. The challenge now will be to dissect the complex interactions between intestinal communities (not only bacteria but also including fungi and bacteriophages) and to delineate the functional and metabolic effects of modulating the gut microbiome and host-microbe relationships. While an altered gut microbiome may cause inflammatory arthritis, modulating the gut microbiome may also offer new avenues for treatment. Therefore, establishing causal associations between host-microbe interactions will be instrumental to a better understanding of disease pathogenesis and lead to identification of new targets and therapeutics. Probiotics, targeted antibiotic treatments, dietary approaches to modulate microbiota and their production of specific metabolites, and even fecal microbiome transplantation (Choi et al. 2018) are being evaluated or considered for treatment of AS. Such approaches have the potential to treat underlying cause(s) of SpA rather than just symptoms. Acknowledgments This work was supported by the Collaborative Research Program Grant #021220CRP1722 awarded to JK, AK, and BA.

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

477

References Ajene AN, Fischer Walker CL, Black RE (2013) Enteric pathogens and reactive arthritis: a systematic review of campylobacter, salmonella and shigella-associated reactive arthritis. J Health Popul Nutr 31:299–307 Akgul O, Ozgocmen S (2011) Classification criteria for spondyloarthropathies. World J Orthop 2: 107–115 Akkoc N, Van Der Linden S, Khan MA (2006) Ankylosing spondylitis and symptom-modifying vs disease-modifying therapy. Best Pract Res Clin Rheumatol 20:539–557 Alan E, Taha R, Clyde W, Teresa P, Mark F (2006) Ankylosing spondylitis, HLA-B27 and Klebsiella - an overview: proposal for early diagnosis and treatment. Curr Rheumatol Rev 2: 55–68 Antoniou AN, Lenart I, Kriston-Vizi J, Iwawaki T, Turmaine M, Mchugh K, Ali S, Blake N, Bowness P, Bajaj-Elliott M, Gould K, Nesbeth D, Powis SJ (2019) Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication. Ann Rheum Dis 78:74–82 Appel H, Kuon W, Kuhne M, Wu P, Kuhlmann S, Kollnberger S, Thiel A, Bowness P, Sieper J (2004) Use of HLA-B27 tetramers to identify low-frequency antigen-specific T cells in chlamydia-triggered reactive arthritis. Arthritis Res Ther 6:R521–R534 Appel H, Maier R, Bleil J, Hempfing A, Loddenkemper C, Schlichting U, Syrbe U, Sieper J (2013) In situ analysis of interleukin-23- and interleukin-12-positive cells in the spine of patients with ankylosing spondylitis. Arthritis Rheum 65:1522–1529 Asquith MJ, Stauffer P, Davin S, Mitchell C, Lin P, Rosenbaum JT (2016) Perturbed mucosal immunity and dysbiosis accompany clinical disease in a rat model of spondyloarthritis. Arthritis Rheumatol 68:2151–2162 Asquith M, Davin S, Stauffer P, Michell C, Janowitz C, Lin P, Ensign-Lewis J, Kinchen JM, Koop DR, Rosenbaum JT (2017) Intestinal metabolites are profoundly altered in the context of HLA-B27 expression and functionally modulate disease in a rat model of spondyloarthritis. Arthritis Rheumatol 69:1984–1995 Asquith M, Sternes PR, Costello ME, Karstens L, Diamond S, Martin TM, Li Z, Marshall MS, Spector TD, Le Cao KA, Rosenbaum JT, Brown MA (2019) HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome. Arthritis Rheumatol 71:1642–1650 Babaie F, Hasankhani M, Mohammadi H, Safarzadeh E, Rezaiemanesh A, Salimi R, Baradaran B, Babaloo Z (2018) The role of gut microbiota and IL-23/IL-17 pathway in ankylosing spondylitis immunopathogenesis: new insights and updates. Immunol Lett 196:52–62 Baeten D, Sieper J, Braun J, Baraliakos X, Dougados M, Emery P, Deodhar A, Porter B, Martin R, Andersson M, Mpofu S, Richards HB, Group, M. S. & Group, M. S (2015) Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med 373:2534–2548 Bain CC, Mowat AM (2014) Macrophages in intestinal homeostasis and inflammation. Immunol Rev 260:102–117 Baraliakos X, Brandt J, Listing J, Haibel H, Sörensen H, Rudwaleit M, Sieper J, Braun J (2005) Outcome of patients with active ankylosing spondylitis after two years of therapy with etanercept: clinical and magnetic resonance imaging data. Arthritis Rheum 53(6):856–863 Barkham N, Keen HI, Coates LC, O'Connor P, Hensor E, Fraser AD, Cawkwell LS, Bennett A, Mcgonagle D, Emery P (2009) Clinical and imaging efficacy of infliximab in HLA-B27positive patients with magnetic resonance imaging-determined early sacroiliitis. Arthritis Rheum 60:946–954 Barkhuizen A, Steinfeld S, Robbins J, West C, Coombs J, Zwillich S (2006) Celecoxib is efficacious and well tolerated in treating signs and symptoms of ankylosing spondylitis. J Rheumatol 33(9):1805–1812

478

A. Sharip et al.

Bautista-Molano W, Van Der Heijde D, Landewé R, Lafaurie GI, De Ávila J, Valle-Oñate R, Romero-Sanchez C (2017) Is there a relationship between spondyloarthritis and periodontitis? A case-control study. RMD Open 3:e000547 Benjamin R, Parham P (1992) HLA-B27 and disease: a consequence of inadvertent antigen presentation? Rheum Dis Clin N Am 18:11–21 Berthelot JM, Darrieutort-Laffite C, Trang C, Maugars Y, Le Goff B (2021) Contribution of mycobiota to the pathogenesis of spondyloarthritis. Joint Bone Spine 88:105245 Bisanz JE, Suppiah P, Thomson WM, Milne T, Yeoh N, Nolan A, Ettinger G, Reid G, Gloor GB, Burton JP, Cullinan MP, Stebbings SM (2016) The oral microbiome of patients with axial spondyloarthritis compared to healthy individuals. PeerJ 4:e2095 Bowness P (2015) HLA-B27. Annu Rev Immunol 33:29–48 Boyer GS, Templin DW, Cornoni-Huntley JC, Everett DF, Lawrence RC, Heyse SF, Miller MM, Goring WP (1994) Prevalence of spondyloarthropathies in alaskan eskimos. J Rheumatol 21: 2292–2297 Braun J, Sieper J (2006) Early diagnosis of spondyloarthritis. Nat Clin Pract Rheumatol 2:536–545 Braun J, Sieper J (2007) Ankylosing spondylitis. Lancet 369:1379–1390 Braun J, Van Den Berg R, Baraliakos X, Boehm H, Burgos-Vargas R, Collantes-Estevez E, Dagfinrud H, Dijkmans B, Dougados M, Emery P, Geher P, Hammoudeh M, Inman RD, Jongkees M, Khan MA, Kiltz U, Kvien T, Leirisalo-Repo M, Maksymowych WP, Olivieri I, Pavelka K, Sieper J, Stanislawska-Biernat E, Wendling D, Ozgocmen S, Van Drogen C, Van Royen B, Van Der Heijde D (2011) 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 70:896–904 Breban M, Tap J, Leboime A, Said-Nahal R, Langella P, Chiocchia G, Furet JP, Sokol H (2017) Faecal microbiota study reveals specific dysbiosis in spondyloarthritis. Ann Rheum Dis 76: 1614–1622 Brewerton DA, Hart FD, Nicholls A, Caffrey M, James DC, Sturrock RD (1973) Ankylosing spondylitis and HL-A 27. Lancet 1:904–907 Brown MA (2010) Genetics of ankylosing spondylitis. Curr Opin Rheumatol 22(2):126–132 Brown MA, Laval SH, Brophy S, Calin A (2000) Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 59:883–886 Burcelin R (2016) Gut microbiota and immune crosstalk in metabolic disease. Mol Metab 5:771– 781 Burton P, Clayton D, Cardon L, Craddock N, Duncanson A, Kwiatkowski D, Mccarthy M, Ouwehand W, Samani N, Todd J, Donnelly P, Barrett J, Davison D, Easton D, Evans D, Leung H-T, Marchini J, Morris A, Brown M (2007a) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39:1329– 1337 Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, Mccarthy MI, Ouwehand WH, Samani NJ, Todd JA, Donnelly P, Barrett JC, Davison D, Easton D, Evans DM, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, Mcardle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskivina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Farmer A, Williamson R, Mcguffin P, Young AH, Ferrier IN, Ball SG, Balmforth AJ, Barrett JH, Bishop TD, Iles MM, Maqbool A, Yuldasheva N, Hall AS, Braund PS, Dixon RJ, Mangino M, Stevens S, Thompson JR, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Matthew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP et al (2007b) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39:1329–1337

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

479

Bystrom J, Evans I, Newson J, Stables M, Toor I, Van Rooijen N, Crawford M, Colville-Nash P, Farrow S, Gilroy DW (2008) Resolution-phase macrophages possess a unique inflammatory phenotype that is controlled by camp. Blood 112:4117–4127 Calin A (2006) Ankylosing spondylitis. Medicine 34:396–400 Callhoff J, Sieper J, Weiss A, Zink A, Listing J (2015) Efficacy of TNFalpha blockers in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann Rheum Dis 74:1241–1248 Cardoneanu A, Cozma S, Rezus C, Petrariu F, Burlui AM, Rezus E (2021) Characteristics of the intestinal microbiome in ankylosing spondylitis. Exp Ther Med 22:676 Chang PV, Hao L, Offermanns S, Medzhitov R (2014) The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A 111:2247–2252 Charalambous B, Keen J, Mcpherson M (1988) Collagen-like sequences stabilize homotrimers of a bacterial hydrolase. EMBO J 7:2903–2909 Chen J, Liu C (2005) Sulfasalazine for ankylosing spondylitis. Cochrane Database Syst Rev: CD004800 Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB, Jin HT, Min SY, Ju JH, Park KS, Cho YG, Yoon CH, Park SH, Sung YC, Kim HY (2006) STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J Immunol 176:5652–5661 Choi RY, Asquith M, Rosenbaum JT (2018) Fecal transplants in Spondyloarthritis and uveitis: ready for a clinical trial? Curr Opin Rheumatol 30:303–309 Chukkapalli S, Rivera-Kweh M, Gehlot P, Velsko I, Bhattacharyya I, Calise SJ, Satoh M, Chan EK, Holoshitz J, Kesavalu L (2016) Periodontal bacterial colonization in synovial tissues exacerbates collagen-induced arthritis in B10.RIII mice. Arthritis Res Ther 18:161 Ciccia F, Accardo-Palumbo A, Rizzo A, Guggino G, Raimondo S, Giardina A, Cannizzaro A, Colbert RA, Alessandro R, Triolo G (2014) Evidence that autophagy, but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with ankylosing spondylitis and subclinical gut inflammation. Ann Rheum Dis 73:1566–1574 Ciccia F, Ferrante A, Triolo G (2016) Intestinal dysbiosis and innate immune responses in axial spondyloarthritis. Curr Opin Rheumatol 28:352–358 Cipriani, G., Gibbons, S. J., Kashyap, P. C. & Farrugia, G. 2016. Intrinsic gastrointestinal macrophages: their phenotype and role in gastrointestinal motility Clegg DO (2006) Treatment of ankylosing spondylitis. J Rheumatol Suppl 78:24–31 Cooper C, Carbone L, Michet CJ, Atkinson EJ, O'Fallon WM, Melton LJ 3rd (1994) Fracture risk in patients with ankylosing spondylitis: a population based study. J Rheumatol 21:1877–1882 Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T, Leo P, Cremin K, Pryce K, Harris J, Lee S, Joo KB, Shim SC, Weisman M, Ward M, Zhou X, Garchon HJ, Chiocchia G, Nossent J, Lie BA, Førre Ø, Tuomilehto J, Laiho K, Jiang L, Liu Y, Wu X, Bradbury LA, Elewaut D, Burgos-Vargas R, Stebbings S, Appleton L, Farrah C, Lau J, Kenna TJ, Haroon N, Ferreira MA, Yang J, Mulero J, Fernandez-Sueiro JL, Gonzalez-Gay MA, Lopez-Larrea C, Deloukas P, Donnelly P, Bowness P, Gafney K, Gaston H, Gladman DD, Rahman P, Maksymowych WP, Xu H, Crusius JB, Van Der Horst-Bruinsma IE, Chou CT, Valle-Oñate R, Romero-Sánchez C, Hansen IM, Pimentel-Santos FM, Inman RD, Videm V, Martin J, Breban M, Reveille JD, Evans DM, Kim TH, Wordsworth BP, Brown MA (2013) Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 45: 730–738 Coşkun BN, Öksüz MF, Ermurat S, Tufan AN, Oruçoğlu N, Doğan A, Dalkiliç E, Pehlivan Y (2014) Neutrophil lymphocyte ratio can be a valuable marker in defining disease activity in patients who have started anti-tumor necrosis factor (TNF) drugs for ankylosing spondylitis. Eur J Rheumatol 1(3):101–105 Costello ME, Elewaut D, Kenna TJ, Brown MA (2013) Microbes, the gut and ankylosing spondylitis. Arthritis Res Ther 15:214

480

A. Sharip et al.

Costello ME, Ciccia F, Willner D, Warrington N, Robinson PC, Gardiner B, Marshall M, Kenna TJ, Triolo G, Brown MA (2015) Brief report: intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol 67:686–691 Daikh DI, Chen PP (2014) Advances in managing ankylosing spondylitis. F1000prime Rep 6:78 Dakwar E, Reddy J, Vale FL, Uribe JS (2008) A review of the pathogenesis of ankylosing spondylitis. Neurosurg Focus 24:e2 Dangoria NS, Delay ML, Kingsbury DJ, Mear JP, Uchanska-Ziegler B, Ziegler A, Colbert RA (2002) HLA-B27 misfolding is associated with aberrant intermolecular disulfide bond formation (dimerization) in the endoplasmic reticulum. J Biol Chem 277:23459–23468 Dashti N, Mahmoudi M, Aslani S, Jamshidi A (2018) HLA-B*27 subtypes and their implications in the pathogenesis of ankylosing spondylitis. Gene 670:15–21 Davidson SI, Liu Y, Danoy PA, Wu X, Thomas GP, Jiang L, Sun L, Wang N, Han J, Han H, Visscher PM, Brown MA, Xu H (2011) Association of STAT3 and TNFRSF1A with ankylosing spondylitis in Han Chinese. Ann Rheum Dis 70:289–292 De Vries D, Dekker-Saeys A, Gyodi E, Bohm U, Ivanyi P (1992) Absence of autoantibodies to peptides shared by HLA-B27. 5 and Klebsiella pneumoniae nitrogenase in serum samples from HLA-B27 positive patients with ankylosing spondylitis and Reiter's syndrome. Ann Rheum Dis 51:783–789 Dougados M, Guéguen A, Nakache J, Velicitat P, Veys E, Zeidler H, Calin A (1999) Ankylosing spondylitis: what is the optimum duration of a clinical study? A one year versus a 6 weeks non-steroidal anti-inflammatory drug trial. Rheumatology (Oxford) 38:235–244 Duan Y, Zeng L, Zheng C, Song B, Li F, Kong X, Xu K (2018) Inflammatory links between high fat diets and diseases. Front Immunol 9:2649 Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–1463 Eastmond CJ, Willshaw HE, Burgess SE, Shinebaum R, Cooke EM, Wright V (1980) Frequency of faecal Klebsiella aerogenes in patients with ankylosing spondylitis and controls with respect to individual features of the disease. Ann Rheum Dis 39(2):118–123 Ebringer A (1983) The cross-tolerance hypothesis, HLA-B27 and ankylosing spondylitis. Rheumatology 22:53–66 Ebringer RW, Cawdell DR, Cowling P, Ebringer A (1978) Sequential studies in ankylosing spondylitis. Association of Klebsiella pneumoniae with active disease. Ann Rheum Dis 37:146 Ebringer A, Rashid T, Tiwana H, Wilson C (2007) A possible link between Crohn's disease and ankylosing spondylitis via Klebsiella infections. Clin Rheumatol 26(3):289–297 Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G, Oppermann U, Dilthey A, Pirinen M, Stone MA, Appleton L, Moutsianas L, Leslie S, Wordsworth T, Kenna TJ, Karaderi T, Thomas GP, Ward MM, Weisman MH, Farrar C, Bradbury LA, Danoy P, Inman RD, Maksymowych W, Gladman D, Rahman P, Morgan A, Marzo-Ortega H, Bowness P, Gaffney K, Gaston JS, Smith M, Bruges-Armas J, Couto AR, Sorrentino R, Paladini F, Ferreira MA, Xu H, Liu Y, Jiang L, Lopez-Larrea C, Díaz-Peña R, López-Vázquez A, Zayats T, Band G, Bellenguez C, Blackburn H, Blackwell JM, Bramon E, Bumpstead SJ, Casas JP, Corvin A, Craddock N, Deloukas P, Dronov S, Duncanson A, Edkins S, Freeman C, Gillman M, Gray E, Gwilliam R, Hammond N, Hunt SE, Jankowski J, Jayakumar A, Langford C, Liddle J, Markus HS, Mathew CG, Mccann OT, Mccarthy MI, Palmer CN, Peltonen L, Plomin R, Potter SC, Rautanen A, Ravindrarajah R, Ricketts M, Samani N, Sawcer SJ, Strange A, Trembath RC, Viswanathan AC, Waller M, Weston P, Whittaker P, Widaa S, Wood NW, Mcvean G, Reveille JD, Wordsworth BP, Brown MA, Donnelly P (2011a) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 43:761–767

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

481

Evans DM, Spencer CCA, Pointon JJ, Su Z, Harvey D, Kochan G, Opperman U, Dilthey A, Pirinen M, Stone MA, Appleton L, Moutsianis L, Leslie S, Wordsworth T, Kenna TJ, Karaderi T, Thomas GP, Ward MM, Weisman MH, Farrar C, Bradbury LA, Danoy P, Inman RD, Maksymowych W, Gladman D, Rahman P, Morgan A, Marzo-Ortega H, Bowness P, Gaffney K, Gaston JSH, Smith M, Bruges-Armas J, Couto AR, Sorrentino R, Paladini F, Ferreira MA, Xu HJ, Liu Y, Jiang L, Lopez-Larrea C, Diaz-Pena R, Lopez-Vazquez A, Zayats T, Band G, Bellenguez C, Blackburn H, Blackwell JM, Bramon E, Bumpstead SJ, Casas JP, Corvin A, Craddock N, Deloukas P, Dronov S, Duncanson A, Edkins S, Freeman C, Gillman M, Gray E, Gwilliam R, Hammond N, Hunt SE, Jankowski J, Jayakumar A, Langford C, Liddle J, Markus HS, Mathew CG, Mccann OT, Mccarthy MI, Palmer CNA, Peltonen L, Plomin R, Potter SC, Rautanen A, Ravindrarajah R, Ricketts M, Samani N, Sawcer SJ, Strange A, Trembath RC, Viswanathan AC, Waller M, Weston P, Whittaker P, Widaa S, Wood NW, Mcvean G, Reveille JD, Wordsworth BP, Brown MA, Donnelly P, Spondyloarthri A-A-A, Consor WTCC, Can SRC (2011b) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 43:761–U67 Feng DX, Zhang K, Zhang YM, Nian YW, Zhang J, Kang XM, Wu SF, Zhu YJ (2016) Bilaterally primary cementless total hip arthroplasty for severe hip ankylosis with ankylosing spondylitis. Orthop Surg 8:352–359 Garcia-Montoya L, Gul H, Emery P (2018) Recent advances in ankylosing spondylitis: understanding the disease and management. F1000 Res 7:1512 Gaston JS, Life PF, Granfors K, Merilahti-Palo R, Bailey L, Consalvey S, Toivanen A, Bacon PA (1989) Synovial T lymphocyte recognition of organisms that trigger reactive arthritis. Clin Exp Immunol 76:348–353 Gill T, Rosenbaum JT (2020) Putative pathobionts in HLA-B27-associated spondyloarthropathy. Front Immunol 11:586494 Gill T, Asquith M, Brooks SR, Rosenbaum JT, Colbert RA (2018) Effects of HLA-B27 on gut microbiota in experimental spondyloarthritis implicate an ecological model of dysbiosis. Arthritis Rheumatol 70:555–565 Granfors K, Jalkanen S, Von Essen R, Lahesmaa-Rantala R, Isomäki O, Pekkola-Heino K, Merilahti-Palo R, Saario R, Isomäki H, Toivanen A (1989a) Yersinia antigens in synovialfluid cells from patients with reactive arthritis. N Engl J Med 320:216–221 Granfors K, Ogasawara M, Hill JL, Lahesmaa-Rantala R, Toivanen A, Yu DT (1989b) Analysis of IgA antibodies to lipopolysaccharide in yersinia-triggered reactive arthritis. J Infect Dis 159: 1142–1147 Haibel H, Rudwaleit M, Brandt HC, Grozdanovic Z, Listing J, Kupper H, Braun J, Sieper J (2006) Adalimumab reduces spinal symptoms in active ankylosing spondylitis: clinical and magnetic resonance imaging results of a fifty-two-week open-label trial. Arthritis Rheum 54:678–681 Haibel H, Rudwaleit M, Listing J, Heldmann F, Wong RL, Kupper H, Braun J, Sieper J (2008) Efficacy of adalimumab in the treatment of axial spondyloarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo-controlled trial followed by an open-label extension up to week fifty-two. Arthritis Rheum 58:1981–1991 He A, Xie D, Cai X, Qu B, Kong Q, Xu C, Yang L, Chen X, Jia L (2017) One-stage surgical treatment of cervical spine fracture-dislocation in patients with ankylosing spondylitis via the combined anterior-posterior approach. Medicine 96:e7432–e7432 Hermann E, Zum Büschenfelde KM, Fleischer B, Yu D (1993) HLA-B27-restricted CD8 T cells derived from synovial fluids of patients with reactive arthritis and ankylosing spondylitis. Lancet 342:646–650 Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102 Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, Morelli L, Canani RB, Flint HJ, Salminen S, Calder PC, Sanders ME (2014) The international scientific association for

482

A. Sharip et al.

probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 11:506–514 Hoentjen F, Welling G, Harmsen H, Zhang X, Snart J, Tannock G, Lien K, Churchill T, Lupicki M, Dieleman L (2005) Reduction of colitis by prebiotics in HLA-B27 transgenic rats is associated with microflora changes and immunomodulation. Inflamm Bowel Dis 11:977–985 Hoentjen F, Tannock G, Mulder C, Dieleman L (2006) The prebiotic combination inulin/ oligofructose prevents colitis in HLA-B27 rats by immunomodulation and changes in intestinal microflora. Eur J Gastroenterol Hepatol 18:A27 Inman RD, Davis JC Jr, Heijde D, Diekman L, Sieper J, Kim SI, Mack M, Han J, Visvanathan S, Xu Z, Hsu B, Beutler A, Braun J (2008) Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum 58:3402–3412 Jostins L, Ripke S, Weersma RK, Duerr RH, Mcgovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar J-P, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Büning C, Cohain A, Cichon S, D'Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE, Daly MJ et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491(7422):119–124 Kaipiainen-Seppanen O, Aho K, Heliovaara M (1997) Incidence and prevalence of ankylosing spondylitis in Finland. J Rheumatol 24:496–499 Kang EH, Lee JT, Lee HJ, Lee JY, Chang SH, Cho HJ, Choi BY, Ha YJ, Park KU, Song YW, Van Dyke TE, Lee YJ (2015) Chronic periodontitis is associated with spinal dysmobility in patients with ankylosing spondylitis. J Periodontol 86:1303–1313 Karberg K, Zochling J, Sieper J, Felsenberg D, Braun J (2005) Bone loss is detected more frequently in patients with ankylosing spondylitis with syndesmophytes. J Rheumatol 32(7): 1290–1298 Keidel S, Chen L, Pointon J, Wordsworth P (2013) ERAP1 and ankylosing spondylitis. Curr Opin Immunol 25:97–102 Kenna TJ, Robinson PC, Haroon N (2015) Endoplasmic reticulum aminopeptidases in the pathogenesis of ankylosing spondylitis. Rheumatology 54:1549–1556 Kerr SW, Wolyniec WW, Filipovic Z, Nodop SG, Braza F, Winquist RJ, Noonan TC (1999) Repeated measurement of intestinal permeability as an assessment of colitis severity in HLA-B27 transgenic rats. J Pharmacol Exp Ther 291(2):903–910 Khalessi AA, Oh BC, Wang MY (2008) Medical management of ankylosing spondylitis. Neurosurg Focus 24:e4 Khan MA, Kushner I, Braun WE (1978) A subgroup of ankylosing spondylitis associated with HLA-B7 in American blacks. Arthritis Rheum 21:528–530 Koller H, Koller J, Mayer M, Hempfing A, Hitzl W (2018) Osteotomies in ankylosing spondylitis: where, how many, and how much? Eur Spine J 27, 70(Suppl 1):–100 Kubiak EN, Moskovich R, Errico TJ, Di Cesare PE (2005) Orthopaedic management of ankylosing spondylitis. J Am Acad Orthop Surg 13:267–278 Li M, Dai B, Tang Y, Lei L, Li N, Liu C, Ge T, Zhang L, Xu Y, Hu Y, Li P, Zhang Y, Yuan J, Li X (2019) Altered bacterial-fungal Interkingdom networks in the guts of ankylosing spondylitis patients. mSystems 4:e00176–e00118

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

483

Lin B, Zhang B, Li ZM, Li QS (2014a) Corrective surgery for deformity of the upper cervical spine due to ankylosing spondylitis. Indian J Orthop 48(2):211–215 Lin P, Bach M, Asquith M, Lee AY, Akileswaran L, Stauffer P, Davin S, Pan Y, Cambronne ED, Dorris M, Debelius JW, Lauber CL, Ackermann G, Baeza YV, Gill T, Knight R, Colbert RA, Taurog JD, Van Gelder RN, Rosenbaum JT (2014b) HLA-B27 and human Beta2-microglobulin affect the gut microbiota of transgenic rats. PLoS One 9:e105684 Liu W, Wu Y-H, Zhang L, Liu X-Y, Xue B, Wang Y, Liu B, Jiang Q, Kwang H-W, Wu D-J (2015) Elevated serum levels of IL-6 and IL-17 may associate with the development of ankylosing spondylitis. Int J Clin Exp Med 8:17362–17376 Martin-Esteban A, Sanz-Bravo A, Guasp P, Barnea E, Admon A, De Castro JAL (2017) Separate effects of the ankylosing spondylitis associated ERAP1 and ERAP2 aminopeptidases determine the influence of their combined phenotype on the HLA-B*27 peptidome. J Autoimmun 79:28– 38 Martinez-Gonzalez O, Cantero-Hinojosa J, Paule-Sastre P, Gomez-Magan JC, Salvatierra-Rios D (1994) Intestinal permeability in patients with ankylosing spondylitis and their healthy relatives. Br J Rheumatol 33:644–647 Martínez-González O, Cantero-Hinojosa J, Paule-Sastre P, Gómez-Magán JC, Salvatierra-Ríos D (1994) Intestinal permeability in patients with ankylosing spondylitis and their healthy relatives. Br J Rheumatol 33:644–647 Mcgeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, Mcclanahan TK, O'Shea JJ, Cua DJ (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 10: 314–324 Mcveigh CM, Cairns AP (2006) Diagnosis and management of ankylosing spondylitis. BMJ 333: 581–585 Merilahti-Palo R, Soderstrom KO, Lahesmaa-Rantala R, Granfors K, Toivanen A (1991) Bacterial antigens in synovial biopsy specimens in yersinia triggered reactive arthritis. Ann Rheum Dis 50:87–90 Mitulescu TC, Stavaru C, Voinea LM, Banica LM, Matache C, Predeteanu D (2016) The role of vitamin D in immuno-inflammatory responses in ankylosing spondylitis patients with and without acute anterior uveitis. J Med Life 9(1):26–33 Molto A, Nikiphorou E (2018) Comorbidities in spondyloarthritis. Front Med (Lausanne) 5:62 Moon KH, Kim YT (2014) Medical treatment of ankylosing spondylitis. Hip Pelvis 26:129–135 Morris G, Berk M, Carvalho AF, Caso JR, Sanz Y, Maes M (2016) The role of microbiota and intestinal permeability in the pathophysiology of autoimmune and neuroimmune processes with an emphasis on inflammatory bowel disease type 1 diabetes and chronic fatigue syndrome. Curr Pharm Des 22:6058–6075 Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng BJ, Ruether A, Schreiber S, Weichenthal M, Gladman D, Rahman P, Schrodi SJ, Prahalad S, Guthery SL, Fischer J, Liao W, Kwok PY, Menter A, Lathrop GM, Wise CA, Begovich AB, Voorhees JJ, Elder JT, Krueger GG, Bowcock AM, Abecasis GR (2009) Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 41:199–204 Nakamura YK, Janowitz C, Metea C, Asquith M, Karstens L, Rosenbaum JT, Lin P (2017) Short chain fatty acids ameliorate immune-mediated uveitis partially by altering migration of lymphocytes from the intestine. Sci Rep 7:11745 Nakata K, Hanai T, Take Y, Osada T, Tsuchiya T, Shima D, Fujimoto Y (2018) Disease-modifying effects of COX-2 selective inhibitors and non-selective NSAIDs in osteoarthritis: a systematic review. Osteoarthr Cartil 26:1263–1273 Ochi T, Feng Y, Kitamoto S, Nagao-Kitamoto H, Kuffa P, Atarashi K, Honda K, Teitelbaum DH, Kamada N (2016) Diet-dependent, microbiota-independent regulation of IL-10-producing lamina propria macrophages in the small intestine. Sci Rep 6:27634 Ogrendik M (2015) Periodontal pathogens are likely to be responsible for the development of ankylosing spondylitis. Curr Rheumatol Rev 11(1):47–49

484

A. Sharip et al.

Paun A, Danska JS (2016) Modulation of type 1 and type 2 diabetes risk by the intestinal microbiome. Pediatr Diabetes 17:469–477 Pedersen SJ, Maksymowych WP (2019) The pathogenesis of ankylosing spondylitis: an update. Curr Rheumatol Rep 21:1–10 Pointon JJ, Harvey D, Karaderi T, Appleton LH, Farrar C, Stone MA, Sturrock RD, Brown MA, Wordsworth BP (2010) Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene. Genes Immun 11:490–496 Qian BP, Mao SH, Jiang J, Wang B, Qiu Y (2017) Mechanisms, predisposing factors, and prognosis of intraoperative vertebral subluxation during pedicle subtraction osteotomy in surgical correction of thoracolumbar kyphosis secondary to ankylosing spondylitis. Spine (Phila Pa 1976) 42(16):E983–E990 Rashid T, Ebringer A (2007) Ankylosing spondylitis is linked to Klebsiella--the evidence. Clin Rheumatol 26(6):858–864 Rath HC, Wilson KH, Sartor RB (1999) Differential induction of colitis and gastritis in HLA-B27 transgenic rats selectively colonized with Bacteroides vulgatus or Escherichia coli. Infect Immun 67:2969–2974 Redford AH, Trost JR, Sibbitt WL Jr, Fangtham M, Emil NS, Singh S, Bankhurst AD (2019) HLA-B27 spondyloarthritis and spotted fever rickettsiosis: case-based review. Rheumatol Int 39:1643–1650 Reveille JD (2011) The genetic basis of spondyloarthritis. Ann Rheum Dis 70(Suppl 1):I44–I50 Reveille JD, Weisman MH (2013) The epidemiology of back pain, axial spondyloarthritis and HLA-B27 in the United States. Am J Med Sci 345(6):431–436 Rodriguez-Cabezas ME, Galvez J, Camuesco D, Lorente MD, Concha A, Martinez-Augustin O, Redondo L, Zarzuelo A (2003) Intestinal anti-inflammatory activity of dietary fiber (Plantago Ovata seeds) in HLA-B27 transgenic rats. Clin Nutr 22:463–471 Rosenbaum JT, Asquith MJ (2016a) The microbiome: a revolution in treatment for rheumatic diseases? Curr Rheumatol Rep 18:62 Rosenbaum JT, Asquith MJ (2016b) The microbiome: a revolution in treatment for rheumatic diseases? Curr Rheumatol Rep 18:1–7 Rosenbaum JT, Davey MP (2011) Time for a gut check: evidence for the hypothesis that HLA-B27 predisposes to ankylosing spondylitis by altering the microbiome. Arthritis Rheum 63:3195– 3198 Rosenbaum JT, Lin P, Asquith M, Costello ME, Kenna TJ, Brown MA (2014) Does the microbiome play a causal role in spondyloarthritis? Clin Rheumatol 33:763–767 Rudwaleit M, Siegert S, Yin Z, Eick J, Thiel A, Radbruch A, Sieper J, Braun J (2001) Low T cell production of TNFalpha and IFNgamma in ankylosing spondylitis: its relation to HLA-B27 and influence of the TNF-308 gene polymorphism. Ann Rheum Dis 60:36–42 Sampaio-Maia B, Simoes-Silva L, Pestana M, Araujo R, Soares-Silva IJ (2016) The role of the gut microbiome on chronic kidney disease. Adv Appl Microbiol 96:65–94 Sari I, Ozturk MA, Akkoc N (2015) Treatment of ankylosing spondylitis. Turk J Med Sci 45:416– 430 Schepens MA, Schonewille AJ, Vink C, Van Schothorst EM, Kramer E, Hendriks T, Brummer RJ, Keijer J, Van Der Meer R, Bovee-Oudenhoven IM (2009) Supplemental calcium attenuates the colitis-related increase in diarrhea, intestinal permeability, and extracellular matrix breakdown in HLA-B27 transgenic rats. J Nutr 139:1525–1533 Scher JU, Ubeda C, Artacho A, Attur M, Isaac S, Reddy SM, Marmon S, Neimann A, Brusca S, Patel T, Manasson J, Pamer EG, Littman DR, Abramson SB (2015) Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol 67:128–139 Schlosstein L, Terasaki PI, Bluestone R, Pearson CM (1973) High association of an Hl-A antigen, W27, with ankylosing spondylitis. N Engl J Med 288:704–706 Schultz M, Munro K, Tannock GW, Melchner I, Gottl C, Schwietz H, Scholmerich J, Rath HC (2004) Effects of feeding a probiotic preparation (SIM) containing inulin on the severity of

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

485

colitis and on the composition of the intestinal microflora in HLA-B27 transgenic rats. Clin Diagn Lab Immunol 11:581–587 Seregin SS, Rastall DP, Evnouchidou I, Aylsworth CF, Quiroga D, Kamal RP, Godbehere-Roosa S, Blum CF, York IA, Stratikos E, Amalfitano A (2013) Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens. Autoimmunity 46:497–508 Sharip A, Kunz J (2020) Understanding the pathogenesis of spondyloarthritis. Biomolecules 10: 1461 Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A (2002) Ankylosing spondylitis: an overview. Ann Rheum Dis 61(Suppl 3):iii8–ii18 Sieper J, Klopsch T, Richter M, Kapelle A, Rudwaleit M, Schwank S, Regourd E, May M (2008) Comparison of two different dosages of celecoxib with diclofenac for the treatment of active ankylosing spondylitis: results of a 12-week randomised, double-blind, controlled study. Ann Rheum Dis 67(3):323–329 Smith NM, Maloney NG, Shaw S, Horgan GW, Fyfe C, Martin JC, Suter A, Scott KP, Johnstone AM (2020) Daily fermented whey consumption alters the fecal short-chain fatty acid profile in healthy adults. Front Nutr 7:165 Solmaz D, Kozaci D, Sari İ, Taylan A, Önen F, Akkoç N, Akar S (2016) Oxidative stress and related factors in patients with ankylosing spondylitis. Eur J Rheumatol 3(1):20–24 Song IH, Poddubnyy DA, Rudwaleit M, Sieper J (2008) Benefits and risks of ankylosing spondylitis treatment with nonsteroidal Antiinflammatory drugs. Arthritis Rheum 58:929–938 Spor A, Koren O, Ley R (2011) Unravelling the effects of the environment and host genotype on the gut microbiome. Nat Rev Microbiol 9:279–290 Steinert A, Radulovic K, Niess J (2016) Gastro-intestinal tract: the leading role of mucosal immunity. Swiss Med Wkly 146:W14293 Stone MA, Payne U, Schentag C, Rahman P, Pacheco-Tena C, Inman RD (2003) Comparative immune responses to candidate arthritogenic bacteria do not confirm a dominant role for Klebsiella pneumonia in the pathogenesis of familial ankylosing spondylitis. Rheumatology (Oxford) 43(2):148–155 Syrbe U, Sieper J (2020) Chapter 36 - Spondyloarthritis. In: Rose NR, Mackay IR (eds) The autoimmune diseases, 6th edn. Academic Press, Cambridge, MA Tani Y, Tiwana H, Hukuda S, Nishioka J, Fielder M, Wilson C, Bansal S, Ebringer A (1997) Antibodies to Klebsiella, proteus, and HLA-B27 peptides in Japanese patients with ankylosing spondylitis and rheumatoid arthritis. J Rheumatol 24:109–114 Tian P, Li B, He C, Song W, Hou A, Tian S, Meng X, Li K, Shan Y (2016) Antidiabetic (type 2) effects of lactobacillus G15 and Q14 in rats through regulation of intestinal permeability and microbiota. Food Funct 7(9):3789–3797 Tilg H (2015) Cruciferous vegetables: prototypic anti-inflammatory food components. Clin Phytosci 1:10 Tito RY, Cypers H, Joossens M, Varkas G, Van Praet L, Glorieus E, Van Den Bosch F, De Vos M, Raes J, Elewaut D (2017) Brief report: dialister as a microbial marker of disease activity in spondyloarthritis. Arthritis Rheumatol 69:114–121 Tlaskalova-Hogenova H, Stepankova R, Hudcovic T, Tuckova L, Cukrowska B, LodinovaZadnikova R, Kozakova H, Rossmann P, Bartova J, Sokol D, Funda DP, Borovska D, Rehakova Z, Sinkora J, Hofman J, Drastich P, Kokesova A (2004) Commensal bacteria (Normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunol Lett 93:97–108 Toyonaga T, Matsuura M, Mori K, Honzawa Y, Minami N, Yamada S, Kobayashi T, Hibi T, Nakase H (2016) Lipocalin 2 prevents intestinal inflammation by enhancing phagocytic bacterial clearance in macrophages. Sci Rep 6:35014 Vaile JH, Meddings JB, Yacyshyn BR, Russell AS, Maksymowych WP (1999) Bowel permeability and CD45RO expression on circulating CD20+ B cells in patients with ankylosing spondylitis and their relatives. J Rheumatol 26:128–135

486

A. Sharip et al.

Van Der Linden S, Van Der Heijde D (2000) Clinical aspects, outcome assessment, and management of ankylosing spondylitis and postenteric reactive arthritis. Curr Opin Rheumatol 12:263– 268 Van Der Linden S, Valkenburg HA, Cats A (1984a) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 27(4): 361–368 Van Der Linden SM, Valkenburg HA, De Jongh BM, Cats A (1984b) The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population. Arthritis Rheum 27:241–249 Vander Cruyssen B, Munoz-Gomariz E, Font P, Mulero J, De Vlam K, Boonen A, VazquezMellado J, Flores D, Vastesaeger N, Collantes E, Group, A.-R.-R. W (2010) Hip involvement in ankylosing spondylitis: epidemiology and risk factors associated with hip replacement surgery. Rheumatology (Oxford) 49:73–81 Vandooren B, Noordenbos T, Ambarus C, Krausz S, Cantaert T, Yeremenko N, Boumans M, Lutter R, Tak PP, Baeten D (2009) Absence of a classically activated macrophage cytokine signature in peripheral spondyloarthritis, including psoriatic arthritis. Arthritis Rheum 60:966– 975 Viitanen JV, Kokko ML, Lehtinen K, Suni J, Kautiainen H (1995) Correlation between mobility restrictions and radiologic changes in ankylosing spondylitis. Spine 20:492–496 Vosse D, Van Der Heijde D, Landewe R, Geusens P, Mielants H, Dougados M, Van Der Linden S (2006) Determinants of hyperkyphosis in patients with ankylosing spondylitis. Ann Rheum Dis 65:770–774 Ward MM, Deodhar A, Akl EA, Lui A, Ermann J, Gensler LS, Smith JA, Borenstein D, Hiratzka J, Weiss PF, Inman RD, Majithia V, Haroon N, Maksymowych WP, Joyce J, Clark BM, Colbert RA, Figgie MP, Hallegua DS, Prete PE, Rosenbaum JT, Stebulis JA, Van Den Bosch F, Yu DT, Miller AS, Reveille JD, Caplan L (2016) American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol 68(2):282–298 Wei JC, Sung-Ching HW, Hsu YW, Wen YF, Wang WC, Wong RH, Lu HF, Gaalen FA, Chang WC (2015) Interaction between HLA-B60 and HLA-B27 as a better predictor of ankylosing spondylitis in a Taiwanese population. PLoS One 10(10):e0137189 Wen C, Zheng Z, Shao T, Liu L, Xie Z, Le Chatelier E, He Z, Zhong W, Fan Y, Zhang L, Li H, Wu C, Hu C, Xu Q, Zhou J, Cai S, Wang D, Huang Y, Breban M, Qin N, Ehrlich SD (2017) Quantitative metagenomics reveals unique gut microbiome biomarkers in ankylosing spondylitis. Genome Biol 18:142 Xu J, Zeng M, Xie J, Wen T, Hu Y (2017) Cementless total hip arthroplasty in patients with ankylosing spondylitis: a retrospective observational study. Medicine (Baltimore) 96:e5813 Yago T, Nanke Y, Kawamoto M, Kobashigawa T, Yamanaka H, Kotake S (2017) IL-23 and Th17 disease in inflammatory arthritis. J Clin Med 6:81 Yang L, Wang L, Wang X, Xian CJ, Lu H (2016) A possible role of intestinal microbiota in the pathogenesis of ankylosing spondylitis. Int J Mol Sci 17:2126 Zhang L, Zhang Y-J, Chen J, Huang X-L, Fang G-S, Yang L-J, Duan Y, Wang J (2018) The association of HLA-B27 and Klebsiella pneumoniae in ankylosing spondylitis: a systematic review. Microb Pathog 117:49–54 Zhou C, Zhao H, Xiao XY, Chen BD, Guo RJ, Wang Q, Chen H, Zhao LD, Zhang CC, Jiao YH, Ju YM, Yang HX, Fei YY, Wang L, Shen M, Li H, Wang XH, Lu X, Yang B, Liu JJ, Li J, Peng LY, Zheng WJ, Zhang CY, Zhou JX, Wu QJ, Yang YJ, Su JM, Shi Q, Wu D, Zhang W, Zhang FC, Jia HJ, Liu DP, Jie ZY, Zhang X (2020) Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis. J Autoimmun 107:102360 Zhu W, He X, Cheng K, Zhang L, Chen D, Wang X, Qiu G, Cao X, Weng X (2019) Ankylosing spondylitis: etiology, pathogenesis, and treatments. Bone Res 7:22

18

Microorganisms in the Pathogenesis and Management of Ankylosing Spondylitis

487

Zink A, Braun J, Listing J, Wollenhaupt J (2000) Disability and handicap in rheumatoid arthritis and ankylosing spondylitis--results from the German Rheumatological Database. German Collaborative Arthritis Centers. J Rheumatol 27:613–622

Microorganisms in Pathogenesis and Management of Psoriasis Arthritis (PsA)

19

Dobrică Elena-Codruța, Banciu Laura Mădălina, Voiculescu Vlad Mihai, and Găman Amelia Maria

Abstract

Psoriatic arthritis is a chronic inflammatory disease with a destructive course that can lead to severe functional impairment. It is one of the common complications of psoriasis, with a growing prevalence, the underlying mechanisms being not yet fully elucidated. The intestinal microbiota is made up of all the microorganisms that colonize the intestinal mucosa, being characterized by a great diversity and individual variability and quantitative or qualitative variations in its composition leading to a wide range of pathologies. Research in recent years has shown that understanding how the human body and microbiota interact and tolerate reciprocally is the starting point in understanding the pathophysiology of many inflammatory diseases, including psoriatic arthritis. Moreover, it has been observed that in addition to commensal microorganisms, other pathogenic microorganisms, such as bacteria, fungi, and viruses, are also involved in its appearance and exacerbation. A complete understanding of these mechanisms will thus be the starting point in the personalized treatment of psoriatic arthritis and other inflammatory diseases. D. Elena-Codruța (*) Department of Dermatology, Elias University Hospital, Bucharest, Romania University of Medicine and Pharmacy of Craiova, Craiova, Romania B. L. Mădălina Department of Dermatology, Elias University Hospital, Bucharest, Romania V. V. Mihai Department of Dermatology, Elias University Hospital, Bucharest, Romania “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania G. A. Maria University of Medicine and Pharmacy of Craiova, Craiova, Romania # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_19

489

490

D. Elena-Codruța et al.

Keywords

Psoriasis arthritis · Microorganisms · Microbiota · HIV · SARS-CoV2 · Streptococcus · Chlamydia

19.1

Introduction

Psoriasis is a chronic dermatological condition, with an inflammatory substrate and an important immune component, characterized by excessive proliferation of keratinocytes and the appearance of erythematous, scaly lesions with variable distribution (Nestle et al. 2009). Even though psoriasiform manifestations have been described in the literature since 2000 years ago, the first clear definition of this condition was given by the English physician Robert Willan in 1808 (Russell 1950; Benedek 2013) when he classifies psoriasis as leprosy. Psoriasis is included in the category of common dermatological diseases with a global prevalence ranging between 0.14% and 3.6% worldwide and an incidence that can reach 320 cases per 100,000 inhabitants, the highest values being found in Central Europe and North America (Dogra and Mahajan 2016; Parisi et al. 2020). One of the common complications with a significant impact on the quality of life of patients with psoriasis is psoriatic arthritis (PsA). Although the association between the two pathologies is presented since the first half of the nineteenth century, PsA is recognized as an independent entity only a century later, in 1964 (Dogra and Mahajan 2016). It is defined as a chronic inflammatory condition from the category of spondyloarthropathies, with a progressive character that leads to irreversible joint damage, with severe functional impotence (Ogdie and Weiss 2015). A significant percentage of patients diagnosed with psoriasis will develop joint damage, its prevalence ranging from 0.05 to 0.25% in the general population to 6–41% in the population with psoriasis, the percentage increasing with the duration of the underlying disease (Langley et al. 2005; Ogdie and Weiss 2015). Moreover, these epidemiological values may be underestimated, according to the study by Mease et al. suggesting an underdiagnosis of this pathology in over 40% of cases (Mease et al. 2014). PsA strongly influences the quality of life, in the last decades many scores being developed in order to assess this aspect, including YLD (years lived with disability) and DALY (disability-adjusted life year) (represented by the sum between the YLD and the years lost due to decreased life expectancy caused by the disease), both experiencing a progressive increase in the last three decades in patients with PsA (AlQassimi et al. 2020). Although pathologies with a peak prevalence around the sixth decade, psoriasis and PsA are common pathologies in children, PsA having a prevalence of up to 1.2% in them and representing up to 8% of juvenile arthritis (AlQassimi et al. 2020). Microorganisms, both commensals (from the skin, intestinal, oral, genital microbiota) and pathogenic, play an important role in the pathophysiology of immune-mediated diseases. The mechanisms involved are multiple, among the best known being the action of their metabolites on the function of regulatory T

19

Microorganisms in Pathogenesis and Management of Psoriasis Arthritis (PsA)

491

cells and the increase of Toll-like receptor (TLR) expression (Thrastardottir and Love 2018; Wu et al. 2020). They thus modulate the innate and acquired immune response since the intrauterine stage, being responsible for maintaining the tolerance-inflammation balance (Picchianti-Diamanti et al. 2017). These mechanisms have been an important point of interest for research in the last decade, as evidenced by the impressive number of articles on microbiota published in databases, which are growing year by year, with over 2000 articles published in the last 10 years, of which 399 in the last year (PubMed 2021). These scientific data lead to the observation that there is a dynamic human-microorganism relationship; the disruption of this balance seems to be at the origin of diseases with previously unexplained pathogenesis, such as psoriasis and PsA, inflammatory bowel disease, atopic dermatitis, neurological diseases, etc. (Zorba et al. 2020; Wu et al. 2020; Khan et al. 2019).

19.2

Morbidity and Clinical Manifestation of PsA

Psoriatic arthritis is a chronic inflammatory joint disease, heterogeneous in terms of epidemiology, pathophysiology, clinical manifestations, comorbidities, or treatment modalities. The clinical presentation of PsA is varied, but the presence of inflammatory arthritis, skin manifestations, and the absence of rheumatoid factor are diagnostic criteria. Regarding the association of cutaneous psoriasis, studies show that psoriasis precedes joint manifestations in approximately 60–70% of cases; arthritis may begin before cutaneous manifestations in 15–20% of cases or may occur simultaneously within a year in 15–20% of cases (Kerschbaumer et al. 2016). Due to the heterogeneity of clinical manifestations, multiple classifications of PsA have been made, the oldest of which is Moll and Wright (Table 19.1) (Tiwari and Brent 2021).

Table 19.1 Moll and Wright classification of PsA (Tiwari and Brent 2021) Type of PsA Asymmetric oligoarthritis Symmetrical polyarthritis Distal arthritis Mutilating arthritis Spondylitis

Number of affected joints and localization 5 small/large joints Distal interphalangeal joints Joints of the hands and feet –

Characteristics Most common type of PsA Similar to rheumatoid arthritis (positive rheumatoid factor) – Joint deformities, destructive pattern Sacroiliitis may be present Damage of the peripheral joints may be present

492

19.3

D. Elena-Codruța et al.

Clinical Manifestations of Psoriatic Arthritis

19.3.1 Articular/Periarticular 19.3.1.1 Articular Peripheral arthritis: There are three patterns of joint damage: polyarticular, oligoarticular and distal interphalangeal, most likely due to changes with the evolution of the disease. The manifestations of the disease are joint pain, local erythema, and joint immobility, and in evolution it can be associated with a purple coloration of the joints and distal edema of the fingers. Mutilated arthritis has excessive bone resorption with finger telescope, “pencil-in-cup” appearance, and bone ankylosis (Gladman et al. 2005; Eder et al. 2009). Spondylitis: According to studies, spondylitis, manifestation of axial PsA, differs from ankylosing spondylitis by lower severity with better mobility; asymmetric sacroiliitis, often unilateral; lower male preponderance; lower association with HLA B27; or more frequent impairment of cervical spine (Nash 2009). Axial involvement in PsA consists in affecting the dynamics of the vertebrae with squaring of vertebrae, marginal and paramarginal syndesmophytes, sclerosis, paravertebral ossification, and atlantoaxial subluxations. Inflammation of the intervertebral and sacroiliac joints (sacroiliitis) is manifested by low back pain and changes in joint mobility, but sometimes in about 25% of cases, patients may have silent axial disease (Chandran 2019). 19.3.1.2 Periarticular: Enthesitis and Dactylitis Are Two Distinctive Signs of Psoriatic Arthritis Entheses are insertion structures of ligaments, tendons, capsules, and bone fascia that are repeatedly subjected to mechanical stress. Anatomically, the entheses are made up of soft tissue (ligament, tendons, fibrocartilage) and hard tissue (calcified fibrocartilage, adjacent bone) and at the same time are anatomically and functionally associated with the synovium forming the “synovio-entheseal” complex (Bagel and Schwartzman 2018). Enthesitis is inflammation of the joints, which can occur in several joints simultaneously, most commonly occurring in the lower limbs, involving the plantar fascia and Achilles tendon. Clinically it is manifested by pain in the affected joints and other signs of Celsus: erythema, edema, and functional impotence at the insertion sites. Studies have shown the importance of the IL-23/IL-17, IL-22, and TNF-alpha axis in the pathogenesis of enthesitis (Sakkas et al. 2013). Dactylitis: “Sausage-shaped finger” is a distinctive sign, useful in the diagnosis of PsA (16–49% of patients with PsA), but it can also be a distinctive sign in gout, spondylitis, sarcoidosis, etc. In PsA, dactylitis is asymmetrical, affecting the lower limbs and involves several fingers simultaneously (Kaeley et al. 2018). It is clinically manifested as uniform inflammation of the fingers, between the metacarpophalangeal and interphalangeal joints, more frequently in the feet than in the hands, but can occur simultaneously in both locations. Thus, dactylitis presents as a hard, erythematous inflammation of the fingers in the acute stage or asymptomatic edema in the chronic evolution by inflammation of the soft tissues. Dactylitis is

19

Microorganisms in Pathogenesis and Management of Psoriasis Arthritis (PsA)

493

considered a sign of the severity of the disease because it is associated with bone destruction and polyarticular damage (Dubash et al. 2020). Nails: Inflammation of the distal interphalangeal joint is extensive, so the inflammatory process often involves the nails. It is also considered that the nails are functionally connected to the joints of the distal interphalangeal joints through the extensor tendon which is attached to the terminal phalanx and connects to the nail root. The most common manifestations present at the level of the nail bed and the nail matrix are nail pitting, onycholysis, and leukonychia (Cassell et al. 2007).

19.3.2 Extraarticular In PsA, extraarticular manifestations are common, especially associated with axial disease and long-term disease. These can be ocular, manifested by ocular inflammation, uveitis and conjunctivitis, gastrointestinal (Crohn’s disease, ulcerative colitis), urogenital (urethritis, balanitis, prostatitis, cervicitis, vaginitis), and cardiovascular (branch blocks, intraventricular blocks, increased vascular stiffness) (Kerschbaumer et al. 2016). Metabolic syndrome and increased insulin resistance may also be associated as a consequence of chronic inflammation, and these patients may also develop autoimmune thyroiditis, especially in female patients (Antonelli et al. 2006).

19.4

Pathophysiology of PsA: Molecular Mechanisms and the Role of Gut and Skin Microbiota

The intestinal environment consists of bacteria, viruses, and fungi but also microbial metabolites such as short-chain fatty acids, trimethylamine N-oxides, or bacteriadriven outer membrane vesicles that interact to ensure local homeostasis. The intestinal flora includes almost 100 trillion cells, belonging to over 1000 species, being defined by The National Institutes of Health Human Microbiome Project as a true “superorganism” both physiologically and pathologically. Like the intestine, the skin has its own microbiome, deeply involved in the development and function of the immune system and in promoting inflammation in autoimmunity (Proctor 2011; Chen et al. 2020). Dysbiosis is a change in this microenvironment with increasing numbers of microorganisms, increased bacterial colonization, and by-products that affect the communication between the microbiota and the immune system (Parker et al. 2018). This can lead to the recruitment of Th17 lymphocytes, inhibition of regulatory T cells with local inflammation, migration of intestinal T cells, and consequent inflammation in other organs such as the skin or joints. Dysbiosis can affect the skin barrier and trigger autoimmune and inflammatory processes such as psoriasis and PsA, inflammatory bowel disease, and atopic dermatitis (Carvalho and Hedrich 2021; Wu et al. 2020; Khan et al. 2019). Psoriatic arthritis can be considered a systemic disease that is part of the group of spondyloarthropathies. Regarding the involvement of microbiota in the onset and evolution of PsA, there are currently numerous studies that associate the

494

D. Elena-Codruța et al.

pathophysiology of spondyloarthropathy with dysbiosis. Psoriasis and PsA have multiple etiologies involving many internal and external factors, which are not fully known, but which could be connected through the microbiome. Currently, the microbiome is a topic of interest in investigating the etiologies of inflammatory immune diseases, studies finding that the intestinal microbiome can affect extraintestinal structures by immunomodulation, a real “skin-joint-gut” axis being involved in psoriatic arthritis (Eppinga et al. 2014a, b). According to Carvalho and Saad, there are several mechanisms by which microbiome alterations can affect and modulate the immune system and the course of inflammatory diseases, some of those mechanisms being incompletely studied yet: – Exacerbation of the mucosal immune response leads to increased levels of IgA in the fecal samples of patients with PsA (Salas-Cuestas et al. 2017). – Patients with PsA show altered intestinal permeability due to the proinflammatory microclimate, with the expansion of lymphoid cells, activation of Th9, and decrease in regulatory cells, along with the aforementioned change in the balance between Th1 and Th17 (Carvalho and Saad 2013). – Micro-RNAs (miRNA) play an important role in regulating inflammatory processes. The expression of microRNA21-5p in intestinal epithelial cells, induced by commensal bacteria, has a role in modulating intestinal permeability by ADP ribosylation factor 4 (ARF4) which influences the occludin and claudin tight junction proteins. However, miRNA overexpression caused by damage to the intestinal microclimate leads to excessive inflammation. The species that induce miRNA-21 are Salmonella typhimurium, Mycobacterium, and Helicobacter pylori (Nakata et al. 2017). In the joints, bone marrow, spleen, and lymph nodes, miRNA-146a plays a protective, anti-inflammatory role, but its role in maintaining the intestinal barrier is controversial. However, significantly elevated levels of miRNA-146a were found in patients with inflammatory bowel disease. MiRNA-146a expression is activated by intestinal bacteria; alteration of its expression can exacerbate inflammation in susceptible patients and even spread to other structures such as joints, bone structures. Thus, the expression of microbiota-dependent miRNAs may become a therapeutic target with a role in maintaining intestinal homeostasis (Runtsch et al. 2015). – The destruction of the intestinal barrier and translocation of gut bacteria-derived outer membrane vesicles leads to the presence of bacterial DNA in the peripheral blood and synovial fluid of patients with PsA and other inflammatory joint diseases too (Carvalho and Saad 2013). Intestinal bacterial colonization begins at birth by exposing the newborn to the vaginal and/or cutaneous microbial flora and varies significantly depending on the maternal microbiota, the genetics of the host, and the feeding process of the newborn and infant. After the first year (which is a year of permanent changes in the microbiota composition), with the start of diversification, it begins to maintain its

19

Microorganisms in Pathogenesis and Management of Psoriasis Arthritis (PsA)

495

structure, becoming resistant and relatively stable over time throughout life (Yang et al. 2016; Turroni et al. 2020). Multiple factors can be involved in the alteration of this balance, among which the most common are the abuse of antibiotics and diversification with inappropriate foods, both of which cause in children an abnormal development of the innate immune system and implicitly a chronic inflammatory status. Changes in the microbiota also occur in the context of aging associated with various factors: diet, stress, medications, and recurrent infections. It appears that dysbiosis may stimulate the production of IL-17, a cytokine with a crucial role in the development of autoimmune diseases (Raychaudhuri et al. 2012; Wilkins et al. 2019; OlejniczakStaruch et al. 2021). An autoimmune disease can increase the risk of association with other autoimmune diseases, leading to their overlap such as psoriasis and PsA. This can be explained by dysbiosis by reducing commensal germs: lactobacilli, bifidobacteria, and colonization with pathogens: Salmonella spp., Helicobacter pylori, and Escherichia coli disrupting local homeostasis, causing local and distal inflammation. Intestinal germs can pass into the bloodstream due to the production of inflammatory cytokines in the intestinal mucosa. These bacteria or fungi get from the intestines into the blood; then through the bloodstream, they can be confined to the joints, the favorite area for antigens. Thus, in susceptible individuals, this can lead to the development of a chronic form of arthritis, in this case PsA (Eppinga et al. 2014a, b). The immune system and the microbiota are influenced in a bidirectional manner. In the case of PsA, an increase in activated CD4+ and CD8+ lymphocytes was observed in the peripheral blood and synovial membrane. Intestinal dysbiosis causes CD4+ differentiation into effector or regulatory T cells of major importance in maintaining the balance of immunity. The imbalance can cause chronic inflammation in the joints, gut, or skin. Regarding psoriatic arthritis, abundant expression of the Th17 subset that produces cytokines such as IL-17F, IL-17A, TNF, IL-21, and IL-22 has been observed (Fig. 19.1). It is an important therapeutic target and the

Fig. 19.1 Interrelation between gut dysbiosis: immune system and joint inflammation in patients with PsA (Dobrică Elena-Codruța)

496

D. Elena-Codruța et al.

main inducer of inflammation in psoriasis, able to regulate osteoclastogenesis in psoriatic arthritis and affect several organs, causing systemic manifestations. Studies show the association between intestinal inflammation and joint inflammation in spondyloarthropathies, also shown by the fact that patients with spondyloarthropathy more often associate inflammatory bowel diseases, such as Crohn’s disease or ulcerative colitis. Psoriatic arthritis is associated with subclinical intestinal inflammation, with an increased risk of developing Crohn’s disease and subsequent histological changes. The human microbiome has been intensively studied, but lately the attention is also directed to the human fungal and yeast microbial community at the skin, genital, and gastrointestinal level, both commensal and pathological. Immune system alteration, genetic predisposition, and microbial dysbiosis can cause fungal infections. The skin and mucous membranes are protected from the action of fungi by the expression of antimicrobial peptides, the action of complement, and the secretion of antibodies against fungi (Iliev and Underhill 2013). An important role in the antifungal response is attributed to Th17 cells, so that IL-17 defects are strongly correlated with severe forms of inflammatory bowel disease and candidiasis superinfections. Intestinal diseases can compromise the host’s ability to control the intestinal mycobiome, resulting in changes in its composition (Puel et al. 2011). It should be mentioned that there is an interaction between mycobiome and microbiome, the strongest example being the promotion of fungal growth after prolonged antibiotic treatments, so the microbiome can be considered a barrier against fungal pathogens. However, this relationship is bidirectional; in turn commensal fungi protect against pathogenic bacteria through direct competition with intestinal pathogens, interaction with the intestinal epithelium, and the host immune system (Iliev et al. 2012). For example, strains of S. cerevisiae boulardii have been used to treat Clostridium difficile-induced diarrhea (Eppinga et al. 2014a, b). Alteration of the mycobiome can be involved in the aggravation of psoriasis and psoriatic arthritis by the same mechanism dependent on Th17 lymphocytes, the overexpression of those lymphocytes subtype being some of the characteristics of the immune response to the presence of commensal fungi (Hurabielle et al. 2020).

19.5

Dietary Changes and PsA and the Role of Probiotic and Antibiotic in PsA

The treatment of PsA is complex, requiring both dietary measures and drug treatment that combine several therapeutic agents. As it is known, eating habits significantly influence the state of health, and diet is a modifiable factor, directly involved in the optimal functioning of the immune system. There are clinical studies that show that intermittent fasting (Ramadan fasting) can improve the clinical manifestations of PsA by improving activity scores, dactylitis, and enthesitis through its modulation of the immune system. Intermittent fasting has been shown to reduce proinflammatory cytokines and Th17 cell activity and increase regulatory T cells, and this may have implications for the management of patients with PsA (Adawi et al. 2019). On the

19

Microorganisms in Pathogenesis and Management of Psoriasis Arthritis (PsA)

497

other hand, the Mediterranean diet which consists of high consumption of fruits, vegetables, fish, and cereals and is rich in antioxidants and anti-inflammatory nutrients seems to have multiple benefits on morbidity and mortality (Sofi et al. 2014). The Mediterranean diet can influence the intestinal microbiota with the improvement of the inflammatory response, but it can have anti-inflammatory effects in antioxidants, resveratrol, oleic acid, monounsaturated fatty acids, and polyphenol extract with beneficial effects on inflammatory joint diseases (Caso et al. 2020). Enteral dysbiosis can be regulated by dietary measures or the ingestion of probiotic strains. Studies show that taking probiotics like Bifidobacterium or Lactobacillus can significantly improve psoriasis skin lesions, so many studies are being done to see their effectiveness in controlling the disease in PsA (Navarro-López et al. 2019). Studies have shown the paradoxical effect of anti-TNF therapy in the management of psoriasis. Thus, it represents a line of treatment, but through incompletely studied mechanisms, probably through the modulation of the microbiota, with subsequent immunological changes, it can induce psoriatic lesions (Niess and Danese 2014). This paradox is also found in the case of antibiotic therapy: pathogenic infections are the basis of dysbiosis involved in psoriatic arthritis; however, the damage to the intestinal microbiota following antibiotic therapy aggravates arthritis by inducing IL-17A. This would be explained by the “hygiene hypothesis” that underlies several autoimmune diseases: the unjustified use of antibiotic therapy causes changes in the intestinal microbiota with the promotion of fungal colonization. This would justify the use of antifungals as a therapeutic weapon in PsA management (Eppinga et al. 2014a, b).

19.6

Other Microorganisms Involved in Pathophysiology of PsA

Although in the last years the role of the microbiota in the pathophysiology of many inflammatory diseases has been intensively studied, multiple scientific studies highlight possible correlations between infections with pathogenic microorganisms (bacteria, viruses, fungi) and the onset of inflammatory diseases such as PsA (Punzi et al. 2000).

19.6.1 Streptococcal Infections and PsA This idea has been approached since the 1950s during the first cases of onset or exacerbation of psoriasis at a short distance from a beta-hemolytic streptococcal infection. In the following years, numerous mechanisms have been proposed to explain the association between guttate psoriasis and beta-hemolytic streptococcal infection, the best-known mechanism being molecular mimicry between streptococcal M6 protein and skin keratin I (K14) (McFadden et al. 1991; Villeda-Gabriel et al. 1998; Valdimarsson et al. 2009; Thorleifsdottir et al. 2012). This mimicry, along with abnormal immune phenomena tonsils, responsible for inducing the CLA (cutaneous lymphocyte-associated antigen) molecule on the surface of

498

D. Elena-Codruța et al.

T lymphocytes, causes skin infiltration with oligoclonal T lymphocytes, responsible for recognizing self-skin structures and generating inflammation (Leung et al. 1995; Sigurdardottir et al. 2013a, b). This phenomenon leads to the generation of skin-homing T lymphocytes and has been the most important mechanism in the last years by which streptococcal infections exacerbate or initiate guttate psoriasis (Sigurdardottir et al. 2013a, b). Although the idea of the involvement of microorganisms in the pathophysiology of psoriasis appeared in the 1950s, it was not until 1982 that the first articles on the role of streptococcal infections in the pathophysiology of PsA appeared. Vasey et al. had suggested a higher titer of antistreptococcal endotoxin antideoxyribonuclease B antibodies in those with PsA than control groups (Vasey et al. 1982). Moreover, an association between an excess of HLA-A * 0207 heterozygotes and the occurrence of PsA is demonstrated, several mechanisms being proposed to explain it: low antistreptococcal defense by the defective presentation of streptococcal M antigens, impaired T cytotoxic-dependent immune response, as well as a similarity between the HLA-A2 amino acid sequences and the M proteins of Streptococcus pyogenes (Dong et al. 1995; Muto et al. 1996). Also, like guttate psoriasis, in PsA, the existence of molecular mimicry between synovial and cartilaginous structures and streptococcal M5 protein has been demonstrated, which explains the preferential targeting of these structures by T lymphocytes (Baird et al. 1991).

19.6.2 Staphylococcal Infections and PsA Regarding staphylococcal infections, although less studied so far, they also seem to play a role in the pathophysiology of PsA and in the occurrence of arthralgias and cutaneous psoriasiform manifestations (Thrastardottir and Love 2018; Rademaker et al. 2019). Thus, some studies show an association between the presence of staphylococcal superantigens and APs, these patients having not only an increased titer of antistaphylococcal antibodies but also a modified activity of mononuclear cells in peripheral blood. Thus, patients with lumbago-type pain triggered after staphylococcal infections show after laboratory tests an exaggerated response of mononuclear cells. At the same time, an increased synovial expression of T V beta 10,10,15,19 lymphocyte receptors was found in these patients (Yamamoto et al. 1999). Another important staphylococcal structure with a role in triggering PsA appears to be the peptidoglycan in the bacterial membrane wall, these patients having elevated levels of anti-peptidoglycan antibodies according to data published by Rahman et al. These antibodies appear to play a role in the pathophysiology of all seronegative arthritis, with significant differences in titer in these patients from the healthy control group or from those with seropositive or mechanical arthritis (Rahman et al. 1990).

19

Microorganisms in Pathogenesis and Management of Psoriasis Arthritis (PsA)

499

19.6.3 Chlamydia Infections and APs It is well known that infections with Chlamydia spp., a strictly pathogenic intracellular parasite, are responsible for the appearance of numerous inflammatory pathologies, including seronegative arthritis. Stinco et al. demonstrated in study on a group of 64 psoriasis patients (12 with APs) the presence of subclinical infection with Chlamydia psittaci in a significantly higher proportion in the study group compared to the healthy population ( p < 0.0001) (Stinco et al. 2012). Fabris et al. demonstrated significant differences in the quantity of DNA of Chlamydia psittaci from mononuclear cells in patients with seronegative arthritis compared to the healthy population or those with seropositive arthritis ( p ¼ 0.0078) (Fabris et al. 2011). Moreover, a prevalence of infection with this intracellular pathogen was found in patients with PsA of approximately 16.7% (Fabris et al. 2011). Another species of Chlamydia mentioned to be associated with psoriatic arthritis is Chlamydia trachomatis, responsible for many sexually transmitted diseases, including urethritis, salpingitis, etc. A study conducted by Lapadula et al. show an increased titer of immunoglobulin A antibodies against Chlamydia trachomatis in patients with PsA (Lapadula et al. 1992). In addition to streptococcal, staphylococcal, and Chlamydia infections, the hypothesis of involvement of other microorganisms in the onset or exacerbation of PsA has been raised, without being able to establish clear pathophysiological mechanisms. Thus, numerous cases of PsA triggered or exacerbated by various infections have been reported in the literature in the last decades, but the small number of presented patients and the absence of randomized studies have not made it possible to establish statistically significant correlations or find pathophysiological mechanisms to explain this association. Among the highlighted microorganisms are Helicobacter pylori, Yersinia enterocolitica, Campylobacter fetus, Campylobacter jejunum, Yersinia pseudotuberculosis, Klebsiella planticola, Pseudomonas putida, Salmonella typhimurium, and Porphyromonas gingivalis (Lapadula et al. 1992; Punzi et al. 2000; Gérard et al. 2001; Patrikiou et al. 2018; Rademaker et al. 2019).

19.6.4 Human Immunodeficiency Virus Infection and PsA In the last decade, multiple studies involving patients from underdeveloped countries have been conducted to investigate the role of HIV infection (epidemic in South African countries) in the occurrence and evolution of inflammatory diseases. Among them, psoriasis and inflammatory arthropathy (including PsA) appear to have an onset and evolution closely related to the evolution of HIV infection (Morar et al. 2010). Thus, since the 1990s, Arnett et al. pointed out that exacerbated psoriasis or aggravated PsA may be indicators of infection with this virus in the categories of people considered at risk (Arnett et al. 1991). Moreover, Park et al. present psoriasis as one of the ways of clinical onset of this infection (Park et al. 2018). Although with a prevalence similar to that of the general population, PsA in HIV-positive patients is more severe, with generally asymmetric, oligoarticular

500

D. Elena-Codruța et al.

distribution, with damage in the large joints, with rapid evolution to erosive, mutilating forms; it may occur even at the onset of the cutaneous lesions. The pathophysiological mechanism considered to be involved is a direct one, the virus acting through the proinflammatory effect directly on the synovial tissue, high concentrations of p24 antigen, and viral DNA being found in the synovial fluid (Adizie et al. 2016; Park et al. 2018). Another indirect mechanism has been proposed, which highlights the role of T lymphocytes in the pathophysiology of both diseases, HIV infection causing a change in the ratio of CD 4+ lymphocytes/CD 8+ lymphocytes, in the sense of decreasing this ratio, and implicitly increasing IL-17 level (through the secretion of this interleukin by the lymphocytes CD 8+) with an essential role in aggravating psoriasis (Morar et al. 2010; Thrastardottir and Love 2018).

19.6.5 SARS-CoV-2 Infection and PsA The SARS-CoV-2 pandemic which started in 2019 is currently the biggest problem worldwide, being responsible so far for over four million deaths (COVID 2021). The pathophysiology of viral infection is still incompletely known, but one of the main responsible mechanisms is considered to be the release of large amounts of proinflammatory cytokines due to the destruction of cells by the virus (Song et al. 2020). The body’s response to infection depends on many risk factors, including obesity, diabetes, cardiovascular disease, smoking, and most recently, the composition of the microbiota (De Lusignan et al. 2020; Yeoh et al. 2021). Thus, it was observed that patients infected with the SARS-CoV-2 virus have a modified composition of the intestinal microbiota that does not correct even after treating the infection (Wu et al. 2021). The remote complications of this infection are numerous, from those in the otorhinolaryngology and respiratory spheres to the neurological, digestive, cutaneous, and even osteoarticular (Kordzadeh-Kermani et al. 2020). Thus, in the context of inflammation caused by infection, in the last year, numerous cases of reactive arthritis have been reported, including psoriatic arthritis. They appeared at variable distances from the onset of the specific symptoms of the infection, in young people, with a personal or family history of inflammatory diseases or psoriasis, accompanied or not by psoriasis cutaneous manifestations (Novelli et al. 2021; Mease et al. 2021; Zhou et al. 2021). The treatment of patients with psoriatic arthritis should be reconsidered given the tendency of self-isolation and decreased presentation to the doctor in the context of the pandemic. The treatment must be individualized, and the data from the literature are contradictory: it is recommended, as in any infection, the transient cessation of biological disease-modifying antirheumatic drug (DMARD) therapies with subsequent resumption depending on the severity of the disease. However, in the context of the cytokine storm, immunosuppressants have a beneficial effect in limiting inflammation that occurs as an exaggerated response to viral infection.

19

Microorganisms in Pathogenesis and Management of Psoriasis Arthritis (PsA)

501

Thus, studies show that patients with autoimmune diseases are vulnerable to viral infection, but they are additionally protected from cytokine storms due to the medication used to control the disease (Favalli et al. 2020; Keskin et al. 2021).

19.7

Oxidative Stress and Psoriasis Arthritis

Reactive oxygen species (ROS) are entities generated by mitochondrial cellular respiration processes and by enzymatic activity. Initially considered by-products with a toxic role at the cellular level, their role in intercellular signaling, in modulating the bioavailability of nutrient oxide, and in cell differentiation is currently being intensively studied (Auten and Davis 2009). Those effects are dependent on the quantity of ROS. In large quantities, they can alter cell structures through the effect on proteins, carbohydrates, lipids, and cellular nuclear material that leads to decreased enzymatic activity, increased inflammation, apoptosis, and decreased cell proliferation. Maintaining an optimal level of ROS is a continuous process that involves a permanent balance between oxidant and antioxidant activity, tilting this balance in the direction of increasing ROS leading to oxidative stress. The tilt of the balance in this sense can be achieved either by excessive production of ROS (by exposure to pollutants, tobacco, alcohol, infections, inflammation, etc.) or by decreasing the capacity of antioxidant systems (Das and Roychoudhury 2014; Pizzino et al. 2017; Epingeac et al. 2020). In the last years, the role of ROS has been proposed in the occurrence of inflammatory diseases, including psoriasis and psoriatic arthritis. On the other hand, a chronic inflammatory status is associated with an increased ROS level. This theory is supported not only by the large number of ROS generated in the skin by increased exposure to environmental factors and by the involvement in psoriasis of many enzymatic pathways dependent on the level of oxidative stress, such as NFk-beta, JAK, and MAP kinase pathway, but also by the positive response of psoriasis manifestations to antioxidant treatment (Zhou et al. 2009; Wagener et al. 2013). The same phenomenon was observed in psoriatic arthritis, Coaccioli et al. highlighting low levels of total antioxidant capacity and high levels of serum hydroperoxide in these patients ( p ¼ 0.005) (Coaccioli et al. 2009). Moreover, the role of bacterial, viral, and parasitic infections on the oxidative balance in the body is already known, as they generate significant amounts of ROS, some articles even emphasizing the role of antioxidant therapy in the treatment of infection-induced arthritis (Ivanov et al. 2017; Pourrajab et al. 2020).

19.8

Conclusions

Psoriatic arthritis is one of the complications of psoriasis associated with a significant decrease in quality of life that can progress to severe functional impotence. Therapeutic management is challenging, with joint damage often difficult to respond to treatment, requiring higher doses and a long period of treatment until the first

502

D. Elena-Codruța et al.

results appear, which may be associated with decreased compliance and adherence to treatment. The involvement of microorganisms, both commensal and pathogenic, in the pathophysiology of psoriatic arthritis is an incompletely studied pathway, but which in the last decades has been a point of interest for many researchers. More and more microorganisms appear to be involved in the onset or exacerbation of psoriasis arthritis and other inflammatory diseases. Thus, dysbiosis and oxidative stress seem to play a complex role in modulating T lymphocyte-dependent immunity, a complete understanding of the responsible mechanisms being the starting point in the personalized treatment of psoriatic arthritis.

References Adawi M et al (2019) The impact of intermittent fasting (Ramadan fasting) on psoriatic arthritis disease activity, enthesitis, and dactylitis: a multicentre study. Nutrients 11(3):601 Adizie T et al (2016) Inflammatory arthritis in HIV positive patients: a practical guide. BMC Infect Dis 16(1):100 AlQassimi S et al (2020) Global burden of psoriasis—comparison of regional and global epidemiology, 1990 to 2017: global burden of psoriasis. Int J Dermatol 59(5):566–571 Antonelli A et al (2006) High prevalence of thyroid autoimmunity and hypothyroidism in patients with psoriatic arthritis. J Rheumatol 33(10):2026–2028 Arnett FC, Reveille JD, Duvic M (1991) Psoriasis and psoriatic arthritis associated with human immunodeficiency virus infection. Rheum Dis Clin N Am 17(1):59–78 Auten RL, Davis JM (2009) Oxygen toxicity and reactive oxygen species: the devil is in the details. Pediatr Res 66(2):121–127 Bagel J, Schwartzman S (2018) Enthesitis and dactylitis in psoriatic disease: a guide for dermatologists. Am J Clin Dermatol 19(6):839–852 Baird RW et al (1991) Epitopes of group A streptococcal M protein shared with antigens of articular cartilage and synovium. J Immunol 146(9):3132–3137 Benedek TG (2013) Psoriasis and psoriatic arthropathy, historical aspects: part I. J Clin Rheumatol 19(4):193–198 Carvalho AL, Hedrich CM (2021) The molecular pathophysiology of psoriatic arthritis-the complex interplay between genetic predisposition, epigenetics factors, and the microbiome. Front Mol Biosci 8:662047 Carvalho BM, Saad MJA (2013) Influence of gut microbiota on subclinical inflammation and insulin resistance. Mediat Inflamm 2013:986734 Caso F et al (2020) Mediterranean diet and psoriatic arthritis activity: a multicenter cross-sectional study. Rheumatol Int 40(6):951–958 Cassell SE et al (2007) The modified nail psoriasis severity index: validation of an instrument to assess psoriatic nail involvement in patients with psoriatic arthritis. J Rheumatol 34(1):123–129 Chandran V (2019) Psoriatic spondylitis or ankylosing spondylitis with psoriasis: same or different? Curr Opin Rheumatol 31(4):329–334 Chen L et al (2020) Skin and gut microbiome in psoriasis: gaining insight into the pathophysiology of it and finding novel therapeutic strategies. Front Microbiol 11:589726 Coaccioli S et al (2009) Evaluation of oxidative stress in rheumatoid and psoriatic arthritis and psoriasis. Clin Ter 160(6):467–472 COVID (2021) Covid live update: 221,443,644 cases and 4,580,020 deaths from the Coronavirus worldometer Worldometers.info. https://www.worldometers.info/coronavirus/ (accessed 5 September 2021)

19

Microorganisms in Pathogenesis and Management of Psoriasis Arthritis (PsA)

503

Das K, Roychoudhury A (2014) Reactive oxygen species (ROS) and response of antioxidants as ROS-scavengers during environmental stress in plants. Front Environ Sci 2. https://doi.org/10. 3389/fenvs.2014.00053 de Lusignan S et al (2020) Risk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study. Lancet Infect Dis 20(9):1034–1042 Dogra S, Mahajan R (2016) Psoriasis: epidemiology, clinical features, co-morbidities, and clinical scoring. Indian Dermatol Online J 7(6):471–480 Dong RP et al (1995) Characterization of T cell epitopes restricted by HLA-DP9 in streptococcal M12 protein. J Immunol 154(9):4536–4545 Dubash S et al (2020) Sat0413 dactylitis is associated with disease severity and ultrasound defined erosive damage in very early, dmard naïve psoriatic arthritis. Ann Rheum Dis 79(Suppl 1): 1159–1160 Eder L, Chandran V, Gladman DD (2009) From ankylosis to pencil-in-cup deformity in psoriatic arthritis: a case report. Clin Exp Rheumatol 27(4):661–663 Epingeac ME et al (2020) Crosstalk between oxidative stress and inflammation in besity. Rev Chim 71(1):228–232 Eppinga H, Thio HB et al (2014a) The gut microbiome dysbiosis and its potential role in psoriatic arthritis. Int J Clin Rheumatol 9(6):559–565 Eppinga H, Konstantinov SR et al (2014b) The microbiome and psoriatic arthritis. Curr Rheumatol Rep 16(3):407 Fabris M et al (2011) Chlamydophila psittaci subclinical infection in chronic polyarthritis. Clin Exp Rheumatol 29(6):977–982 Favalli EG et al (2020) COVID-19 infection and rheumatoid arthritis: faraway, so close! Autoimmun Rev 19(5):102523 Gérard HC et al (2001) Chromosomal DNA from a variety of bacterial species is present in synovial tissue from patients with various forms of arthritis. Arthritis Rheum 44(7):1689–1697 Gladman DD et al (2005) Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 64 Suppl 2(suppl_2):ii14–ii17 Hurabielle C et al (2020) Immunity to commensal skin fungi promotes psoriasiform skin inflammation. Proc Natl Acad Sci U S A 117(28):16465–16474 Iliev ID, Underhill DM (2013) Striking a balance: fungal commensalism versus pathogenesis. Curr Opin Microbiol 16(3):366–373 Iliev ID et al (2012) Interactions between commensal fungi and the C-type lectin receptor dectin-1 influence colitis. Science (New York, NY) 336(6086):1314–1317 Ivanov AV, Bartosch B, Isaguliants MG (2017) Oxidative stress in infection and consequent disease. Oxidative Med Cell Longev 2017:3496043 Kaeley GS et al (2018) Dactylitis: a hallmark of psoriatic arthritis. Semin Arthritis Rheum 48(2): 263–273 Kerschbaumer A et al (2016) An overview of psoriatic arthritis - epidemiology, clinical features, pathophysiology and novel treatment targets. Wien Klin Wochenschr 128(21–22):791–795 Keskin Y, Koz G, Nas K (2021) What has changed in the treatment of psoriatic arthritis after COVID-19? Eurasian J Med 53(2):132–136 Khan I et al (2019) Alteration of gut microbiota in inflammatory bowel disease (IBD): cause or consequence? IBD treatment targeting the gut microbiome. Pathogens 8(3):126 Kordzadeh-Kermani E, Khalili H, Karimzadeh I (2020) Pathogenesis, clinical manifestations and complications of coronavirus disease 2019 (COVID-19). Future Microbiol 15(13):1287–1305 Langley RGB, Krueger GG, Griffiths CEM (2005) Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis 64 Suppl 2(suppl_2):ii18–ii23; discussion ii24-5 Lapadula G et al (1992) Anti-enterobacteria antibodies in psoriatic arthritis. Clin Exp Rheumatol 10(5):461–466

504

D. Elena-Codruța et al.

Leung DY et al (1995) Bacterial superantigens induce T cell expression of the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen, via stimulation of interleukin 12 production. J Exp Med 181(2):747–753 McFadden J, Valdimarsson H, Fry L (1991) Cross-reactivity between streptococcal M surface antigen and human skin. Br J Dermatol 125(5):443–447 Mease PJ et al (2014) Comparative performance of psoriatic arthritis screening tools in patients with psoriasis in European/North American dermatology clinics. J Am Acad Dermatol 71(4): 649–655 Mease PJ et al (2021) Psoriasis and psoriatic arthritis in the context of the COVID-19 pandemic: a plenary session from the GRAPPA 2020 annual meeting. J Rheumatol 2021(Supplement): jrheum.201671 Morar N et al (2010) HIV-associated psoriasis: pathogenesis, clinical features, and management. Lancet Infect Dis 10(7):470–478 Muto M et al (1996) Significance of antibodies to streptococcal M protein in psoriatic arthritis and their association with HLA-A*0207. Tissue Antigens 48(6):645–650 Nakata K et al (2017) Commensal microbiota-induced microRNA modulates intestinal epithelial permeability through the small GTPase ARF4. J Biol Chem 292(37):15426–15433 Nash P (2009) Assessment and treatment of psoriatic spondylitis. Curr Rheumatol Rep 11(4): 278–283 Navarro-López V et al (2019) Efficacy and safety of oral administration of a mixture of probiotic strains in patients with psoriasis: a randomized controlled clinical trial. Acta Derm Venereol 99(12):1078–1084 Nestle FO, Kaplan DH, Barker J (2009) Psoriasis. N Engl J Med 361(5):496–509 Niess JH, Danese S (2014) Anti-TNF and skin inflammation in IBD: a new paradox in gastroenterology? Gut 63(4):533–535 Novelli L et al (2021) A case of psoriatic arthritis triggered by SARS-CoV-2 infection. Rheumatology (Oxford, England) 60(1):e21–e23 Ogdie A, Weiss P (2015) The epidemiology of psoriatic arthritis. Rheum Dis Clin N Am 41(4): 545–568 Olejniczak-Staruch I et al (2021) Alterations of the skin and gut microbiome in psoriasis and psoriatic arthritis. Int J Mol Sci 22(8):3998 Parisi R et al (2020) National, regional, and worldwide epidemiology of psoriasis: systematic analysis and modelling study. BMJ (Clinical research ed) 369:m1590 Park M et al (2018) A case of ostraceous psoriasis with psoriatic arthritis in an AIDS patient. Indian J Dermatol 63(6):512–514 Parker A et al (2018) Host-microbe interaction in the gastrointestinal tract: host-microbe interaction in the GI tract. Environ Microbiol 20(7):2337–2353 Patrikiou E et al (2018) AB0932 Helicobacter pylori antigen specific antibodies in psoriatic arthritis. In: Psoriatic arthritis. BMJ Publishing Group Ltd and European League Against Rheumatism, London, pp 1591–1591 Picchianti-Diamanti A, Rosado MM, D’Amelio R (2017) Infectious agents and inflammation: the role of microbiota in autoimmune arthritis. Front Microbiol 8:2696 Pizzino G et al (2017) Oxidative stress: harms and benefits for human health. Oxidative Med Cell Longev 2017:1–13 Pourrajab B et al (2020) The effects of probiotic/synbiotic supplementation compared to placebo on biomarkers of oxidative stress in adults: a systematic review and meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr 62(2):490–507 Proctor LM (2011) The human microbiome project in 2011 and beyond. Cell Host Microbe 10(4): 287–291 PubMed (2021) https://pubmed.ncbi.nlm.nih.gov/ Puel A et al (2011) Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin17 immunity. Science (New York, NY) 332(6025):65–68

19

Microorganisms in Pathogenesis and Management of Psoriasis Arthritis (PsA)

505

Punzi L et al (2000) Psoriatic arthritis exacerbated by salmonella infection. Clin Rheumatol 19(2): 167–168 Rademaker M et al (2019) Psoriasis and infection. A clinical practice narrative. Australas J Dermatol 60(2):91–98 Rahman MU et al (1990) High levels of antipeptidoglycan antibodies in psoriatic and other seronegative arthritides. J Rheumatol 17(5):621–625 Raychaudhuri SP, Raychaudhuri SK, Genovese MC (2012) IL-17 receptor and its functional significance in psoriatic arthritis. Mol Cell Biochem 359(1–2):419–429 Runtsch MC et al (2015) MicroRNA-146a constrains multiple parameters of intestinal immunity and increases susceptibility to DSS colitis. Oncotarget 6(30):28556–28572 Russell B (1950) Lepra, psoriasis, or the Willan-Plumbe syndrome? Br J Dermatol Syph 62(9): 358–361 Sakkas LI et al (2013) Enthesitis in psoriatic arthritis. Semin Arthritis Rheum 43(3):325–334 Salas-Cuestas F et al (2017) Higher levels of secretory IgA are associated with low disease activity index in patients with reactive arthritis and undifferentiated spondyloarthritis. Front Immunol 8: 476 Sigurdardottir SL et al (2013a) The association of sore throat and psoriasis might be explained by histologically distinctive tonsils and increased expression of skin-homing molecules by tonsil T cells: the association of psoriasis and sore throat. Clin Exp Immunol 174(1):139–151 Sigurdardottir SL et al (2013b) The role of the palatine tonsils in the pathogenesis and treatment of psoriasis: the role of the palatine tonsils in psoriasis. Br J Dermatol 168(2):237–242 Sofi F et al (2014) Mediterranean diet and health status: an updated meta-analysis and a proposal for a literature-based adherence score. Public Health Nutr 17(12):2769–2782 Song P et al (2020) Cytokine storm induced by SARS-CoV-2. Clin Chim Acta 509:280–287 Stinco G et al (2012) Detection of DNA of Chlamydophila psittaci in subjects with psoriasis: a casual or a causal link?: Chlamydophila psittaci and psoriasis. Br J Dermatol 167(4):926–928 Thorleifsdottir RH et al (2012) Improvement of psoriasis after tonsillectomy is associated with a decrease in the frequency of circulating T cells that recognize streptococcal determinants and homologous skin determinants. J Immunol 188(10):5160–5165 Thrastardottir T, Love TJ (2018) Infections and the risk of psoriatic arthritis among psoriasis patients: a systematic review. Rheumatol Int 38(8):1385–1397 Tiwari V, Brent LH (2021) Psoriatic arthritis. In: StatPearls. StatPearls Publishing, Treasure Island (FL) Turroni F et al (2020) The infant gut microbiome as a microbial organ influencing host well-being. Ital J Pediatr 46(1):16 Valdimarsson H et al (2009) Psoriasis--as an autoimmune disease caused by molecular mimicry. Trends Immunol 30(10):494–501 Vasey FB, Deitz C, Fenske NA, Germain BF, Espinoza LR (1982) Possible involvement of group a streptococci in the pathogenesis of psoriatic arthritis. J Rheumatol 9(5):719–722 Villeda-Gabriel G et al (1998) Recognition of Streptococcus pyogenes and skin autoantigens in guttate psoriasis. Arch Med Res 29(2):143–148 Wagener FADTG, Carels CE, Lundvig DMS (2013) Targeting the redox balance in inflammatory skin conditions. Int J Mol Sci 14(5):9126–9167 Wilkins LJ, Monga M, Miller AW (2019) Defining dysbiosis for a cluster of chronic diseases. Sci Rep 9(1):12918 Wu W-JH, Zegarra-Ruiz DF, Diehl GE (2020) Intestinal microbes in autoimmune and inflammatory disease. Front Immunol 11:597966 Wu Y et al (2021) Altered oral and gut microbiota and its association with SARS-CoV-2 viral load in COVID-19 patients during hospitalization. NPJ Biofilms Microbiomes 7(1):61 Yamamoto T, Katayama I, Nishioka K (1999) Peripheral blood mononuclear cell proliferative response against staphylococcal superantigens in patients with psoriasis arthropathy. Eur J Dermatol 9(1):17–21

506

D. Elena-Codruța et al.

Yang I et al (2016) The infant microbiome: implications for infant health and neurocognitive development. Nurs Res 65(1):76–88 Yeoh YK et al (2021) Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut 70(4):698–706 Zhou Q, Mrowietz U, Rostami-Yazdi M (2009) Oxidative stress in the pathogenesis of psoriasis. Free Radic Biol Med 47(7):891–905 Zhou Q et al (2021) SARS-CoV-2 infection induces psoriatic arthritis flares and enthesis resident plasmacytoid dendritic cell Type-1 interferon inhibition by JAK antagonism offer novel spondyloarthritis pathogenesis insights. Front Immunol 12:635018 Zorba M et al (2020) The possible role of oral microbiome in autoimmunity. Int J Women’s Dermatol 6(5):357–364

Microorganisms in Pathogenesis and Management of Systemic Lupus Erythematosus (SLE)

20

Ping Yi, Ming Zhao, and Qianjin Lu

Abstract

Systemic lupus erythematosus (SLE) is a type of multisystem involved autoimmune inflammatory disease with high heterogenous clinical manifestation and various etiologies, featuring overexpressed pathogenic autoantibodies and overactivation of autoreactive immune cells. Genetic, environmental, and hormonal factors all contribute to the pathogenesis of SLE. Over decades, alteration of the diversity and composition of microbiota, as well as microbiota-derived metabolites, has been found in lupus-like spontaneous and/or inducible mouse models and SLE patients. Among them, gut microbial dysbiosis, generally a lower Firmicutes/Bacteroidetes ratio, has been reported to correlate with autoantibody production and activation of immune cells. Accumulated studies have focused on the interaction of the host and microbiota and the mechanisms of microbiota-triggered autoimmunity. However, the underlying mechanisms of microbiota in the pathogenesis of SLE remain a matter of debate. In this chapter, we elaborated patterns and functions of microbiota in physiological conditions and summarized the association of intestinal, oral, cutaneous, and plasma microbiota with the pathogenesis of SLE, especially intestinal microbiota. Intestinal microbiota plays a crucial role in the occurrence and progression of SLE P. Yi · M. Zhao Department of Dermatology, Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, China Q. Lu (*) Department of Dermatology, Second Xiangya Hospital, Hunan Key Laboratory of Medical Epigenomics, Central South University, Changsha, China Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_20

507

508

P. Yi et al.

through three major mechanisms including leaky gut and gut microbiota translocation, molecular mimicry, and metabolites like short-chain fatty acids (SCFAs) and microbial tryptophan catabolites, suggesting the potential efficacy of intervention of gut microbiota in the management of SLE. Numerous microbiotarelated treatments of SLE covering dietary intervention, probiotics, antibiotics, and drugs, as well as fecal microbiota transplantation (FMT), have been explored and preliminarily applied in the assessment of SLE and intended to repair the aberrant intestinal microbiota environment and reduce the adverse influence caused by gut microbial dysbiosis. Keywords

Microorganisms · Gut microbial dysbiosis · Systemic lupus erythematosus · Pathogenesis · Management

Abbreviations AhR AMP ANA APC ARDs B. fragilis bDMARD Breg COVID-19 CQ CSR DMARDs dsDNA DSS EBNA1 eDNA FMT GALT GC GF HCQ HDAC HU1 IFN IL IMQ LC40

Aryl hydrocarbon receptor Antimicrobial protein Antinuclear antibody Antigen-presenting cell Autoimmune rheumatic diseases Bacteroides fragilis Biological disease-modifying antirheumatic drug Regulatory B cell Coronavirus disease 2019 Chloroquine Class switch recombination Disease-modifying antirheumatic drugs Double-strand DNA Dextran sulfate solution Epstein-Barr virus nuclear antigen-1 Extracellular DNA Fecal microbiota transplantation Gut-associated lymphoid tissue Germinal center Germ-free Hydroxychloroquine Histone deacetylation Histone-like protein 1 Interferon Interleukin Imiquimod Lactobacillus fermentum CECT5716

20

Microorganisms in Pathogenesis and Management of Systemic. . .

lpr LPS MLN MS NAC NLR NOD NSAIDs PAMP PBMC pDC PRR RA RCT rDNA RG RG2 RMDs RS SARS-CoV-2 SCFA SHM sIgA SLE SNF1 TC Tfh Tg TGF-β Th TLR TPC Treg tsDMARD vWFA

20.1

509

Lymphoproliferation Lipopolysaccharide Mesenteric lymph node Multiple sclerosis N-acetylcysteine Nucleotide-binding and oligomerization domain-like receptor Nonobese diabetic Nonsteroidal anti-inflammatory drugs Pathogen-associated molecular pattern Peripheral blood mononuclear cell Plasmacytoid dendritic cell Pattern recognition receptor Rheumatoid arthritis Randomized controlled trial Ribosomal DNA Ruminococcus gnavus RG strain CC55_001C Rheumatic and musculoskeletal diseases Resistant starch Severe acute respiratory syndrome coronavirus 2 Short-chain fatty acid Somatic hypermutation Secretory immunoglobulin A Systemic lupus erythematosus (SWR  NZB) F1 B6.Sle1.Sle2.Sle3 triple congenic Follicular helper T Transgenic Transforming growth factor-β T helper Toll-like receptor A conjugate of tuftsin and PC Regulatory T cell Targeted synthetic disease-modifying antirheumatic drug von Willebrand factor type A domain protein

Introduction

Three basic life forms, archaea, bacteria and eukaryota, exist on earth, which cover trillions of cell-free, unicellular, or multicellular creatures. Microbes are defined as organisms existing in nature that are sightless with naked eye and visible under optical or electron microscope, comprising bacteria, virus, fungus, mycoplasma, etc.

510

P. Yi et al.

They live widely in human habitat and body. According to the sequencing data, the genome of microbiota in human body is 150 times greater than that from human cells (Qin et al. 2010). Human hosts live with microorganisms in a perfect symbiosis pattern, including gut, oral, cutaneous, vagina, and plasma microbiota, which are easily influenced by environmental factors such as diet, medicine, and environmental microbiota. The host provides nutrients for symbiotic microbiota, and the latter produces metabolites such as short-chain fatty acids (SCFAs) and vitamins that are of benefit to the host. Among healthy individuals, human microbiome in each habitat presents highly variable diversity and abundance. In this case, the host and its symbiotic microbiota form a “holobiont.” Turbulence of this “holobiont” may contribute to the progression of multiple diseases. In particular, the gut microbiota has become a hotspot over the past decades. Projects such as the American Gut Project, the Canadian Microbiome Initiative, the Human Metagenome Consortium Japan, and the International Human Microbiome Consortia have been conducted to explore the importance of gut microbiota in human health and disease. Gut microorganism is known to be the largest commensal in human body and consists of bacteria and other key microorganisms, such as archaea, viruses, phages, yeast, and fungi (Cani 2018). As it was calculated, the human gut contained more than 10 trillion diverse commensals in its huge mucosa surface (200–300 m2) (Adak and Khan 2019). Trillions of bacteria in the gut microbiome have complex and extensive effects on many aspects including food metabolism, nutrient synthesis, pathogen defense, and maintenance of the integrity of the mucosal barrier and participate in maintaining the steady state of human health (Selber-Hnatiw et al. 2017). In addition, they play crucial roles in the establishment of innate and adaptive immunity of the host. The role of microbiota in health and specific metabolic and immunological disorders and new microbiota-related therapeutics has been intensively explored due to the advancement of genetic and the metagenomic tools in the last 18 years. SLE is a multisystem involved and women predisposed prototypical autoimmune inflammatory disease, especially in African American women and other ethnic minority women. SLE is characterized with heterogenetic clinical phenotypes, accompanied by potential lethal renal and cardiovascular complications and infection, contributing to the difficulties of individualized treatment and outcome optimization (Kiriakidou and Ching 2020). The reported incidence of SLE was up to 23.2/ 100,000 person-years in North America (Rees et al. 2017). Immunological abnormality comprises overactivated T- and B-cell responses, the failure of immune tolerance against autoantigens, altered cytokine patterns, and the defect of clearance of apoptotic cells, leading to multiorgan damage involving the skin, joint, blood, kidney, etc. (Tsokos 2020; Tsokos et al. 2016). The pathogenesis of SLE remains unclear yet. The higher incidence of SLE in African Americans than West Africans with similar genetic background supports the association of environmental factors and the pathogenesis of SLE. Up to now, the interaction of genetic, epigenetic, environmental, and hormonal factors has been demonstrated to participate in the occurrence and development of SLE. A variety of medications including glucocorticoids, antimalarial agents, immunosuppressive agents, nonsteroidal

20

Microorganisms in Pathogenesis and Management of Systemic. . .

511

anti-inflammatory drugs, and B cell-targeting biological agents have been already applied in the treatment of SLE and have improved the prognosis of most SLE patients. However, the efficacy remains unsatisfactory in some refractory patients, thus appealing more safety and effective therapy for long-term remission. Given the great abundance and pivotal roles of microbiota in human body, it has been extensively studied in physiology and pathology among various autoimmunity diseases, especially the SLE.

20.2

Patterns and Functions of Microbiota in Physiological Conditions

20.2.1 Patterns of Microbiota in Physiological Conditions The microbiota in human body maintains dynamic balance with the change of the inner and external environment. The microbiota diversity and compositions are varied during different life stages. The unborn fetus is not exposed to any microbiota initially, and the born baby starts to contact the external environment and gradually develop a normal ecosystem in microbiota and host. This primary microbiota is influenced by several factors such as the delivery modes (cesarean delivery or vaginal delivery), infant diet, hospitalization, etc. (Biasucci et al. 2008). It has been revealed that babies fed with breast milk tend to have the microbiota predominated by Bifidobacteria, while the babies fed with formula are enriched in Lactobacilli, Escherichia coli, Bacteroides fragilis, and Clostridium difficile (Penders et al. 2006). Similarly, the changes in diet, lifestyle, infection risk, and chronic inflammation contribute to the microbiota alterations in the elder (Ottman et al. 2012). Besides, the process of aging itself also impacts the features of microbiota. The 16SrRNA gene sequencing has revealed the decrease in microbiota diversity and abundance in elders compared to young adults (Mäkivuokko et al. 2010). High abundance of Escherichia coli and Bacteroidetes and a decrease in Firmicutes/Bacteroidetes ratio have been observed in elderly individuals (Mariat et al. 2009). Apart from aging, diet is another element shaping the enterotypes. For instance, diet rich in protein and animal fat induces an increase of Bacteroidetes, while carbohydrate predominated diet is linked to Prevotella enrichment (Wu et al. 2011). Studies also showed that the shift of diet from hunter-gatherer to farming induced differential oral microbiota communities that are associated with disease progression (Adler et al. 2013). Therefore, microbiota alterations are constant throughout lifetime under the influence of multiple factors.

20.2.2 Functions of Microbiota In normal conditions, microbiota colonizing in host habitats maintains the dynamic equilibrium and interacts with host through specific pathways. Functions of microbiota mainly involve in two important aspects of physiological activity in

512

P. Yi et al.

healthy individuals: (1) interfering the metabolisms of host and (2) regulating the immune system. Microbiota involve in multiple metabolic processes in human body, especially in the gastrointestinal tract. A majority of carbohydrates, proteins, and lipids are digested in the gastrointestinal tract (GIT) (Adak and Khan 2019). Particularly, the dietary fibers are indigestible for human themselves due to the lack of the corresponding enzymes (Anderson et al. 2009). However, microbiota possesses effective enzymes for multiple dietary fibers, which enable them to utilize these nourishments and produce some metabolites such as SCFAs that can influence the gut environment of its host. For example, healthy microbiota produces SCFAs and interacts with innate pattern recognition receptors (PRRs) of immune cells to maintain steady barrier function (Wells et al. 2017). The SCFAs can be also absorbed by human gut and provide approximately 10% of caloric sources (Duncan et al. 2007). Moreover, microorganisms interact with host immune system and play a vital role in immune homeostasis. In gut, microbiota can shape the innate immune system relating to multiple immune cells such as the gut-associated lymphoid cells, innate lymphoid cells, and conventional natural killer cells. The formation of gut-associated lymphoid tissues (GALTs) is largely impacted by the gut microbiota (Adachi et al. 1997). Depletion of commensal flora in mice suppresses the generation of Peyer’s patches (Moreau and Corthier 1988), an indispensable component of GALTs. A clinical trial focusing on antibiotics-use-induced changes of innate and adaptive immune responses to influenza vaccination reported that antibiotics-driven gut microbiota depletion impaired antibody response in human subjects with low immunity, revealing the immunomodulatory function of gut microbiome in distinct pathways (Hagan et al. 2019). Innate immune cells in the gastrointestinal tract recognize pathogen-associated molecular patterns (PAMPs) of gut microorganisms with PRRs-toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain-like receptors (NLR) and affect their composition (Cani 2018; O'Neill et al. 2013). Besides, early B-cell development that occurs in the intestine experiences immune tolerance through the similar mechanism in the bone marrow, and the interactions between B cells and intestinal microbiota promote regulatory B-cell (Breg) function and mucosal homeostasis (Zouali 2021). Meanwhile, skin microbiota was demonstrated to regulate the production of some innate immune factors such as the epithelial antimicrobial proteins (AMPs) (Gallo and Hooper 2012), which are capable of killing some skin pathogens containing bacteria, fungi, virus, etc. Skin microbiota also controls the host defense by modulating the complement system (Chehoud et al. 2013), indicating microbiota indifferent sites of human body functions in the development and regulation of immune system through diverse mechanisms.

20

Microorganisms in Pathogenesis and Management of Systemic. . .

20.3

513

Microorganisms in Pathogenesis of SLE

As previous mentioned, microorganisms orchestrate human immunity in physiological conditions. In contrast, dysbiosis contributes to pathogenesis of multiple diseases especially those related to the autoimmunity, for instance, autoimmune pancreatitis, systemic IgG4-related disease, encephalitis, type 1 diabetes, rheumatoid arthritis (RA), and multiple sclerosis (MS) (Guerreiro et al. 2018; Han et al. 2018; Xu et al. 2020; Brown et al. 2021; Yoshikawa et al. 2021). Among them, the development of SLE is intertwined with the inherent instability and unbalance of microorganism locating at the gut, oral cavity, skin, plasma, etc. Recent studies have shed light on the interaction between microorganism perturbation and SLE, as well as the underlying mechanisms.

20.3.1 Intestinal Microbiota Human gut microbiota, named “forgotten organ,” is a complex assemblage consisting of more than 100 trillion microorganisms (Gill et al. 2006). Five bacteria phyla, Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria, and Verrucomicrobiota, dominate intestinal microbiota (2012). Gut microbiota exhibits diverse patterns during different periods, influenced by host genetic background, diet, medicine, and interplay with other microbes (Buford 2017). In turn, the patterns and features of intestinal microbiota are capable of affecting the gut microenvironment and systemic metabolism, as well as innate and adaptive immunity (Sánchez et al. 2015; De Oliveira et al. 2017); thereby gut dysbiosis results in turbulence of some biological processes and host immunity. Lachnospiraceae (phylum Firmicutes), the main component of human intestinal flora, can produce butyrate essential for the growth of microbiota and host epithelia and correlates with obesity and the prevention of colon cancer (Meehan and Beiko 2014). Specific intestinal flora, such as segmented filamentous bacteria and Citrobacter rodentium, could induce the production of pro-inflammatory T helper type 17 (Th17) cells and aggravate autoimmune tissues damage through colonizing in the small intestinal epithelium (Atarashi et al. 2015). Clostridia strains could inhibit the inflammatory response by inducing the production of Tregs (Atarashi et al. 2013). To our best knowledge, roles of intestinal microbiota have been extensively studied in the pathogenesis of SLE, and the differences of the gut microbiota between SLE patients and healthy controls have been discovered and associated with the disease activity.

20.3.1.1 Profiles of Intestinal Microbiota in Mice and SLE Patients Intestinal Microbiota in Lupus Mice A variety of murine models that can simulate the disease development of human SLE have been intensively employed to explore the intestinal microbiota patterns in SLE, including lupus-spontaneous models induced by genetic factors and inducible

514

P. Yi et al.

murine models induced by environmental factors. Studies of the gut microorganisms in lupus mouse models were summarized in Table 20.1. MRL/lpr mouse is a classical lupus-spontaneous mouse model with the lymphoproliferation (lpr) mutation in the gene encoding Fas antigen protein that mediates cell apoptosis (Watanabe-Fukunaga et al. 1992). Several studies have showed that compared with BALB/c mice, gut microbial α-diversity and Firmicutes/Bacteroidetes ratio are decreased in MRL/lpr lupus-prone mice (He et al. 2020a; Wang et al. 2021). It has been also reported that the alterations of increased Ruminococcus torques and Blautia and decreased genera Desulfovibrio are shared in SLE patients and MRL/lpr mice (Chen et al. 2021). The resident flora Lactobacilli metabolizes carbohydrates to produce lactic acid, and some species of the Lactobacilli are often used as probiotics in clinical practice because of their antiinflammatory properties. Interestingly, abundance of the Lactobacilli was differentially detected in several lupus-spontaneous and inducible murine models, such as MRL/lpr, NZB/W F1, TLR7.1 transgenic (Tg) C57B1/6, and B6.Sle1.Sle2.Sle3 triple congenic (TC) mouse model. Significant decrease of Lactobacilli and elevation of Lachnospiraceae have been identified in young female MRL/lpr lupus-prone mice; subsequently, enriched sporulation- and bacterial motility-related pathways in lupus-prone mice were predicted by the metagenomic analysis (Zhang et al. 2014). Similarly, depletion of Lactobacillales in the gut microbiota of MRL/lpr model has been identified in another study, and the renal function and survival rate were positively correlated to the Lactobacillales level (Mu et al. 2017b). It has been showed that gut microbiota of NZB/WF1 mice was in a dynamic alteration before to after the disease onset and greater abundances of representative bacterial species were observed with the development of lupus, of which the Lactobacilli level was positively associated with the renal function (Luo et al. 2018). Moreover, increased microbial diversity and enrichment of three bacterial taxa containing the genera Lactobacillus, Desulfovibrio, and the family Rikenellaceae have been noticed in gut microbiota of lupus-prone TLR7.1 Tg C57B1/6 mice and topical imiquimod (IMQ) (a TLR7 agonist)-treated non-genetically modified C57B1/6 mice through highthroughput 16S ribosomal DNA (rDNA) sequencing. Among them, L. reuteri translocated outside the gut and is closely related to the generation of autoimmunity (Zegarra-Ruiz et al. 2019). Intestinal microbiota of TC mice features Firmicutes phylum and the Actinobacteria phylum (Ma et al. 2019). Comparable bacterial diversity and greater abundance of Prevotellaceae, Paraprevotella, and Lactobacillus in TC mice mirror the similar alterations of gut microbiota in TLR7.1 Tg and IMQ-inducible B6 mice (Choi et al. 2020). Besides, fecal microbiota transplantation from lupus mice to healthy mice leads to the appearance of lupus characteristics. TC mice are B6.Sle1.Sle2.Sle3 triple congenic lupus-prone mice, which exhibit lupus phenotypes and intestinal microbiota disorders in their old age. Ma et al. explored fecal microbiota distribution from C57/BL6 mice and SLE-prone TC mice and the influence of fecal microbiota transplantation on the gut microbiota and lupus phenotypes of recipient mice. Results demonstrated that the intestinal microbiota community richness and diversity of SLE-prone mice have been decreased and transplantation of fecal microbiota

20

Microorganisms in Pathogenesis and Management of Systemic. . .

515

Table 20.1 Studies of the gut microorganisms in lupus mouse models Study Zhang et al. (2014)

Model MRL/lpr

Mu et al. (2017b)

MRL/lpr

He et al. (2020a)

MRL/lpr

Chen et al. (2021)

MRL/lpr

Wang et al. (2021)

MRL/lpr

Luo et al. (2018) ZegarraRuiz et al. (2019) ZegarraRuiz et al. (2019)

NZB/W F1 TLR7.1 Tg C57BL/6 IMQinducible WT C57BL/6 TC

Ma et al. (2019)

Choi et al. (2020)

TC

Alterations in microorganism A decrease in Lactobacillaceae and an increase in Lachnospiraceae A decrease in Lactobacillales

A decrease in Firmicutes phylum, Clostridia class, Clostridiales order, and Lachnospiraceae family, an increase in Bacteroidetes, Bacteroidia, and Bacteroidales An increase in Ruminococcus torques and Blautia, a decrease in genera Desulfovibrio A lower Firmicutes/ Bacteroidetes ratio, a decrease in Peptostreptococcaceae under Firmicutes phylum and enrichment of Rikenellaceae under Bacteroidetes phylum Greater abundance of lactobacilli Greater abundance of Lactobacillus, Desulfovibrio, and Rikenellaceae Greater abundance of Lactobacillus, Desulfovibrio, and Rikenellaceae Feature Firmicutes phylum (Erysipelotrichia, Erysipelotrichales, Erysipelotrichaceae, and Turicibacter) and the Actinobacteria phylum (unidentified Actinobacteria) Greater abundance of Prevotellaceae, Paraprevotella, and Lactobacillus

Mechanisms NA

Induce inflammatory environment by increasing IL-6 and decreasing IL-10; induce Th17 phenotypes NA

Promote inflammation via microbial peptides Lead to gut oxidative stress, barrier function impairment, mucosal immune dysregulation, and elevated autoimmune disease markers NA Increase the number of pDCs and activate IFN pathways TLR7-pDC-IFN axis

Increase anti-dsDNA antibodies; change the distribution of immune cells and promote the immune response; upregulate expression of certain lupus susceptibility genes Induce anti-dsDNA IgG antibodies, as well as the expansion of GC B cells and Tfh cells

Abbreviations: dsDNA double-strand DNA, GC germinal center, IFN interferon, IL interleukin, IMQ imiquimod, NA not available, pDCs plasmacytoid dendritic cells, TC B6.Sle1.Sle2.Sle3 triple congenic, Tfh follicular helper T, Th17 T helper type 17, TLR toll-like receptor, WT wildtype

516

P. Yi et al.

from SLE-prone mice to germ-free (GF) mice induced the generation of anti-doublestrand DNA (dsDNA) antibodies and inflammatory response, as well as regulated the expression of SLE susceptibility genes (Ma et al. 2019). Likewise, transplant gut microbiota from aged TC mice into GF control mice induced the production of antidsDNA antibodies and the expansion of follicular helper T (Tfh) cells as well as germinal center (GC) B cells, which closely associated with lupus progression (Choi et al. 2020). Intestinal microbiota alteration has been a common phenomenon in SLE mouse model, but its interplay with the disease progression may vary with different backgrounds. As mentioned above, Lactobacillus is the most frequently changed bacteria genera, though its profiles were not in consistence in different lupus mouse models. As speculated, this difference may be determined by the heterogeneity of gut microbiota compositions and the inter-reaction with the host, genetical background, and the pathogenesis of lupus (Richard and Gilkeson 2018). For example, MRL/lpr mouse model could express a full panel of lupus-related autoantibodies including anti-dsDNA, anti-Ro, anti-Sm, anti-La autoantibodies, and antinuclear antibodies (ANAs), manifested with systemic lymphadenopathy, proteinuria, and other lupus-like pathological changes (Pisetsky et al. 1982), while NZB/WF1 mice predominately produce ANA and anti-dsDNA and develop glomerulonephritis and mild vasculitis (Dixon et al. 1978). Intestinal Microbiota in SLE Patients Similar with murine model, SLE patients develop specific intestinal microbiota patterns. The ratio of the two dominated phyla Firmicutes and Bacteroidetes in human gut microbiome (Eckburg et al. 2005) is changed in multiple situations such as obesity (Magne et al. 2020), Alzheimer’s disease (Vogt et al. 2017), and aging (Mariat et al. 2009). A Spanish cross-sectional study in inactive SLE patients revealed a significantly lower Firmicutes/Bacteroidetes ratio, decreased Lachnospiraceae and Ruminococcaceae, enriched Bacteroidaceae and Prevotellaceae, as well as activated oxidative phosphorylation and glycan utilization pathways in microbiota of SLE patients (Hevia et al. 2014). Similarly, decreased Firmicutes/Bacteroidetes ratio has been also reported in three Chinese and one Netherlandish studies (He et al. 2016; Van Der Meulen et al. 2019; Guo et al. 2020b; Zhao et al. 2020). However, the absence of Firmicutes/Bacteroidetes ratio alteration between SLE patients and healthy controls has been demonstrated in Southern and Southeast Chinese studies (Zhu 2018; Li et al. 2019). The pathobiont Enterobacteriaceae, Enterococci, Actinobacteria, Veillonella, or Streptococcus and Campylobacter are increased, and the probiotic Bifidobacterium is decreased in feces from SLE patients, in which Streptococcus, Campylobacter, Veillonella, and Enterococci are positively associated with the disease activity of SLE (Zhu 2018; Li et al. 2019). Moreover, a one-fold higher ratio of Firmicutes/Bacteroidetes with decreased Bacteroidetes and increased Proteobacteria in southern Chinese was found in southern Chinese population (He et al. 2020b). On the one hand, this discrepancy might root in the differences of populations and region of subjects. On the other hand, decreased Bacteroidetes correlates to the pathogenesis of

20

Microorganisms in Pathogenesis and Management of Systemic. . .

517

nonalcoholic fatty liver disease and metabolic syndrome, and its fermentation production SCFAs from the fibers are capable to improve the disease status (Leung et al. 2016; Canfora et al. 2019). An American study in active SLE patients by Luo et al. has reported no alteration of Firmicutes/Bacteroidetes ratio with decreased genera Odoribacter and an unnamed genus in the family Rikenellaceae, as well as increased Blautia and Gram-negative bacteria like Proteobacteria (Luo et al. 2018). Increased Proteobacteria was reported in a Northeast Chinese study by Wei et al., as well as the significant increased abundance of the family Enterobacteriaceae and a decreased in the family Ruminococcaceae, Prevotellaceae, and family_XI_o_Clostridiales (Wei et al. 2019). On the contrary, an Italian study reported greater abundance of Bifidobacterium, Ruminiclostridium, Streptococcus, U. m. of Coriobacteriaceae family, and U. m. of Enterobacteriaceae family (Bellocchi et al. 2019). Moreover, using fecal 16SrRNA analyses, Azzouz et al. have revealed the reduction of microbial species diversity in SLE patients. Among them, Ruminococcus gnavus (RG) of the Lachnospiraceae family has increased greater than five-fold and been associated with lupus disease activity (Azzouz et al. 2019). Enrichment of RG contributed to the development of lupus nephritis because of the overproduction of antibody targeting strain-restricted cell wall lipoglycan (Azzouz et al. 2019). Another American longitudinal cohort confirmed the potential pathogenic role of Lactobacillus spp. in SLE patients (ZegarraRuiz et al. 2019). More recently, the shotgun sequencing has been applied in exploration of intestinal microbiota, which provides more detailed information on genera and family change for microbiota. Sequencing of fecal metagenomes from 117 non-treated, 52 post-treated SLE patients, and 115 matched healthy donors in Northeast China connoted that microbial constitutions and functions were different between SLE and healthy population. Specifically, species of Clostridium spp. ATCC BAA-442, Atopobium rimae, Shuttleworthiasatelles, Bacteroides fragilis (B. fragilis), Actinomyces massiliensis, and Clostridium leptum were elevated in non-treated SLE patients and decreased in post-treatment patients (Chen et al. 2021). Additionally, synthesis of lipopolysaccharide (LPS) was boosted, while the generation of branched-chain amino acid was decelerated in SLE gut (Chen et al. 2021). Branched-chain amino acid has been proposed as a critical regulator for gut health, immune modulation, and metabolism (Nie et al. 2018). Interestingly, some oral microbiota-origin bacteria were enriched in gut of SLE patients (Chen et al. 2021), suggesting the possibility that migration of oral microbiota to gut is a pathway for intestinal microbiota alteration. Summarily, the unique patterns of intestinal microbiota can distinguish SLE patients from healthy controls. However, the detailed changes on genera, family, or species of microbiota are inconsistent in different studies, possibly because of the multifactor differences in race, lifestyle, diet, age, etc.

518

P. Yi et al.

20.3.1.2 The Role and Mechanism of Gut Microbiota in the Pathogenesis of SLE Leaky Gut and Gut Microbiota Translocation Gut microbiotas live in an environment generated by the gut barrier and intestinal contents. Gut barrier is mainly composed of the mucus layer, the epithelial layer connected with tight junction proteins, and the lamina propria containing innate and adaptive immune cells, which prevents microbial invasion in physiological conditions, synergized with antimicrobial peptides and proteins and secretory immunoglobulin A (sIgA) (König et al. 2016). In normal conditions, the gut microbiota only locate at intestinal wall and not transfer to vessels and other internal organs due to the stabilization of gut barrier. Accumulated researches have been carried out on how the gut microbiota migrate and interact with the internal microenvironment. Until now, a well-known theory is the “leaky gut” characterized with destruction of the gut barrier. The intestinal epithelial and endothelial cells are equipped with tight junctions and adherent junctions (Luissint et al. 2016). Absence of expression of the junction proteins such as occludin, zonula occludens-1, cingulin, vascular endothelial cadherin, and β-catenin results in the loss of gut barrier integrity. As a result, the gut microbiota and toxin are translocated into other tissues or organs and aberrantly activate immune and inflammatory response. A “leaky gut” has been identified in MRL/lpr and NZB/W F1 mice, with remarkable decreased tight junction proteins and increased permeability of the intestinal wall. Antigen-presenting cells (APCs) are activated by the translocation of the intestinal flora and migrate to the mesenteric lymph nodes (MLNs) to further activate CD4+T cells secreting interleukin (IL)-6 and other pro-inflammatory cytokines and induce the production of autoantibodies by B cells, as well as inhibit the immunosuppressant activity of Tregs (Mu et al. 2017b; Manfredo Vieira et al. 2018). Endotoxin (also known as LPS) is one of the components of the cell wall of Gram-negative bacteria, mostly from the intestine. Researchers noticed that the level of LPS in the blood was higher in MRL/lpr mice compared to their counterparts and the endotoxemia was alleviated after inoculated with Lactobacillus strains (Mu et al. 2017b), a kind of microbiota contributing to the maintenance of gut epithelial barrier function (Dicksved et al. 2012). In the plasma of SLE patients, the level of LPS is elevated significantly and positively correlated with the level of serum anti-dsDNA antibodies (Ogunrinde et al. 2019). Further, mouse model with dextran sulfate solution (DSS)-induced leaky gut is more susceptible to lupus. Mechanically, DSS-induced leaky gut enhances the translocation of molecular components from gut pathogens to MLNs and subsequently induces the cell stress and spleen apoptosis in wildtype and FcGRIIb / lupus mice; thereafter lupus activity is worsen due to increased anti-dsDNA immunoglobulin under the high burdens of apoptosis (ThimUam et al. 2020). Importantly, a specific gut commensal Enterococcus gallinarum has been uncovered as a predominant pathobiont that caused the leaky gut. E. gallinarum could downregulate the expression of molecules related to gut barrier functions, especially the Enpp3 that was capable of elevating the abundance of interferon (IFN) signature-

20

Microorganisms in Pathogenesis and Management of Systemic. . .

519

associated plasmacytoid dendritic cells (pDCs) (Furuta et al. 2017; Manfredo Vieira et al. 2018). In the GF C57BL/6 mice mono-colonized with E. gallinarum, E. gallinarum has been found in the mesenteric veins, MLNs, and liver, and the adherent junction proteins were significantly downregulated. Similarly, the proteins for lymphatic endothelial tight junctions (claudin-2, claudin-3, and claudin-5) have been suppressed. Further, Th17 cells were increased once mono-colonization, which were critical for systemic autoantibody production. Moreover, whole-genome sequencing illustrated that E. gallinarum encoded the shikimate pathway, which was the source of the aryl hydrocarbon receptor (AhR) ligands (Stockinger et al. 2014). AhR participates in Th17-mediated innate antimicrobial defense through the AhR-CYP1A1 pathway (Moura-Alves et al. 2014). Additionally, treatment with vancomycin in (NZW  BXSB)F1 mice could decrease the Th17 cells, Tfh cells, as well as their cytokines (Manfredo Vieira et al. 2018). Interestingly, enrichment of E. gallinarum was not found in feces of lupus-prone mice, which proposed that the translocation may be not determined by the overabundance, but the characteristics of the predominant itself, evidenced by no excessive bacterial load and obvious infection signs in most clinical SLE patients. It has been further reported that E. gallinarum was present in liver biopsy samples of patients with SLE and autoimmune hepatitis, but not in liver tissues of healthy people and patients with non-autoimmune hepatitis (Manfredo Vieira et al. 2018). Despite the aforementioned elements, biofilms of gut microbiota also impact the translocation and pathogen-host interactions. Many bacteria live in the biofilms that are formed by one or more species of bacteria in a three-dimensional structure, generally composed of the bacteria and self-secreted extracellular matrix (Costerton 1999). Biofilms protect bacteria from the stressful environments, toxic agent, and the host’s immune system (Sharma et al. 2019). Amyloid-containing biofilms have been considered to involve in multiple systemic autoimmune diseases (Miller et al. 2021). Gallo, P. M. group uncovered an immunogenic complex formed by the amyloid protein curli and bacterial DNA during biofilm formation (Gallo et al. 2015). This complex could stimulate immune cells such as DCs, producing type I IFNs, a critical factor in SLE pathogenesis. Infection of lupus-prone mice with curli-producing bacteria led to higher production of autoantibody compared with curli-depleted bacteria (Gallo et al. 2015). Further, the anti-curli/extracellular DNA (eDNA) antibodies relevant to the disease flares have been observed in plasma from SLE patients, and a cross-reaction existed between the curli/eDNA complexes and lupus autoantigens such as dsDNA (Pachucki et al. 2020). Histone-like protein 1 (HU1) belonging to DNABII proteins is also a major component of bacterial biofilm and has been recognized in serum of 47% patients with SLE. The anti-HU1 levels has been significantly correlated with the lupus nephritis occurrence, because of the cross-recognition of antibodies against HU1 to disulfide isomerase (P4HB) on the renal cell surface (Fu et al. 2021). These evidences have demonstrated the crucial roles of components in bacterial biofilm in SLE pathogenesis. Given the leaky gut, they transferred into and interacted with the host immune system, triggering severer SLE manifestation.

520

P. Yi et al.

Molecular Mimicry The bacteria trigger the autoimmunity and provide the inflammation signaling required for immune activation via presenting antigens that share same sequences or immunogenicity with the host antigens, called molecular mimicry. The foreign antigens may activate autoimmunity that is primarily mediated by T cells and B cells through the mechanism of molecular mimicry, subsequently inducing excessive antibodies in genetic susceptible individuals (Cusick et al. 2012). The earliest evidence that molecular mimicry triggers autoimmune diseases comes from a Harvard study on rheumatic fever. As early as 1962, researchers discovered type A Streptococcus-related immune cells and immune precipitates in the heart of a boy who died of rheumatic fever after being infected with Streptococcus, indicating that the cross antigenicity between protein antigens of type A Streptococcus and the tissues of heart valve induces the cross immune response to attack the host heart tissues. Molecular mimicry has been recognized to induce the autoimmunity in SLE, and the Ro60 in lupus patients has been appreciated. Anti-Ro60 antibodies are known to participate in the pathogenesis of multiple autoimmune diseases, especially in the SLE (Greiling et al. 2018). A retrospective study of plasma samples from 13,032 patients with positive ANAs showed that anti-Ro60 antibodies were mostly presented in adult patients with systemic lupus (Robbins et al. 2019). Micah T McClain et al. discovered that a peptide from Epstein-Barr virus nuclear antigen-1 (EBNA1) protein cross-interacted with Ro60 and immunization of rabbits with EBNA1 epitope induced the generation of multiple autoantibodies against Ro60, finally developing clinical symptoms of lupus (Mcclain et al. 2005). Ro60 orthologs have been identified in human gut, oral, and skin commensal bacterial species in patients with lupus (Greiling et al. 2018). The microbial Ro60 ribonucleoproteins were immunoprecipitated by plasma from Ro60-positive lupus patients, and the Ro60 autoantigen-specific CD4+ memory T cell derived from lupus patients could be stimulated by Ro60-containing bacteria. Besides, anti-human Ro60 T and B cell responded in GF mice once mono-colonized with a gut commensal expressing Ro60 orthologs, thus producing the human Ro60 autoantibodies and inducing lupus symptoms (Greiling et al. 2018). Meanwhile, Professor Agnieszka Szymula and colleagues have detected more mimicry peptides that were able to activate Ro60reactive T cells in bacteria from human oral cavity, gut, skin, and vagina, namely, the vWFA88–102 in Prevotella disiens, vWFA90–104 in Pseudomonas mendocina, vWFA88–102 in Bacteroides finegoldii, etc. (Szymula et al. 2014). On this setting, commensal Ro60 orthologs or mimicry peptides cross-reactivate the Ro60-specific T cells and trigger the autoimmunity, aligned with the production of autoantibodies. In addition to Ro60 mimicry molecule, antigens derived from RG cross-reacted with the anti-dsDNA antibodies in lupus patients (Azzouz et al. 2019). It presented that the extract of the RG strain CC55_001C (RG2) significantly suppressed the binding of lupus serum IgG to native DNA in a dose-dependent manner, suggesting the great potential of the RG2 extract in triggering autoimmunity against human DNA. Amyloid curli, one of the components of bacterial biofilm, could form a fibrous complex with bacterial DNA during the formation of the biofilm, which can

20

Microorganisms in Pathogenesis and Management of Systemic. . .

521

initiate immune activation and autoantibody production in lupus-prone and wildtype mice (Gallo et al. 2015). Besides, some bacterial peptides as potential mimic molecules were found by a study in Peking Union Medical College Hospital, through comparing the genome of differential intestinal flora of SLE with peptides of known autoantigen epitopes of SLE. The researchers confirmed that the peptides produced by the two bacteria Odoribacter splanchnicus and Akkermansia muciniphila, which were highly similar with the epitopes of the two common autoantigens in SLE patients, Smith and Fas antigen, activated CD4+T and B cells of SLE patients in vitro and participate in the occurrence and development of SLE through the mechanism of molecular mimicry (Chen et al. 2020a).

Metabolites Gut microbiota-derived metabolites including SCFAs, microbial tryptophan catabolites, trimethylamine, secondary bile acids, branched-chain amino acids, polyamines, and bacterial vitamins, have been reported to regulate host immune responses and participate in the pathogenesis of immune-related inflammatory diseases (Yang and Cong 2021). As an example, dysregulation of secondary bile acids contributes to attenuation of autoimmune uveitis through suppressing the activation of DCs via TGR5 signaling (Hu et al. 2021). In regard to SLE, gut microbiota-derived metabolites also play a significant role. SCFA, an important metabolite produced by intestinal microbes metabolizing dietary fiber, including acetic acid, propionic acid, butyric acid, etc., serves as the major energy source for intestinal epithelial cells. SCFA can not only maintain the integrity of the intestinal barrier and inhibit the colonization of deleterious pathogens but also regulate the host immune response and affect the occurrence and development of autoimmune diseases. The presence of SCFA largely relies on intestinal microbiota; intestinal Firmicutes/Bacteroidetes ratio was positively correlated with SCFA concentration (Sanchez et al. 2020). The researchers have also found that Lachnoclostridium, Lachnospira, and Sutterella were reduced in the intestinal flora of patients with SLE and other autoimmune diseases. Lachnospiraceae is a family of bacteria capable of producing SCFA, such as butyric acid, suggesting alteration in SCFA contributed to the suppression of pathogenic microorganism that mediated SLE progression (Bellocchi et al. 2019). Low dose of SCFAs can directly affect the intrinsic function of B cells, moderately enhance CSR, and act as HDAC inhibitors rather than energy substrates in B cells. They can also participate in signal transduction and weaken intestinal and systemic T cell-dependent immune responses (Sanchez et al. 2020). Another important gut microbiota-derived metabolite in SLE is tryptophan metabolite. Kynurenine, the metabolite of tryptophan metabolism, was increased in the feces and serum of lupus-prone mice, indicating the potential association of altered tryptophan metabolism and autoimmunity in SLE (Choi et al. 2020). Low tryptophan dietary has been found to attenuate lupus phenotypes through modulating gut microbiota, the expression of genes involved in gut epithelial integrity, as well as autoimmune activation by increasing the suppressing function of Tregs and decreasing Th17 frequency (Choi et al. 2020).

522

P. Yi et al.

Fig. 20.1 Potential mechanisms of gut microbiota involved in the pathogenesis of systemic lupus erythematosus (SLE). SLE patients are characterized with decreased microbiota diversity and altered components of gut microbiota. Leaky gut-mediated microbiota translocation, molecular mimicry, and metabolites mediate the pathogenesis of SLE. The gut barrier is destructed, and the pathobionts translocate into other sites such as the liver, mesenteric veins, and lymph nodes. Autoantibodies are produced during the inter-reaction between microbiota and host. Immune cells including T cells, B cells, and dendritic cells (DCs) participate in the pathogen recognition, antibody production, and cytokine release, triggering the generation of autoimmunity

Figure 20.1 describes potential mechanisms of gut microbiota involved in the pathogenesis of SLE.

20.3.1.3 Sexual Bias of Gut Microbiota in SLE Patients The incidence rate of SLE among women was nine times higher than that among men according to a Lupus Surveillance Program in New York County (Izmirly et al. 2017). However, SLE tends to be more aggressive and develops more rapid organ damage in men, for instance, serositis, cardiovascular disease, and nephritis (Andrade et al. 2007). This sexual bias is related to the differences in lifestyles and hormone level between men and women. In individuals with genetic susceptibility, the commensal microbial community may modulate the autoimmunity by altering hormone levels (Markle et al. 2013). Recently, it has been reported that the dissimilar gut commensal in men and women also contributed to the female-predisposed

20

Microorganisms in Pathogenesis and Management of Systemic. . .

523

feature of lupus. Gut microbiota of the MRL/lpr murine model is different between males and females, and an overrepresentation of Lachnospiraceae has been found in female mice with earlier onset or severer lupus (Zhang et al. 2014). Interestingly, male and female MRL/lpr mice also respond differently to Lactobacillus treatment. The ameliorated inflammatory environment was found in female and castrated male mice, but not in intact male after Lactobacillus treatment (Mu et al. 2017b), indicating that the response may be largely determined by sex hormone. Further, an increase of testosterone and metabolomic alterations occurred, and the inflammation and autoantibody production were suppressed after the transfer of microbiota from adult male nonobese diabetic (NOD) mice into immature females (Markle et al. 2013). The level of testosterone is correlated with the production of sIgA in mucosa, inferring that testosterone may enhance immunity against abnormal gut commensal microbiota and reduce the possibility of autoimmunity.

20.3.2 Oral Microbiota in SLE Patients As a part of the upper digestive tract, oral cavity possesses the second complex commensal microbiota in the human body, comprising of bacteria, archaea, viruses, fungi, and protozoa (Wade 2013). It was noticed that there were about 108 microbial cells in only a milliliter of saliva (Marsh et al. 2016). More than 700 distinct prokaryotic taxa have been found in the oral cavity by various studies (Dewhirst et al. 2010). Among them, Streptococcus mitis, Streptococcus oralis, and Streptococcus peroris are the most abundant bacteria. Most of the oral microbiota inhabit different niches formed at the surface of mouth such as the gingival crevicular and gingival sulcus, which impact the health of oral cavity (Zhang et al. 2018). Compositions and conditions of such microbiota are largely determined by the availability of nutrients, oxygen, and the pH-mediating effect of saliva (Wilson M 2009). In pathological states, the pathogens account for majority of the oral microbiota and interact with the local or systemic environment. Alterations of oral microbiota components and decreased microbial diversity in lupus have been determined previously. On the one side, lupus changes the oral microbiota and leads to local inflammation. Initially, increased Lactobacilli, Streptococcus mutans, and Candida albicans in the oral cavity were reported by a Norway study in 1999 (Jensen et al. 1999). A Brazilian research demonstrated that Staphylococcus epidermidis, Candida albicans, and Klebsiella oxytoca were the most enriched microbiota species in SLE patients and there were no differences in compositions of microbiota between patients with and without SLE (De Araújo Navas et al. 2012). Later, this conclusion was overturned since it has been clarified that bacteria in charge of the periodontal disease such as Selenomonas, Prevotella nigrescens, and Fretibacterium were significantly increased in SLE patients compared with healthy controls (Corrêa et al. 2017). Further, results indicated that SLE patients were prone to have a history of periodontitis during young age and that SLE patients with high bacteria loads and reduced microbial diversity tend to develop more severe periodontitis (Corrêa et al. 2017). Alterations in oral microbiota for

524

P. Yi et al.

periodontal diseases were associated with the systemic inflammation, featuring raised secretion of pro-inflammatory cytokines systematically, thereby influencing the activation of SLE. In particular, 14 subgingival bacteria were increased in patients with SLE, and compared to inactive SLE patients and healthy controls, the oral bacteria including Treponema denticola and Tannerella forsythia were remarkably elevated in active SLE patients (Pessoa et al. 2019). Li et al. proposed that families Moraxellaceae, Lactobacillaceae, and Veillonellaceae were surged, while families Sphingomonadaceae, Halomonadaceae, and Xanthomonadaceae were declined in Chinese SLE patients (Li et al. 2020a). Besides, oral microbiota differences have been noticed in different autoimmune diseases; for example, primary Sjögren’s syndrome and SLE shared the same gut microbiota but distinct oral microbiota (Van Der Meulen et al. 2019). On the other side, SLE patients produced more antibodies against oral bacteria such as Porphyromonas gingivalis, Treponema denticola, Aggregatibacter actinomycetemcomitans, and Capnocytophaga ochracea, and the antibody titers were correlated with the level of anti-dsDNA antibodies (Bagavant et al. 2019). Moreover, it has been reported that von Willebrand factor type A domain protein (vWFA) from the oral microbe Capnocytophaga ochracea derived a peptide imitating the Ro60 antigen and stimulated the Ro60-reactive T cells, thereby promoting the generation of antiRo60 antibodies and severe lupus profiles (Szymula et al. 2014). Compared with healthy controls, the reduction in saliva α-biodiversity, increased Proteobacteria, and decreased class Betaproteobacteria relative of clinical severity have been revealed in mothers with positive anti-Ro antibodies who had a baby of neonatal lupus, suggesting the association of oral microbiome and anti-Ro reactivity (Clancy et al. 2020).

20.3.3 Cutaneous Microbiota in SLE Patients The integrity and health of human skin is crucial for pathogens defense, which is partially maintained by the homeostasis of its commensals (Oh et al. 2016). Cutaneous microbiota is stable in structure and composition over time, though site and individual specificity are common, which is primarily impacted by the temperature, moisture, PH, topography shape, etc. (Costello et al. 2009). Previous studies have shed light on the roles of skin microbiota in immune regulation, lipid metabolism, and resistance to foreign bacteria (Scharschmidt and Fischbach 2013; Belkaid and Segre 2014; Grice 2015). The differential skin microbial patterns have been intensively studied and identified in multiple dermatological diseases, for instance, atopic dermatitis, acne, and psoriasis (Kong et al. 2012; Ganju et al. 2016; O'Neill and Gallo 2018). A recent study by Huang et al. focusing on the skin microbiota profiles of SLE patients compared with the healthy and dermatomyositis individuals has discovered a decrease in cutaneous microbiota diversity and evenness in SLE patients and the association between cutaneous microbial community abnormality and some lupus clinical characteristics, for example, gender, low complement level, myositis, and renal situation. Furthermore, bacterial taxa including Staphylococcus

20

Microorganisms in Pathogenesis and Management of Systemic. . .

525

aureus and Staphylococcus epidermidis serve as effective biomarkers for skin lesion of lupus, and Staphylococcus aureus infection pathway was activated in lupus (Huang et al. 2020). These results indicated that cutaneous microbiota played indispensable roles in progression of SLE both locally and systemically. However, the current study about skin commensals and SLE remains insufficient to provide a further insight.

20.3.4 Circulating Microbiota in SLE Patients 20.3.4.1 Circulating Bacterium Blood was previously deemed sterile in normal conditions. Nevertheless, research found that bacteria in blood were associated with the pathogenesis of several diseases. For instance, cancer-specific microbiol sequences in blood have been identified in various cancer types (Poore et al. 2020), and circulating microbiota was also detected in patients with chronic inflammation (Potgieter et al. 2015). Further, it was hypothesized that the blood microbiota and microbiol components like endotoxin were translocated from other sites of the human body such as the leaky gut (Fukui 2015). Therefore, microbiota alterations in blood were secondary to other lesions and may be in dynamic. The group of Elizabeth Ogunrinde has explored the plasma antibodies and microbiome in SLE patients and their firstdegree relatives (Ogunrinde et al. 2019). Elevated level of LPS has been identified in SLE patients and their children, and LPS was positively associated with the antidsDNA antibodies in plasma of their first-degree relatives. The circulating microbiota (phylum Firmicutes) of the first-degree relatives showed a reduction in diversity. Interestingly, this difference was not observed in the SLE patients themselves, which may be a result of multiple factors such as the application of immunosuppressive drugs in SLE patients. Additionally, Zhenwu Luo and colleagues have figured out the patterns of plasma microbiome in SLE patients using 16S DNA sequencing and demonstrated that microbiome in plasma contributed to the production of autoantibodies in lupus (Luo et al. 2020). Results indicated that enrichment of circulating microbiota genera such as the Desulfovibrio, Desulfoconvexum, and Desulfofrigus was linked to the increase of various plasma autoantibodies such as those against dsDNA, nucleosome, and histone (Luo et al. 2020). 20.3.4.2 Circulating Viruses Moreover, the virome in peripheral blood mononuclear cells (PBMCs) has been explored in a study by Guo et al. (2020a). Virome diversity was dramatically elevated in PBMCs from SLE patients compared with the healthy control. Besides, the viral taxa were potent in judging disease activity and distinguishing between SLE patients and healthy individuals with an AUC of 0.883 and 0.695 for viral species and genus, respectively (Guo et al. 2020a). The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has attracted scientists’ attention on the association of SARS-CoV-2 and SLE. The usage of immunosuppressive drugs indicates the possibility of a higher infection

526

P. Yi et al.

risk, and overactivated immune response of SLE patients might induce cytokine storm and damage systematic tissues and organs after coronavirus infection, suggesting SLE patients might be vulnerable to SARS-CoV-2. Notably, the occurrence of autoantibodies against type I IFNs was associated with life-threatening SARS-CoV-2 infection with pneumonia (Bastard et al. 2020), and such antibodies might be produced by SLE patients. Especially, SLE in patients with comorbidities like chronic kidney disease tends to develop severe coronavirus disease 2019 (COVID-19); thus SLE would influence the outcome of COVID-19 (Mageau et al. 2021; Pablos et al. 2020). Reassuringly, antibody response against SARS-CoV-2 has been proven not prevented by SLE (Aringer 2021; Saxena et al. 2021). Interestingly, a cohort study in Northeast Italy about SARS-CoV-2 infection incidence of 916 patients (including 397 SLE patients) with autoimmune rheumatic diseases (ARDs) has revealed similar infection incidence compared with general population (Zen et al. 2020). A questionnaire survey of 417 SLE patients in Italy and Lombardy also found that SARS-CoV-2 infection incidence was only moderately elevated in SLE patients and behavioral prevention and containment policies played a main role in preventing COVID-19 for SLE patients (Ramirez et al. 2020). Additionally, COVID-19 had the negative effect on mental health of SLE patients, and the risk of anxiety, depression, and sleep disorders was elevated according to GAD-7 scale, PHQ-9 scale, and the Insomnia Severity Index scale (Wańkowicz et al. 2020). There has been a crucial problem whether the odds of COVID-19 hospitalization in patients with rheumatic diseases were affected by medication exposure. The data from the COVID-19 Global Rheumatology Alliance physician-reported registry has been reported that 10 mg/day glucocorticoid usage increased hospitalization, the use of TNF inhibitor reduced hospitalization, while there were no association of antimalarial drugs, conventional disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and biological reagents with COVID-19 hospitalization in patients with rheumatic diseases (Gianfrancesco et al. 2020), indicating the recovery from SARS-CoV-2 infection in patients with rheumatological disease would not be delayed by systematic drugs except from glucocorticoid (10 mg/day). Similarly, the usage of biological (bDMARD) or targeted synthetic disease-modifying antirheumatic drug (tsDMARD) in patients with rheumatic and musculoskeletal diseases (RMDs) had not influenced the disease course and mortality of COVID-19 (Sanchez-Piedra et al. 2020). The usage of glucocorticoid and immunosuppressive drugs sometimes led to asymptomatic SARS-CoV-2 infection (Schioppo et al. 2021). Besides, the functions of prophylaxis and treatment of antimalarial drugs like hydroxychloroquine (HCQ) and chloroquine (CQ) in COVID-19 have been controversial because of the side effects and dosing consideration, etc. (Chen et al. 2020b; Gautret et al. 2020; Gianfrancesco et al. 2020; Konig et al. 2020; Ferreira et al. 2021; Sbidian et al. 2020). However, antimalarial drugs serve as the cornerstone therapy in the treatment of SLE patients, and the withdrawal of antimalarial drugs might result in the flare of lupus; thus avoiding the withdrawal of antimalarial drugs during the pandemic of COVID-19 is essential (Yazdany and Kim 2020). Compared with medication exposure, other factors, such as age and systemic autoimmune condition, were

20

Microorganisms in Pathogenesis and Management of Systemic. . .

527

regarded as risk factors of COVID-19 for patients with ARDs (Freites Nuñez et al. 2020). Last but not least, COVID-19 vaccination in SLE patients might rarely cause disease flares, although a part of patients developed low immune response to the vaccine because of the usage of immunosuppressants like mycophenolate mofetil and methotrexate, as well as a low level of humoral immune response (Moyon et al. 2022; Izmirly et al. 2022). The studies of gut, oral, cutaneous, and circulating microorganisms in SLE patients are summarized in Table 20.2.

20.4

Microorganisms in Management and Treatment of SLE

Based on the fact that microorganism disorders in multiple habitat sites of the human body participate in the progression of SLE, several strategies have been developed to regulate the composition and abundance of microorganisms, especially for the intestinal microbiota. However, most of them are still in the stage of animal experiment. Current approaches mainly include dietary intervention, probiotics, FMT, and others. A list of these microorganism-related interventions is provided in Table 20.3. Figure 20.2 provides an integrated summary of three major microorganism-related approaches for management of SLE.

20.4.1 Dietary Intervention 20.4.1.1 Calorie Intake and SLE Nutrients are the indispensable elements for maintenance of human life, containing carbohydrates, proteins, essential fatty acids, fiber, vitamins, minerals, etc. To our best knowledge, multiple types of them involve in the pathological processes of SLE. For example, it has been proposed that excess intake of carbohydrate was correlated with high risk of SLE and obesity was a risk factor for low-grade inflammation which may contribute to the occurrence of SLE comorbidities (Elkan et al. 2012). The obese SLE patients tend to have a poorer prognosis and severer organ damage compared with those without obesity (Kang et al. 2020). Therefore, limitation of calorie intake substantially inhibited the SLE progression, as well as its complications. However, the low-calorie diet may result in fatigue among individuals with SLE (Davies et al. 2012). Importantly, the calorie intake level was associated with the immune status that may mediate the progression of SLE. In NZB/NZW F1 mouse model, restricting calorie intake could reduce the serum anti-dsDNA level. Meanwhile, calorie directly suppressed the frequency and activity of B-cell population, aligned with the enrichment of naïve CD4+T and CD8+T cells (Sun et al. 2004). Parallel to this, another study has shown that calorie restriction diet significantly reduced the ratios of B/T cell and CD4+/CD8+ T cell in NZB/NZW F1 mouse model compared with their counterparts (Urao et al. 1995). These evidences showed the impact of calorie intake on immune cells, especially on restraining the abnormal expression of T cells. Besides, calorie can interfere with the expression of immune-related molecules, subsequently modulating the immune status of the

528

P. Yi et al.

Table 20.2 Studies of microorganisms in patients with systemic lupus erythematosus (SLE) Number (experiment/ control Study group) Gut microorganism Hevia et al. 20 inactive/ (2014) 20

He et al. (2016) Zhu (2018)

45/48 32/26

Country

Alterations in microorganism

Spain

A lower Firmicutes/ Bacteroidetes ratio, a decrease in Firmicutes families

Southeast China Southeast China

A lower Firmicutes/ Bacteroidetes ratio No alteration of Firmicutes/Bacteroidetes ratio, Proteobacteria, and Fusobacteria, decreased Bifidobacterium, increased Enterobacteriaceae, Enterococci, Actinobacteria, and Veillonella No alteration of Firmicutes/Bacteroidetes ratio, decreased Bifidobacterium, an increase in the genera Streptococcus, Campylobacter, and Veillonella, the species anginosus and dispar A higher Firmicutes/ Bacteroidetes ratio, a decrease in abundance of Bacteroidetes (class Bacteroidia and order Bacteridales) and an increase in Proteobacteria (class Gammaproteobacteria, order Enterobacteriales and family Enterobacteriaceae)

Li et al. (2019)

19 active, 21 inactive/ 22

Southern China

He et al. (2020b)

21/10

Southern China

Mechanisms An overrepresentation of oxidative phosphorylation and glycan utilization pathways NA Influence plasma cytokines such as IL-1b, IL-1ra, IL-10, IL-12, TNF-α, and IL-17

NA

Disrupt lipid metabolism

(continued)

20

Microorganisms in Pathogenesis and Management of Systemic. . .

529

Table 20.2 (continued)

Study Wei et al. (2019)

Number (experiment/ control group) 16/14

Country Northeast China

Chen et al. (2021)

117/115

Northeast China

Guo et al. (2020b)

17/20

Northwest China

Zhao et al. (2020)

20/20

Eastern China

Luo et al. (2018)

14 active/17

USA

Azzouz et al. (2019)

14 active, 47 inactive/ 17

USA

Alterations in microorganism An increase in phylum Proteobacteria and the family Enterobacteriaceae, a decreased in the family Ruminococcaceae, Prevotellaceae, and family_XI_o_Clostridiales An increase in Clostridium sp. ATCC BAA-442, Atopobium rimae, Shuttleworthiasatelles, Actinomyces massiliensis, B. fragilis, and Clostridium leptum A lower Firmicutes/ Bacteroidetes ratio, an increase in the phylum Bacteroidetes and Proteobacteria, a decrease in the phylum Gemmiger and Dialister A lower Firmicutes/ Bacteroidetes ratio, increased genus Lactobacillus, Lachnospira, Turicibacter, and Bifidobacterium, and decreased genus Allobaculum No alteration of Firmicutes/Bacteroidetes ratio, increased Blautia and gram-negative bacteria like Proteobacteria, decreased genera Odoribacter and an unnamed genus in the family Rikenellaceae Greater representation of Ruminococcus gnavus of the Lachnospiraceae family

Mechanisms Regulate some proteins and the oxidation-related enzymes

Promote inflammation via microbial peptides

Upregulate immune cytokines including IL-17, IL-21, IL-2R, TWEAK, IL-35, IFN-γ, and IL-10 NA

NA

Produce elevated serum anti-RG antibodies against translocated RG (continued)

530

P. Yi et al.

Table 20.2 (continued)

Study ZegarraRuiz et al. (2019) Bellocchi et al. (2019)

Number (experiment/ control group) 28/50

Country USA

27/27

Italy

van der 30/965 Meulen et al. (2019) Oral microorganism Jensen 20/20 et al. (1999) de Araújo 40/40 Navas et al. (2012) Corrêa 52/52 et al. (2017)

Netherlands

Norway

Brazil

Brazil

Pessoa et al. (2019)

31 active, 29 inactive/ 31

Brazil

Li et al. (2020a)

20/19

China

Alterations in microorganism An increase in Lactobacillus spp.

Mechanisms NA

A reduction of Lachnoclostridium, Lachnospira, and Sutterella, greater abundance of Bifidobacterium, Ruminiclostridium, Streptococcus, U. m. of Coriobacteriaceae family, and U. m. of Enterobacteriaceae family A lower Firmicutes/ Bacteroidetes ratio and higher relative abundance of Bacteroides species

Influence metabolic function

Increased Lactobacilli, Streptococcus mutans, and Candida albicans Enriched with Candida albicans, Staphylococcus epidermidis, and Klebsiella oxytoca Elevated proportions of Fretibacterium, Prevotella nigrescens, and Selenomonas Elevated Treponema denticola and Tannerella forsythia

NA

Elevated families Lactobacillaceae, Veillonellaceae, and Moraxellaceae, decreased families Sphingomonadaceae, Halomonadaceae, and Xanthomonadaceae

NA

NA

Increase local inflammation by high-level IL-6, IL-17, and IL-33 Increase proinflammatory cytokines systemically NA

(continued)

20

Microorganisms in Pathogenesis and Management of Systemic. . .

531

Table 20.2 (continued) Number (experiment/ control Study group) Cutaneous microorganism Huang 69/49 et al. (2020)

Country China

Circulating microorganism Ogunrinde 21/19 USA et al. (2019)

Luo et al. (2020)

19/30

USA

Guo et al. (2020a)

10/10

China

Alterations in microorganism

Mechanisms

Elevated Staphylococcus, especially Staphylococcus aureus and Staphylococcus epidermidis

Activate Staphylococcus aureus infection pathway

Increased Bacteroidetes, Firmicutes, Proteobacteria, and Planctomycetes, decreased Actinobacteria and Gemmatimonadetes Increased Desulfoconvexum, Desulfofrigus, Desulfovibrio, Draconibacterium, Planococcus, and Psychrilyobacter Elevated PBMC virome, including proportions of Caudovirales, Herpesvirales, Ortervirales, Picornavirales, and unclassified bacterial viruses

Influence serum autoantibody production

Increase the levels of various plasma autoantibodies

Related with cellular and metabolic processes

Abbreviations: B. fragilis Bacteroides fragilis, IFN interferon, IL-1ra interleukin-1 receptor antagonist, NA not available, RG Ruminococcus gnavus, TNF tumor necrosis factor, TWEAK tumor necrosis factor-like weak inducer of apoptosis

human body. The platelet-derived growth factor subunit A, a core inflammatory ligand, was found to be regulated by the calorie-restricted diet, with a result of palliation in lupus nephritis (Troyer et al. 1997).

20.4.1.2 Other Dietary Interventions Strategies of diet-mediated microorganism intervention have been developed to modulate the progression of SLE. A study by Johnson et al. indicated that the acidic pH water could slow the pace of nephritis in (SWR  NZB) F1 (SNF1) lupus-prone mice compared with those treated with neutral pH water (Johnson et al. 2015). Differences of gut microbiota between acidic pH water and neutral pH water intake mice have been determined by using the 16S rRNA gene-targeted sequencing.

532

P. Yi et al.

Table 20.3 Therapeutic methods related to the intestinal microorganisms in the management of SLE Therapeutic methods Dietary intervention Acidic pH water Johnson et al. (2015)

Research diets Inc. D11112226 (commercial rodent diets) Edwards et al. (2017) Caloric restriction Vorobyev et al. (2019) Polyphenol intake Cuervo et al. (2015)

RS Zegarra-Ruiz et al. (2019)

Dietary fiber/butyrate and propionate supplement He et al. (2020a), Sanchez et al. (2020)

Mechanisms An increase in Lactobacillus reuteri, Turicibacter spp., and the Firmicutes/Bacteroidetes ratio Decrease proteinuria, C3 and IgG; influence cytokine production, fecal microbiota, microRNA level, and DNA methylation Suppress weight gain, circulating ANA production, kidney damage Polyphenol intake from apple and orange positively correlate to Bifidobacterium and Lactobacillus, respectively, reported to be decreased in SLE Suppress the overgrowth of the pathobiont Lactobacillus reuteri that increases pDC and interferon pathway via SCFAs from RS Inhibit autoantibody production and autoimmunity through upregulating Aicda and Prdm1-targeted microRNA via HDAC inhibitory activity of SCFAs; increase abundance of Firmicutes, Clostridia, Clostridiales, Lachnospiraceae, Ruminococcaceae, Peptostreptococcaceae, Ruminiclostridium, Oscillibacter, Romboutsia, Lachnoclostridium, Coprococcus, Ruminococcus, Clostridium leptum, and Dorea spp.; and reduce proportion of Bacteroidetes, Bacteroidia, and Bacteroidales

Advantages and disadvantages NA

Contain casein and no phytoestrogens

NA

NA

NA

Function in a dose-dependent fashion

(continued)

20

Microorganisms in Pathogenesis and Management of Systemic. . .

533

Table 20.3 (continued) Therapeutic methods Valproic acid White et al. (2014)

Low tryptophan dietary Choi et al. (2020)

Probiotics Lactobacillus treatment Mu et al. (2017b)

Lactobacillus rhamnosus and Lactobacillus delbrueckii Mardani et al. (2018)

LC40 Toral et al. (2019)

Lactobacillus paracasei GMNL-32, Lactobacillus reuteri GMNL-89, and L. reuteri GMNL-263 Hsu et al. (2017) Oral B. fragilis ATCC 25285 Li et al. (2020b)

Drugs and others Vancomycin administration Mu et al. (2017a), Mu et al. (2019)

Mechanisms Suppress CSR, SHM, and the differentiation of plasma cells, decrease autoantibodies through inhibiting histone deacetylases Influence gut microbiota, autoimmune activation, and the expression of genes involved in gut epithelial integrity Increase IL-10 and decrease IgG2a; skew the Treg-Th17 balance towards a Treg phenotype Decrease the number of Th1– Th17 cells and reduce the level of IFN-γ and IL-17, reduce the level of ANA, antidsDNA, and anti-RNP antibodies Reduce elevated T, B, Treg, and Th-1 cells in MLNs and plasma pro-inflammatory cytokines in lupus mice; increase the Bifidobacterium count Suppress hepatic apoptosis, inflammatory indicators, and hepatic IL-1β, IL-6, and TNF-α proteins

Advantages and disadvantages NA

NA

Sex hormone-dependent, female-predisposed benefit

NA

Prevent vascular disorders in SLE

Ameliorate liver disorders in SLE

Relieve intestinal inflammation and regulate B-cell immune responses by increasing CD1d level and reducing CD86 level in B cells partly by Est-1 and SHP-2 signaling pathway; correct Th17-Treg unbalance

Relieve the activity of MRL/ lpr mice and symptoms of lupus nephritis

Induce immunosuppressive IL-10 and suppress proinflammatory IL-17 and IFN-γ; increase the barrier function of the intestinal epithelium; enrich the abundance of Lactobacillus animalis

Administration during the pre-disease period exacerbates disease with disease stage-dependent effects; exacerbate lupus in postpartum mice after pregnancy and lactation (continued)

534

P. Yi et al.

Table 20.3 (continued) Therapeutic methods Mixed antibiotics (ampicillin, neomycin, metronidazole, and vancomycin) Mu et al. (2017a), de la Visitación et al. (2021)

TPC Neuman et al. (2019)

Antioxidant NAC Wang et al. (2021)

Bromofuranone He et al. (2019) Oral bacterial DNA from the gut microbiota Mu et al. (2020) FMT Zhang et al. (2020)

Mechanisms Remove Lachnospiraceae and increase the relative abundance of Lactobacillus spp.; decrease IL-17producing cells and increase the level of circulating IL-10; attenuate T-cell imbalance; improve the function of endothelia and oxidative stress state of vessels Decrease abundances of beneficial Akkermansia and increase abundance of several genera; reduce the levels of proteinuria through increasing the level of anti-inflammatory IL-10, decreasing levels of pro-inflammatory mediators, and the Treg cell expansion Affect the microbial composition, decrease Rikenellaceae, and increase Akkeransiaceae, Erysipelotrichaceae, and Muribaculaceae; attenuate the systemic autoimmunity (ANA, anti-dsDNA levels, and serum cytokines) Regulate gut microbiota via inhibiting the AI-2/LuxS quorum sensing Induce expansion of Breg cells in MRL/lpr mice Change gut microbiota into normal level; reduce the level of anti-dsDNA autoantibodies and inflammatory cytokines

Advantages and disadvantages Ameliorate lupus-like symptoms and lupus nephritis; inhibit the development of hypertension

Attenuate glomerulonephritis

NA

Promote the efficacy of prednisone; no effect on alleviating lupus Suppress disease onset in MRL/lpr mice Early treatment interferes the therapeutic efficiency of prednisone in MRL/lpr mice

Abbreviations: ANA antinuclear antibody, B. fragilis Bacteroides fragilis, Breg regulatory B cell, C3 complement 3, CSR class switch recombination, dsDNA double-strand DNA, FMT fecal microbiota transplantation, HDAC histone deacetylation, IFN interferon, IL interleukin, LC40 Lactobacillus fermentum CECT5716, MLN mesenteric lymph node, NA not available, NAC Nacetylcysteine, pDC plasmacytoid dendritic cell, RS resistant starch, SCFAs short-chain fatty acids, SHM, SLE systemic lupus erythematosus, somatic hypermutation, Th Thelper, TPC a conjugate of tuftsin and phosphorylcholine, Treg regulatory T cell

20

Microorganisms in Pathogenesis and Management of Systemic. . .

535

Fig. 20.2 Three major approaches of microorganism-related intervention for SLE. Probiotics modulate the gut microbiota, reduce the level of pro-inflammatory cytokines, and increase the number of Treg cells and the level of anti-inflammatory cytokines, thus alleviating the autoimmunity. Dietary interventions consist of changes of dietary structure and the supplement of exogenous molecules, functioning in decrease of pDCs and recovery of normal intestinal microbiota. FMT means the transfer of gut microbiota from healthy individuals to SLE patients, aiming to restore balanced intestinal flora, rebuild intestinal homeostasis, and achieve the treatment of intestinal and extraintestinal diseases. Abbreviations: Treg, regulatory T cell; pDCs, plasmacytoid dendritic cells; FMT, fecal microbiota transplantation

Enrichment of Lactobacillus reuteri and Turicibacter spp. and an increase of Firmicutes/Bacteroidetes ratio were identified in acidic pH water-treated SNF1 mice. Further, to ensure whether these changes influenced the progression of SLE, the microbiota-manipulated mice were established by oral gavage of feces from acidic pH water-recipient mice to neutral pH water-recipient mice. Results revealed that this group of mice showed reduced disease activation with decreased proteinuria and autoantibodies (Johnson et al. 2015). Another dietary interventional study on MRL/lpr mice using three different diets, that is, the Teklad 7013, Harlan 2018, and Research Diets, Inc. D11112226, demonstrated that mice fed with Harlan 2018 had higher Lachnospiraceae in feces compared with D11112226-fed mice, accompanied with severe lupus phenotypes (Edwards et al. 2017). Moreover, Vorobyev and coworkers have treated the lupus-prone NZM2410/J mice with three different diets (caloric restriction, Western diet, and control diet). Results showed that caloric restriction protected NZM2410/J mice from the development of lupus, while most disease symptoms were found in mice fed with Western diet (Vorobyev et al. 2019), revealing that gut microbiota reshaped by different diets has an effect on disease susceptibility. As in-depth analysis has shown, only co-occurrence patterns of functional microbial community 1 and functional fungal community 4 in taxa were relevant to diet, and transcriptomic analysis further indicated that diet, mycobiome, and microbiome correlated with the immune-related genes and pathways (Vorobyev et al. 2019).

536

P. Yi et al.

Except for the alteration of entire dietary construction, exogenous supplement of some dietary elements provides another approach for the management of SLE. Polyphenols from oranges and apples were reported to be closely correlated with the intestinal microorganisms (Cuervo et al. 2015). Flavone, flavanone, and dihydrochalcone intake was positively associated with the gut Blautia, Lactobacillus, and Bifidobacterium, respectively in SLE patients; while there was positive association between dihydroflavonols and Faecalibacterium, reversed correlation between flavonol and Bifidobacterium was identified in the controls. Apples and oranges were in association with the Bifidobacterium and Lactobacillus that were decreased in SLE, providing the idea that elements from daily dietary food may be of great significance in controlling SLE progression through modulating the microorganisms (Cuervo et al. 2015). Besides, the effect of dietary resistant starch (RS) on gut microbiota and SLE progression has been determined in the TLR7dependent mouse models of lupus (Zegarra-Ruiz et al. 2019). The results demonstrated that RS intake could suppress disease progression in TLR7.1 Tg mice compared with those without RS supplementation, primarily through downregulating the amount of the gut Lactobacillus reuteri that could increase the pDC and IFN pathway. Nevertheless, RS did not affect the microbial diversity; instead, it deterred the Lactobacillus reuteri translocation from gut to other sites such as the MLN, liver, and spleen via SCFAs from RS. Further analysis illuminated that RS intake elevated the expression of molecules related to gut epithelial integrity and antimicrobial defense. These results indicated that RS protected TLR7.1 Tg mice from lupus development by suppressing gut leakiness and microbiota translocation to distal organs. The similar results have been identified in the ileum, cecum, and colon (Zegarra-Ruiz et al. 2019). Exogenous SCFA could also help to reserve the gut function. He et al. adopted the sodium butyrate to redress the microbiota disorders in MRL/lpr lupus-prone mice and found that butyrate treatment effectively ameliorated the SLE progression (He et al. 2020a). In particular, butyrate could increase the gut microbial adversity and alter the microbial composition in MRL/lpr mice, representing as the increased proportion of Firmicutes, Clostridia, Clostridiales, Lachnospiraceae, Ruminococcaceae, etc. and the decrease of Bacteroidetes, Bacteroidales, and Bacteroidia. Notably, the increase of members of phylum Firmicutes was associated with the improvement in energy metabolism (Turnbaugh et al. 2006). Butyrate also orchestrated the gut microbiota by modulating the pH value of gut lumen (Canani et al. 2011), as well as regulated the immune response by balancing Th17 cells and Tregs (Cao et al. 2018; Zhang et al. 2019). Moreover, the fiber-derived SCFA could epigenetically regulate B-cell intrinsic functions and B-cell differentiation in a dosedependent manner. SCFAs inhibited autoantibody production and autoimmunity through upregulating Aicda- and Prdm1-dampened miRNA by inhibiting the histone deacetylation (HDAC) of miRNA host genes (Sanchez et al. 2020). The oral supplement of valproic acid in MRL/lpr mice suppressed class switch recombination (CSR), somatic hypermutation (SHM), and the differentiation of plasma cells through inhibiting the activity of histone deacetylases, causing the amelioration of lupus (White et al. 2014). Generally, in physical conditions, SCFAs play crucial

20

Microorganisms in Pathogenesis and Management of Systemic. . .

537

roles in preserving the dynamic host defense equilibrium and suppressing the generation of autoimmunity. However, gut microbiota in disease conditions such as in SLE is altered, which in turn reduce the levels of SCFAs (Sanchez et al. 2020). Therefore, exogenous intake of SCFAs such as butyrate is of great potential in modulating the intestinal microorganisms and ameliorating SLE progression.

20.4.2 Probiotics Probiotics refer to a group of live microorganisms that could colonize in the GIT to alter the balance of the host intestinal flora when administered with adequate amount, contributing to a beneficial effect on the host (Gareau et al. 2010). Prebiotics are substrates that are selectively used by host microorganisms and beneficial for the host health, including fructooligosaccharide, galactooligosaccharide, and inulin (Gibson et al. 2017). At present, there is no relevant literature on prebiotics in SLE. Four premises should be met for a microorganism to become a probiotic, as follows: (1) the safety is guaranteed, (2) have the capability to colonize in human gut and secrete antimicrobial components, (3) possess beneficial clinical effect, and (4) keep stable during storage and transit (Nayak 2010). The most common probiotics are Bifidobacterium spp. and Lactobacillus spp. The functional mechanisms of probiotics are versatile in diseases, for instance, attenuating the pro-inflammatory responses by inducing immune tolerance. It has been recognized that several probiotics could secret molecules that are associated with the differentiation of naive CD4+T cells into Treg cells (Josefowicz et al. 2012). Several Lactobacillus and Bifidobacterium strains were reported to induce the production of Treg cells from Th cells (López et al. 2011; Atarashi et al. 2013). Treg cells are capable of generating anti-inflammatory cytokines including IL-10 and transforming growth factor-β (TGF-β) that restrained the proliferation and inflammatory responses of other immune cells (Josefowicz et al. 2012). Modulating the dysregulated cytokines is another mechanism for probiotics in SLE. As an example, it has been recognized that IFN-γ was dramatically elevated in SLE patients, which may contribute to SLE progression. Probiotic such as B. bifidum was suggested to reduce the production of IFN-γ in NK cells (Fink et al. 2007). Previous study has unraveled the efficacy of Lactobacillus paracasei GMNL-32 (GMNL-32), Lactobacillus reuteri GMNL-89 (GMNL-89), and L. reuteri GMNL263 (GMNL-263) in reducing liver injuries in NZB/W F1 mice (Hsu et al. 2017). Treatment with GMNL-263, GMNL-89, and GMNL-263 substantially lowered hepatic apoptosis and inflammation markers, representing as the decrease in matrix metalloproteinase-9 activity, inducible nitric oxide synthase generation, and C-reactive protein (CRP). The hepatic TNF-α, IL-1β, and IL-6 proteins were also suppressed after supplementation of GMNL-263, GMNL-89, and GMNL-263 in lupus mice (Hsu et al. 2017). In pristane-inducible lupus mouse model, Lactobacillus rhamnosus and Lactobacillus delbrueckii treatment reduced the level of ANA, anti-dsDNA, anti-RNP antibodies and pro-inflammatory IFN-γ and IL-17, as well as decreased the number of Th1–Th17 cells (Mardani et al. 2018). Marta Toral et al.

538

P. Yi et al.

have validated the roles of a probiotics, namely, the Lactobacillus fermentum CECT5716 (LC40), in management of lupus of female NZBWF1 mouse model (Toral et al. 2019). Results revealed that mice treated with LC40 were manifested with less aggressive lupus activity and milder splenomegaly and cardiac and renal hypertrophy. LC40 could downregulate the B cells, Treg, and Th-1 cells in MLNs, as well as suppress the release of pro-inflammatory cytokines. Moreover, LC40 was capable of reversing the endothelial dysfunction in vessels of lupus mice by abrogating the increased NADPH oxidase-driven superoxide and eNOS phosphorylation and also participated in the regulation of gut microbiota composition and gut barrier integrity (Toral et al. 2019). These conclusions have shown the significant roles and diverse mechanisms of LC40 in alleviating SLE and preventing vascular disorders, which enabled it to be a potential therapeutic agent. In MRL/lpr mouse model, Lactobacillus treatment has been also proven to decrease the immune deposition in the kidney and increase the level of IL-10, as well as interrupt Th17Treg balance and induce the production of Treg cells, leading to the disease amelioration (Mu et al. 2017b). Similarly, oral B. fragilis ATCC 25285 corrected Th17-Treg unbalance and regulated B-cell immune responses by increasing CD1d level and reducing CD86 level partly by Est-1 and SHP-2 signaling pathway, to attenuate the disease activity and autoantibody production in lupus-prone MRL/lpr mice (Li et al. 2020b).

20.4.3 FMT FMT is a medical procedure which directly alters gut microbiota of the recipient by transferring the fecal material from a healthy donor into the intestinal tract of a patient to restore a healthy balance of gut bacteria. FMT is mainly introduced into the patient’s gastrointestinal tract through gastroscopy, enteroscopy, naso-jejunal tube, enema, and capsule. It has become one of the most important methods to regulate intestinal microbiota disorders in clinical practice and has been considered to be the extremely effective therapy for recurrent or refractory Clostridium difficile infection (Lee et al. 2016). Meanwhile, animal studies and randomized controlled trials (RCTs) have proposed more potential clinical indications for FMT including digestive diseases such as active ulcerative colitis, Crohn’s disease, and irritable bowel syndrome, neurological diseases such as hepatic encephalopathy and autism, and metabolic diseases such as metabolic syndrome and type 2 diabetes (Wu et al. 2017; Kang et al. 2017; Vrieze et al. 2012). However, in autoimmune diseases, such as SLE, RA, and psoriasis, researches on FMT are just beginning; most of them are still at the stage of animal experiments or small-scale phase I clinical trials; the efficacy of FMT remains unknown. SeungChul Choi and colleagues have discovered that horizontal transfer of the gut microbiota by co-housing TC mice and healthy control mice for 6 months, in order that mice could exchange and share the gut microbiota of each other, significantly mitigated autoimmunity responses in TC mice (Choi et al. 2020). Another study found that short-term antibiotic treatment of lupus-susceptible MRL/lpr mice

20

Microorganisms in Pathogenesis and Management of Systemic. . .

539

prior to the onset of lupus would aggravate lupus severity by depleting beneficial gut microbiota and exacerbate gut microbiota dysbiosis. In contrast, transfer of gut microbiota from healthy control mice to MRL/lpr mice at following 1 week after antibiotic exposure repaired antibiotic-induced gut microbiota dysbiosis and attenuated lupus-like pathological symptoms (Zhang et al. 2020). These preliminary attempts in lupus animal models have shown the potential therapeutic effects of FMT in SLE. Meanwhile, the first single-arm clinical trial of FMT for SLE patients is underway to evaluate the safety and efficacy in adult patients with active lupus despite under standard background treatments. Although FMT is currently considered to be a safe and less side effects method for gut microbiota regulation, and the promising immunomodulatory effects of regulated gut microbiota have been readily documented, the safety and efficacy of FMT in complex autoimmune diseases such as SLE is not yet clear. In the future, more mechanistic and clinical studies will be needed to answer these questions in SLE.

20.4.4 Antibiotics and Others Drugs Though early treatment of vancomycin or 2-week oral mixed antibiotics (ampicillin, vancomycin, neomycin, and metronidazole) in female MRL/lpr mice aggravated lupus development (Mu et al. 2020; Zhang et al. 2020), vancomycin administration and/or mixed antibiotics have been demonstrated to ameliorate lupus symptoms in MRL/lpr mice through increasing the level of anti-inflammatory factor IL-10 and reducing the level of pro-inflammatory factor IL-17 and IFN-γ, as well as regulating the components of the intestinal microorganisms characterized with removed Lachnospiraceae and greater abundance of Lactobacillus spp. (Mu et al. 2017a). Furthermore, vancomycin treatment enhanced the defense function of gut barrier to suppress the translocation of LPS, the cell wall component of the pathobiont Proteobacteria that induces lupus (Mu et al. 2017a). In NZBWF1 mice, antibiotics administration could delay the development of hypertension and renal damage through improving the function of endothelial cells and decreasing oxidative stress and Th17 infiltration of vessels (De La Visitación et al. 2021). However, the absence of effective response to vancomycin treatment has been found in postpartum MRL/ lpr mice (referring to mice after pregnancy and lactation) due to the inhibition of indoleamine 2,3-dioxygenase by enriched Lactobacillus animalis and differential production of IL-10 and IFN-γ (Mu et al. 2019). Notably, oral bacterial DNA from the gut microbiota induced the expansion of Breg cells in antibiotic-treated female MRL/lpr mice during the pre-disease stage and suppressed the onset of lupus (Mu et al. 2020). A conjugate of tuftsin and phosphorylcholine (TPC) could slow down the development of glomerulonephritis in SLE by decreasing abundances of Akkermansia and increased abundance of several genera in gut microorganisms, accompanied with reduced pro-inflammatory cytokines, increased IL-10 secretion, and expanded Treg subsets (Neuman et al. 2019). Besides, antioxidant N-

540

P. Yi et al.

acetylcysteine (NAC) changed gut microbial community featuring decreased abundance of Rikenellaceae and enriched Akkeransiaceae, Erysipelotrichaceae, and Muribaculaceae with no alteration in alpha-diversity and improved lupus development in MRL/lpr mice with decreased serum ANA, anti-dsDNA antibodies, and cytokines along with hepatic oxidative stress markers (Wang et al. 2021). Additionally, bromofuranone was reported to alleviate lupus symptoms depending on enhancing the efficacy of prednisone by decreasing Mucispirillum, Oscillospira, Bilophila, and Rikenella and increasing Anaerostipes, but not the function of itself (He et al. 2019), indicating the potential mechanisms of glucocorticoids regulating the gut microbiota in SLE. Glucocorticoid therapy may restore the Firmicutes/ Bacteroides ratio by reducing the level of Bacteroides. It has been shown that post-treated SLE patients with glucocorticoids (SLE+G) shared the similar gut microbiota to healthy controls and the gut microbiota of SLE patients without glucocorticoid treatment (SLE-G) showed significant differences with SLE+G and healthy controls (Guo et al. 2020b).

20.5

Conclusion and Perspective

In conclusion, microorganisms locating at the gut, oral cavity, skin, and blood regulate the progression of SLE through several mechanisms such as interfering the host’s immune response and inflammatory process. The alterations of microbial diversity and compositions have been recognized in both the lupus-prone mice models and SLE patients. Moreover, the gut leakage and molecular mimicry are possible mechanisms underlying the intestinal microbiota-host interaction, which induce the development of autoimmunity in SLE. In the leaky gut, the intestinal barrier is destroyed due to the dysregulated microbiota, which in turn admits the translocation of microorganisms to other tissues or organs. Subsequently, autoimmunity is activated by microbiota and their components, representing as the overproduction of multiple autoantibodies and pro-inflammatory cytokines, as well as reduced anti-inflammatory cytokines. Notably, the anti-Ro60 antibody induced by some Ro60 orthologs from several microbiota has been commonly identified in lupus; thus the anti-Ro60 antibody has been proposed as a diagnostic biomarker for SLE. Besides, the progress of SLE is distinguished between male and female with distinct hormone patterns. On this setting, several therapeutic strategies focusing on the microbiota regulation, especially for the gut commensal, have been suggested for the management of SLE, including dietary intervention, probiotics, drugs, and FMT. These methods are intended to repair the inordinate microbiota environment and reduce the adverse effect caused by microbiota perturbance. Importantly, we have noticed that SCFAs play pivotal roles in regulating specific microbiota that participates in the development of SLE. Actually, SCFA-related mechanisms are involved in a wide spectrum of microbiota-related autoimmunity diseases, including MS (Melbye et al. 2019), RA (Häger et al. 2019), and Crohn’s disease (Parada Venegas et al. 2019), providing a great perspective in clinical applications as an approach of dietary intervention.

20

Microorganisms in Pathogenesis and Management of Systemic. . .

541

References Adachi S, Yoshida H, Kataoka H, Nishikawa S (1997) Three distinctive steps in Peyer's patch formation of murine embryo. Int Immunol 9:507–514 Adak A, Khan MR (2019) An insight into gut microbiota and its functionalities. Cell Mol Life Sci 76:473–493 Adler CJ, Dobney K, Weyrich LS, Kaidonis J, Walker AW, Haak W, Bradshaw CJ, Townsend G, Sołtysiak A, Alt KW, Parkhill J, Cooper A (2013) Sequencing ancient calcified dental plaque shows changes in oral microbiota with dietary shifts of the Neolithic and Industrial revolutions. Nat Genet 45:450-5, 455e1 Anderson JW, Baird P, Davis RH Jr, Ferreri S, Knudtson M, Koraym A, Waters V, Williams CL (2009) Health benefits of dietary fiber. Nutr Rev 67:188–205 Andrade RM, Alarcón GS, Fernández M, Apte M, Vilá LM, Reveille JD (2007) Accelerated damage accrual among men with systemic lupus erythematosus: XLIV. Results from a multiethnic US cohort. Arthritis Rheum 56:622–630 Aringer M (2021) Systemic lupus erythematosus does not prevent antibody responses to SARSCoV-2. Lancet Rheumatol 3:e538–e540 Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, Kim S, Fritz JV, Wilmes P, Ueha S, Matsushima K, Ohno H, Olle B, Sakaguchi S, Taniguchi T, Morita H, Hattori M, Honda K (2013) Treg induction by a rationally selected mixture of clostridia strains from the human microbiota. Nature 500:232–236 Atarashi K, Tanoue T, Ando M, Kamada N, Nagano Y, Narushima S, Suda W, Imaoka A, Setoyama H, Nagamori T, Ishikawa E, Shima T, Hara T, Kado S, Jinnohara T, Ohno H, Kondo T, Toyooka K, Watanabe E, Yokoyama S, Tokoro S, Mori H, Noguchi Y, Morita H, Ivanov I, Sugiyama T, Nuñez G, Camp JG, Hattori M, Umesaki Y, Honda K (2015) Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163:367–380 Azzouz D, Omarbekova A, Heguy A, Schwudke D, Gisch N, Rovin BH, Caricchio R, Buyon JP, Alekseyenko AV, Silverman GJ (2019) Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal. Ann Rheum Dis 78:947–956 Bagavant H, Dunkleberger ML, Wolska N, Sroka M, Rasmussen A, Adrianto I, Montgomery C, Sivils K, Guthridge JM, James JA, Merrill JT, Deshmukh US (2019) Antibodies to periodontogenic bacteria are associated with higher disease activity in lupus patients. Clin Exp Rheumatol 37:106–111 Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, Dorgham K, Philippot Q, Rosain J, Béziat V, Manry J, Shaw E, Haljasmägi L, Peterson P, Lorenzo L, Bizien L, TrouilletAssant S, Dobbs K, De Jesus AA, Belot A, Kallaste A, Catherinot E, Tandjaoui-Lambiotte Y, Le Pen J, Kerner G, Bigio B, Seeleuthner Y, Yang R, Bolze A, Spaan AN, Delmonte OM, Abers MS, Aiuti A, Casari G, Lampasona V, Piemonti L, Ciceri F, Bilguvar K, Lifton RP, Vasse M, Smadja DM, Migaud M, Hadjadj J, Terrier B, Duffy D, Quintana-Murci L, Van De Beek D, Roussel L, Vinh DC, Tangye SG, Haerynck F, Dalmau D, Martinez-Picado J, Brodin P, Nussenzweig MC, Boisson-Dupuis S, Rodríguez-Gallego C, Vogt G, Mogensen TH, Oler AJ, Gu J, Burbelo PD, Cohen JI, Biondi A, Bettini LR, D'angio M, Bonfanti P, Rossignol P, Mayaux J, Rieux-Laucat F, Husebye ES, Fusco F, Ursini MV, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Castagnoli R, Montagna D, Licari A, Marseglia GL, Duval X, Ghosn J, Tsang JS, Goldbach-Mansky R, Kisand K, Lionakis MS, Puel A, Zhang SY, Holland SM, Gorochov G, Jouanguy E, Rice CM, Cobat A, Notarangelo LD, Abel L, Su HC, Casanova JL (2020) Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 370:eabd4585 Belkaid Y, Segre JA (2014) Dialogue between skin microbiota and immunity. Science 346:954– 959 Bellocchi C, Fernández-Ochoa Á, Montanelli G, Vigone B, Santaniello A, Quirantes-Piné R, Borrás-Linares I, Gerosa M, Artusi C, Gualtierotti R, Segura-Carrettero A, Alarcón-Riquelme

542

P. Yi et al.

ME, Beretta L (2019) Identification of a shared microbiomic and metabolomic profile in systemic autoimmune diseases. J Clin Med 8:1291 Biasucci G, Benenati B, Morelli L, Bessi E, Boehm G (2008) Cesarean delivery may affect the early biodiversity of intestinal bacteria. J Nutr 138:1796s–1800s Brown J, Quattrochi B, Everett C, Hong BY, Cervantes J (2021) Gut commensals, dysbiosis, and immune response imbalance in the pathogenesis of multiple sclerosis. Mult Scler 27:807–811 Buford TW (2017) (Dis)Trust your gut: the gut microbiome in age-related inflammation, health, and disease. Microbiome 5:80 Canani RB, Costanzo MD, Leone L, Pedata M, Meli R, Calignano A (2011) Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol 17:1519– 1528 Canfora EE, Meex RCR, Venema K, Blaak EE (2019) Gut microbial metabolites in obesity, NAFLD and T2DM. Nat Rev Endocrinol 15:261–273 Cani PD (2018) Human gut microbiome: hopes, threats and promises. Gut 67:1716–1725 Cao T, Zhang X, Chen D, Zhang P, Li Q, Muhammad A (2018) The epigenetic modification during the induction of Foxp3 with sodium butyrate. Immunopharmacol Immunotoxicol 40:309–318 Chehoud C, Rafail S, Tyldsley AS, Seykora JT, Lambris JD, Grice EA (2013) Complement modulates the cutaneous microbiome and inflammatory milieu. Proc Natl Acad Sci U S A 110:15061–15066 Chen BD, Jia XM, Xu JY, Zhao LD, Ji JY, Wu BX, Ma Y, Li H, Zuo XX, Pan WY, Wang XH, Ye S, Tsokos GC, Wang J, Zhang X (2020a) An autoimmunogenic and proinflammatory profile defined by the gut microbiota of patients with untreated systemic lupus erythematosus. Arthritis Rheumatol 73:232–243 Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, Ling Y, Huang D, Song S, Zhang D, Qian Z, Li T, Shen Y, Lu H (2020b) A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19. Zhejiang Da Xue Xue Bao Yi Xue Ban 49:215–219 Chen BD, Jia XM, Xu JY, Zhao LD, Ji JY, Wu BX, Ma Y, Li H, Zuo XX, Pan WY, Wang XH, Ye S, Tsokos GC, Wang J, Zhang X (2021) An autoimmunogenic and proinflammatory profile defined by the gut microbiota of patients with untreated systemic lupus erythematosus. Arthritis Rheumatol 73:232–243 Choi SC, Brown J, Gong M, Ge Y, Zadeh M, Li W, Croker BP, Michailidis G, Garrett TJ, Mohamadzadeh M, Morel L (2020) Gut microbiota dysbiosis and altered tryptophan catabolism contribute to autoimmunity in lupus-susceptible mice. Sci Transl Med 12:eaax2220 Clancy RM, Marion MC, Ainsworth HC, Blaser MJ, Chang M, Howard TD, Izmirly PM, Lacher C, Masson M, Robins K, Buyon JP, Langefeld CD (2020) Salivary dysbiosis and the clinical spectrum in anti-Ro positive mothers of children with neonatal lupus. J Autoimmun 107:102354 Corrêa JD, Calderaro DC, Ferreira GA, Mendonça SMS, Fernandes GR, Xiao E, Teixeira AL, Leys EJ, Graves DT, Silva TA (2017) Subgingival microbiota dysbiosis in systemic lupus erythematosus: association with periodontal status. Microbiome 5:34 Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R (2009) Bacterial community variation in human body habitats across space and time. Science 326:1694–1697 Costerton JW (1999) Introduction to biofilm. Int J Antimicrob Agents 11:217–221. Discussion 237–9 Cuervo A, Hevia A, López P, Suárez A, Sánchez B, Margolles A, González S (2015) Association of polyphenols from oranges and apples with specific intestinal microorganisms in systemic lupus erythematosus patients. Nutrients 7:1301–1317 Cusick MF, Libbey JE, Fujinami RS (2012) Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol 42:102–111 Davies RJ, Lomer MC, Yeo SI, Avloniti K, Sangle SR, D'cruz DP (2012) Weight loss and improvements in fatigue in systemic lupus erythematosus: a controlled trial of a low glycaemic index diet versus a calorie restricted diet in patients treated with corticosteroids. Lupus 21:649– 655

20

Microorganisms in Pathogenesis and Management of Systemic. . .

543

De Araújo Navas EA, Sato EI, Pereira DF, Back-Brito GN, Ishikawa JA, Jorge AO, Brighenti FL, Koga-Ito CY (2012) Oral microbial colonization in patients with systemic lupus erythematous: correlation with treatment and disease activity. Lupus 21:969–977 De La Visitación N, Robles-Vera I, Toral M, Gómez-Guzmán M, Sánchez M, Moleón J, GonzálezCorrea C, Martín-Morales N, O'Valle F, Jiménez R, Romero M, Duarte J (2021) Gut microbiota contributes to the development of hypertension in a genetic mouse model of systemic lupus erythematosus. Br J Pharmacol 178(18):3708–3729 De Oliveira GLV, Leite AZ, Higuchi BS, Gonzaga MI, Mariano VS (2017) Intestinal dysbiosis and probiotic applications in autoimmune diseases. Immunology 152:1–12 Dewhirst FE, Chen T, Izard J, Paster BJ, Tanner AC, Yu WH, Lakshmanan A, Wade WG (2010) The human oral microbiome. J Bacteriol 192:5002–5017 Dicksved J, Schreiber O, Willing B, Petersson J, Rang S, Phillipson M, Holm L, Roos S (2012) Lactobacillus reuteri maintains a functional mucosal barrier during DSS treatment despite mucus layer dysfunction. PLoS One 7:e46399 Dixon FJ, Andrews BS, Eisenberg RA, Mcconahey PJ, Theofilopoulos AN, Wilson CB (1978) Etiology and pathogenesis of a spontaneous lupus-like syndrome in mice. Arthritis Rheum 21: S64–S67 Duncan SH, Belenguer A, Holtrop G, Johnstone AM, Flint HJ, Lobley GE (2007) Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces. Appl Environ Microbiol 73:1073–1078 Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA (2005) Diversity of the human intestinal microbial flora. Science 308:1635–1638 Edwards MR, Dai R, Heid B, Cecere TE, Khan D, Mu Q, Cowan C, Luo XM, Ahmed SA (2017) Commercial rodent diets differentially regulate autoimmune glomerulonephritis, epigenetics and microbiota in MRL/lpr mice. Int Immunol 29:263–276 Elkan AC, Anania C, Gustafsson T, Jogestrand T, Hafström I, Frostegård J (2012) Diet and fatty acid pattern among patients with SLE: associations with disease activity, blood lipids and atherosclerosis. Lupus 21:1405–1411 Ferreira A, Oliveira ESA, Bettencourt P (2021) Chronic treatment with hydroxychloroquine and SARS-CoV-2 infection. J Med Virol 93:755–759 Fink LN, Zeuthen LH, Christensen HR, Morandi B, Frøkiaer H, Ferlazzo G (2007) Distinct gut-derived lactic acid bacteria elicit divergent dendritic cell-mediated NK cell responses. Int Immunol 19:1319–1327 Freites Nuñez DD, Leon L, Mucientes A, Rodriguez-Rodriguez L, Font Urgelles J, Madrid García A, Colomer JI, Jover JA, Fernandez-Gutierrez B, Abasolo L (2020) Risk factors for hospital admissions related to COVID-19 in patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis 79:1393–1399 Fu W, Liu Y, Liu F, Liu C, Li J, Niu J, Han P, Xu D, Hou J, Ma Y, Feng J, Li Z, Mu R, Yang G (2021) A novel autoantibody induced by bacterial biofilm conserved components aggravates lupus nephritis. Front Immunol 12:656090 Fukui H (2015) Gut-liver axis in liver cirrhosis: how to manage leaky gut and endotoxemia. World J Hepatol 7:425–442 Furuta Y, Tsai SH, Kinoshita M, Fujimoto K, Okumura R, Umemoto E, Kurashima Y, Kiyono H, Kayama H, Takeda K (2017) E-NPP3 controls plasmacytoid dendritic cell numbers in the small intestine. PLoS One 12:e0172509 Gallo RL, Hooper LV (2012) Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol 12:503–516 Gallo PM, Rapsinski GJ, Wilson RP, Oppong GO, Sriram U, Goulian M, Buttaro B, Caricchio R, Gallucci S, Tükel Ç (2015) Amyloid-DNA composites of bacterial biofilms stimulate autoimmunity. Immunity 42:1171–1184 Ganju P, Nagpal S, Mohammed MH, Nishal Kumar P, Pandey R, Natarajan VT, Mande SS, Gokhale RS (2016) Microbial community profiling shows dysbiosis in the lesional skin of vitiligo subjects. Sci Rep 6:18761

544

P. Yi et al.

Gareau MG, Sherman PM, Walker WA (2010) Probiotics and the gut microbiota in intestinal health and disease. Nat Rev Gastroenterol Hepatol 7:503–514 Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Tissot Dupont H, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D (2020) Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 56: 105949 Gianfrancesco M, Hyrich KL, Al-Adely S, Carmona L, Danila MI, Gossec L, Izadi Z, Jacobsohn L, Katz P, Lawson-Tovey S, Mateus EF, Rush S, Schmajuk G, Simard J, Strangfeld A, Trupin L, Wysham KD, Bhana S, Costello W, Grainger R, Hausmann JS, Liew JW, Sirotich E, Sufka P, Wallace ZS, Yazdany J, Machado PM, Robinson PC (2020) Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis 79:859–866 Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, Scott K, Stanton C, Swanson KS, Cani PD, Verbeke K, Reid G (2017) Expert consensus document: the international scientific association for probiotics and prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol 14:491–502 Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ, Samuel BS, Gordon JI, Relman DA, Fraser-Liggett CM, Nelson KE (2006) Metagenomic analysis of the human distal gut microbiome. Science 312:1355–1359 Greiling TM, Dehner C, Chen X, Hughes K, Iñiguez AJ, Boccitto M, Ruiz DZ, Renfroe SC, Vieira SM, Ruff WE, Sim S, Kriegel C, Glanternik J, Chen X, Girardi M, Degnan P, Costenbader KH, Goodman AL, Wolin SL, Kriegel MA (2018) Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus. Sci Transl Med 10:eaan2306 Grice EA (2015) The intersection of microbiome and host at the skin interface: genomic- and metagenomic-based insights. Genome Res 25:1514–1520 Guerreiro CS, Calado Â, Sousa J, Fonseca JE (2018) Diet, microbiota, and gut permeability-the unknown triad in rheumatoid arthritis. Front Med (Lausanne) 5:349 Guo G, Ye L, Shi X, Yan K, Huang J, Lin K, Xing D, Ye S, Wu Y, Li B, Chen C, Xue X, Zhang H (2020a) Dysbiosis in peripheral blood mononuclear cell virome associated with systemic lupus erythematosus. Front Cell Infect Microbiol 10:131 Guo M, Wang H, Xu S, Zhuang Y, An J, Su C, Xia Y, Chen J, Xu ZZ, Liu Q, Wang J, Dan Z, Chen K, Luan X, Liu Z, Liu K, Zhang F, Xia Y, Liu X (2020b) Alteration in gut microbiota is associated with dysregulation of cytokines and glucocorticoid therapy in systemic lupus erythematosus. Gut Microbes 11:1758–1773 Hagan T, Cortese M, Rouphael N, Boudreau C, Linde C, Maddur MS, Das J, Wang H, Guthmiller J, Zheng NY, Huang M, Uphadhyay AA, Gardinassi L, Petitdemange C, Mccullough MP, Johnson SJ, Gill K, Cervasi B, Zou J, Bretin A, Hahn M, Gewirtz AT, Bosinger SE, Wilson PC, Li S, Alter G, Khurana S, Golding H, Pulendran B (2019) Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell 178(1313–1328):E13 Häger J, Bang H, Hagen M, Frech M, Träger P, Sokolova MV, Steffen U, Tascilar K, Sarter K, Schett G, Rech J, Zaiss MM (2019) The role of dietary fiber in rheumatoid arthritis patients: a feasibility study. Nutrients 11:2392 Han H, Li Y, Fang J, Liu G, Yin J, Li T, Yin Y (2018) Gut microbiota and type 1 diabetes. Int J Mol Sci 19:995 He Z, Shao T, Li H, Xie Z, Wen C (2016) Alterations of the gut microbiome in Chinese patients with systemic lupus erythematosus. Gut Pathog 8:64 He Z, Kong X, Shao T, Zhang Y, Wen C (2019) Alterations of the gut microbiota associated with promoting efficacy of prednisone by bromofuranone in MRL/lpr mice. Front Microbiol 10:978 He H, Xu H, Xu J, Zhao H, Lin Q, Zhou Y, Nie Y (2020a) Sodium butyrate ameliorates gut microbiota dysbiosis in lupus-like mice. Front Nutr 7:604283

20

Microorganisms in Pathogenesis and Management of Systemic. . .

545

He J, Chan T, Hong X, Zheng F, Zhu C, Yin L, Dai W, Tang D, Liu D, Dai Y (2020b) Microbiome and metabolome analyses reveal the disruption of lipid metabolism in systemic lupus erythematosus. Front Immunol 11:1703 Hevia A, Milani C, López P, Cuervo A, Arboleya S, Duranti S, Turroni F, González S, Suárez A, Gueimonde M, Ventura M, Sánchez B, Margolles A (2014) Intestinal dysbiosis associated with systemic lupus erythematosus. mBio 5:e01548–e01514 Hsu TC, Huang CY, Liu CH, Hsu KC, Chen YH, Tzang BS (2017) Lactobacillus paracasei GMNL-32, Lactobacillus reuteri GMNL-89 and L. reuteri GMNL-263 ameliorate hepatic injuries in lupus-prone mice. Br J Nutr 117:1066–1074 Hu J, Wang C, Huang X, Yi S, Pan S, Zhang Y, Yuan G, Cao Q, Ye X, Li H (2021) Gut microbiotamediated secondary bile acids regulate dendritic cells to attenuate autoimmune uveitis through TGR5 signaling. Cell Rep 36:109726 Huang C, Yi X, Long H, Zhang G, Wu H, Zhao M, Lu Q (2020) Disordered cutaneous microbiota in systemic lupus erythematosus. J Autoimmun 108:102391 Izmirly PM, Wan I, Sahl S, Buyon JP, Belmont HM, Salmon JE, Askanase A, Bathon JM, Geraldino-Pardilla L, Ali Y, Ginzler EM, Putterman C, Gordon C, Helmick CG, Parton H (2017) The incidence and prevalence of systemic lupus erythematosus in New York County (Manhattan), New York: the manhattan lupus surveillance program. Arthritis Rheumatol 69: 2006–2017 Izmirly PM, Kim MY, Samanovic M, Fernandez-Ruiz R, Ohana S, Deonaraine KK, Engel AJ, Masson M, Xie X, Cornelius AR, Herati RS, Haberman RH, Scher JU, Guttmann A, Blank RB, Plotz B, Haj-Ali M, Banbury B, Stream S, Hasan G, Ho G, Rackoff P, Blazer AD, Tseng CE, Belmont HM, Saxena A, Mulligan MJ, Clancy RM, Buyon JP (2022) Evaluation of immune response and disease status in SLE patients following SARS-CoV-2 vaccination. Arthritis Rheumatol 74(2):284–294 Jensen JL, Bergem HO, Gilboe IM, Husby G, Axéll T (1999) Oral and ocular sicca symptoms and findings are prevalent in systemic lupus erythematosus. J Oral Pathol Med 28:317–322 Johnson BM, Gaudreau MC, Al-Gadban MM, Gudi R, Vasu C (2015) Impact of dietary deviation on disease progression and gut microbiome composition in lupus-prone SNF1 mice. Clin Exp Immunol 181:323–337 Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564 Kang DW, Adams JB, Gregory AC, Borody T, Chittick L, Fasano A, Khoruts A, Geis E, Maldonado J, Mcdonough-Means S, Pollard EL, Roux S, Sadowsky MJ, Lipson KS, Sullivan MB, Caporaso JG, Krajmalnik-Brown R (2017) Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 5:10 Kang JH, Xu H, Choi SE, Park DJ, Lee JK, Kwok SK, Kim SK, Choe JY, Kim HA, Sung YK, Shin K, Lee SS (2020) Obesity increases the incidence of new-onset lupus nephritis and organ damage during follow-up in patients with systemic lupus erythematosus. Lupus 29:578–586 Kiriakidou M, Ching CL (2020) Systemic lupus erythematosus. Ann Intern Med 172:Itc81–Itc96 Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, Nomicos E, Polley EC, Komarow HD, Murray PR, Turner ML, Segre JA (2012) Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res 22:850–859 König J, Wells J, Cani PD, García-Ródenas CL, Macdonald T, Mercenier A, Whyte J, Troost F, Brummer RJ (2016) Human intestinal barrier function in health and disease. Clin Transl Gastroenterol 7:e196 Konig MF, Kim AH, Scheetz MH, Graef ER, Liew JW, Simard J, Machado PM, Gianfrancesco M, Yazdany J, Langguth D, Robinson PC (2020) Baseline use of hydroxychloroquine in systemic lupus erythematosus does not preclude SARS-CoV-2 infection and severe COVID-19. Ann Rheum Dis 79:1386–1388 Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, Weese JS, Collins S, Moayyedi P, Crowther M, Ropeleski MJ, Jayaratne P, Higgins D, Li Y, Rau NV, Kim PT

546

P. Yi et al.

(2016) Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent clostridium difficile infection: a randomized clinical trial. JAMA 315: 142–149 Leung C, Rivera L, Furness JB, Angus PW (2016) The role of the gut microbiota in NAFLD. Nat Rev Gastroenterol Hepatol 13:412–425 Li Y, Wang H-F, Li X, Li H-X, Zhang Q, Zhou H-W, He Y, Li P, Fu C, Zhang X-H, Qiu Y-R, Li J-L (2019) Disordered intestinal microbes are associated with the activity of systemic lupus erythematosus. Clin Sci 133:821–838 Li BZ, Zhou HY, Guo B, Chen WJ, Tao JH, Cao NW, Chu XJ, Meng X (2020a) Dysbiosis of oral microbiota is associated with systemic lupus erythematosus. Arch Oral Biol 113:104708 Li D, Pan Y, Xia X, Liang J, Liu F, Dou H, Hou Y (2020b) Bacteroides fragilis alleviates the symptoms of lupus nephritis via regulating CD1d and CD86 expressions in B cells. Eur J Pharmacol 884:173421 López P, González-Rodríguez I, Gueimonde M, Margolles A, Suárez A (2011) Immune response to Bifidobacterium bifidum strains support Treg/Th17 plasticity. PLoS One 6:e24776 Luissint AC, Parkos CA, Nusrat A (2016) Inflammation and the intestinal barrier: leukocyteepithelial cell interactions, cell junction remodeling, and mucosal repair. Gastroenterology 151:616–632 Luo XM, Edwards MR, Mu Q, Yu Y, Vieson MD, Reilly CM, Ahmed SA, Bankole AA (2018) Gut microbiota in human systemic lupus erythematosus and a mouse model of lupus. Appl Environ Microbiol 84:e02288–e02217 Luo Z, Alekseyenko AV, Ogunrinde E, Li M, Li QZ, Huang L, Tsao BP, Kamen DL, Oates JC, Li Z, Gilkeson GS, Jiang W (2020) Rigorous plasma microbiome analysis method enables disease association discovery in clinic. Front Microbiol 11:613268 Ma Y, Xu X, Li M, Cai J, Wei Q, Niu H (2019) Gut microbiota promote the inflammatory response in the pathogenesis of systemic lupus erythematosus. Mol Med 25:35 Mageau A, Aldebert G, Van Gysel D, Papo T, Timsit JF, Sacre K (2021) SARS-CoV-2 infection among inpatients with systemic lupus erythematosus in France: a nationwide epidemiological study. Ann Rheum Dis 80:1101–1102 Magne F, Gotteland M, Gauthier L, Zazueta A, Pesoa S, Navarrete P, Balamurugan R (2020) The firmicutes/bacteroidetes ratio: a relevant marker of gut dysbiosis in obese patients? Nutrients 12: 1474 Mäkivuokko H, Tiihonen K, Tynkkynen S, Paulin L, Rautonen N (2010) The effect of age and non-steroidal anti-inflammatory drugs on human intestinal microbiota composition. Br J Nutr 103:227–234 Manfredo Vieira S, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, Khan N, Costa FRC, Tiniakou E, Greiling T, Ruff W, Barbieri A, Kriegel C, Mehta SS, Knight JR, Jain D, Goodman AL, Kriegel MA (2018) Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 359:1156–1161 Mardani F, Mahmoudi M, Esmaeili SA, Khorasani S, Tabasi N, Rastin M (2018) In vivo study: Th1-Th17 reduction in pristane-induced systemic lupus erythematosus mice after treatment with tolerogenic Lactobacillus probiotics. J Cell Physiol 234:642–649 Mariat D, Firmesse O, Levenez F, Guimarăes V, Sokol H, Doré J, Corthier G, Furet JP (2009) The firmicutes/bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol 9:123 Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, Von Bergen M, Mccoy KD, Macpherson AJ, Danska JS (2013) Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339:1084–1088 Marsh PD, Do T, Beighton D, Devine DA (2016) Influence of saliva on the oral microbiota. Periodontol 2000(70):80–92 Mcclain MT, Heinlen LD, Dennis GJ, Roebuck J, Harley JB, James JA (2005) Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat Med 11:85–89 Meehan CJ, Beiko RG (2014) A phylogenomic view of ecological specialization in the lachnospiraceae, a family of digestive tract-associated bacteria. Genome Biol Evol 6:703–713

20

Microorganisms in Pathogenesis and Management of Systemic. . .

547

Melbye P, Olsson A, Hansen TH, Søndergaard HB, Bang Oturai A (2019) Short-chain fatty acids and gut microbiota in multiple sclerosis. Acta Neurol Scand 139:208–219 Miller AL, Bessho S, Grando K, Tükel Ç (2021) Microbiome or infections: amyloid-containing biofilms as a trigger for complex human diseases. Front Immunol 12:638867 Moreau MC, Corthier G (1988) Effect of the gastrointestinal microflora on induction and maintenance of oral tolerance to ovalbumin in C3H/HeJ mice. Infect Immun 56:2766–2768 Moura-Alves P, Faé K, Houthuys E, Dorhoi A, Kreuchwig A, Furkert J, Barison N, Diehl A, Munder A, Constant P, Skrahina T, Guhlich-Bornhof U, Klemm M, Koehler AB, Bandermann S, Goosmann C, Mollenkopf HJ, Hurwitz R, Brinkmann V, Fillatreau S, Daffe M, Tümmler B, Kolbe M, Oschkinat H, Krause G, Kaufmann SH (2014) AhR sensing of bacterial pigments regulates antibacterial defence. Nature 512:387–392 Moyon Q, Sterlin D, Miyara M, Anna F, Mathian A, Lhote R, Ghillani-Dalbin P, Breillat P, Mudumba S, De Alba S, Cohen-Aubart F, Haroche J, Pha M, Boutin THD, Chaieb H, Flores PM, Charneau P, Gorochov G, Amoura Z (2022) BNT162b2 vaccine-induced humoral and cellular responses against SARS-CoV-2 variants in systemic lupus erythematosus. Ann Rheum Dis 81:575–583 Mu Q, Tavella VJ, Kirby JL, Cecere TE, Chung M, Lee J, Li S, Ahmed SA, Eden K, Allen IC, Reilly CM, Luo XM (2017a) Antibiotics ameliorate lupus-like symptoms in mice. Sci Rep 7: 13675 Mu Q, Zhang H, Liao X, Lin K, Liu H, Edwards MR, Ahmed SA, Yuan R, Li L, Cecere TE, Branson DB, Kirby JL, Goswami P, Leeth CM, Read KA, Oestreich KJ, Vieson MD, Reilly CM, Luo XM (2017b) Control of lupus nephritis by changes of gut microbiota. Microbiome 5: 73 Mu Q, Cabana-Puig X, Mao J, Swartwout B, Abdelhamid L, Cecere TE, Wang H, Reilly CM, Luo XM (2019) Pregnancy and lactation interfere with the response of autoimmunity to modulation of gut microbiota. Microbiome 7:105 Mu Q, Edwards MR, Swartwout BK, Cabana Puig X, Mao J, Zhu J, Grieco J, Cecere TE, Prakash M, Reilly CM, Puglisi C, Bachali P, Grammer AC, Lipsky PE, Luo XM (2020) Gut microbiota and bacterial DNA suppress autoimmunity by stimulating regulatory B cells in a murine model of lupus. Front Immunol 11:593353 Nayak SK (2010) Probiotics and immunity: a fish perspective. Fish Shellfish Immunol 29:2–14 Neuman H, Mor H, Bashi T, Givol O, Watad A, Shemer A, Volkov A, Barshack I, Fridkin M, Blank M, Shoenfeld Y, Koren O (2019) Helminth-based product and the microbiome of mice with lupus. Msystems 4:e00160–e00118 Nie C, He T, Zhang W, Zhang G, Ma X (2018) Branched chain amino acids: beyond nutrition metabolism. Int J Mol Sci 19:954 Ogunrinde E, Zhou Z, Luo Z, Alekseyenko A, Li QZ, Macedo D, Kamen DL, Oates JC, Gilkeson GS, Jiang W (2019) A link between plasma microbial translocation, microbiome, and autoantibody development in first-degree relatives of systemic lupus erythematosus patients. Arthritis Rheumatol 71:1858–1868 Oh J, Byrd AL, Park M, Kong HH, Segre JA (2016) Temporal stability of the human skin microbiome. Cell 165:854–866 O'Neill AM, Gallo RL (2018) Host-microbiome interactions and recent progress into understanding the biology of acne vulgaris. Microbiome 6:177 O'Neill LA, Golenbock D, Bowie AG (2013) The history of toll-like receptors - redefining innate immunity. Nat Rev Immunol 13:453–460 Ottman N, Smidt H, De Vos WM, Belzer C (2012) The function of our microbiota: who is out there and what do they do? Front Cell Infect Microbiol 2:104 Pablos JL, Galindo M, Carmona L, Lledó A, Retuerto M, Blanco R, Gonzalez-Gay MA, MartinezLopez D, Castrejón I, Alvaro-Gracia JM, Fernández Fernández D, Mera-Varela A, ManriqueArija S, Mena Vázquez N, Fernandez-Nebro A (2020) Clinical outcomes of hospitalised patients with COVID-19 and chronic inflammatory and autoimmune rheumatic diseases: a multicentric matched cohort study. Ann Rheum Dis 79:1544–1549

548

P. Yi et al.

Pachucki RJ, Corradetti C, Kohler L, Ghadiali J, Gallo PM, Nicastro L, Tursi SA, Gallucci S, Tükel Ç, Caricchio R (2020) Persistent bacteriuria and antibodies recognizing Curli/eDNA complexes from Escherichia coli are linked to flares in systemic lupus erythematosus. Arthritis Rheumatol 72:1872–1881 Parada Venegas D, De La Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, Harmsen HJM, Faber KN, Hermoso MA (2019) Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol 10: 277 Penders J, Thijs C, Vink C, Stelma FF, Snijders B, Kummeling I, Van Den Brandt PA, Stobberingh EE (2006) Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 118:511–521 Pessoa L, Aleti G, Choudhury S, Nguyen D, Yaskell T, Zhang Y, Li W, Nelson KE, Neto LLS, Sant'ana ACP, Freire M (2019) Host-microbial interactions in systemic lupus erythematosus and periodontitis. Front Immunol 10:2602 Pisetsky DS, Caster SA, Roths JB, Murphy ED (1982) Ipr gene control of the anti-DNA antibody response. J Immunol 128:2322–2325 Poore GD, Kopylova E, Zhu Q, Carpenter C, Fraraccio S, Wandro S, Kosciolek T, Janssen S, Metcalf J, Song SJ, Kanbar J, Miller-Montgomery S, Heaton R, Mckay R, Patel SP, Swafford AD, Knight R (2020) Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature 579:567–574 Potgieter M, Bester J, Kell DB, Pretorius E (2015) The dormant blood microbiome in chronic, inflammatory diseases. FEMS Microbiol Rev 39:567–591 Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Doré J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, Bork P, Ehrlich SD, Wang J (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464:59–65 Ramirez GA, Gerosa M, Beretta L, Bellocchi C, Argolini LM, Moroni L, Della Torre E, Artusi C, Nicolosi S, Caporali R, Bozzolo EP, Dagna L (2020) COVID-19 in systemic lupus erythematosus: data from a survey on 417 patients. Semin Arthritis Rheum 50:1150–1157 Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W (2017) The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology (Oxford) 56:1945–1961 Richard ML, Gilkeson G (2018) Mouse models of lupus: what they tell us and what they don't. Lupus Sci Med 5:e000199 Robbins A, Hentzien M, Toquet S, Didier K, Servettaz A, Pham BN, Giusti D (2019) Diagnostic utility of separate anti-Ro60 and anti-Ro52/TRIM21 antibody detection in autoimmune diseases. Front Immunol 10:444 Sánchez B, Hevia A, González S, Margolles A (2015) Interaction of intestinal microorganisms with the human host in the framework of autoimmune diseases. Front Immunol 6:594 Sanchez HN, Moroney JB, Gan H, Shen T, Im JL, Li T, Taylor JR, Zan H, Casali P (2020) B cellintrinsic epigenetic modulation of antibody responses by dietary fiber-derived short-chain fatty acids. Nat Commun 11:60 Sanchez-Piedra C, Diaz-Torne C, Manero J, Pego-Reigosa JM, Rúa-Figueroa Í, Gonzalez-Gay MA, Gomez-Reino J, Alvaro-Gracia JM (2020) Clinical features and outcomes of COVID-19 in patients with rheumatic diseases treated with biological and synthetic targeted therapies. Ann Rheum Dis 79:988–990 Saxena A, Guttmann A, Masson M, Kim MY, Haberman RH, Castillo R, Scher JU, Deonaraine KK, Engel AJ, Belmont HM, Blazer AD, Buyon JP, Fernandez-Ruiz R, Izmirly PM (2021) Evaluation of SARS-CoV-2 IgG antibody reactivity in patients with systemic lupus

20

Microorganisms in Pathogenesis and Management of Systemic. . .

549

erythematosus: analysis of a multi-racial and multi-ethnic cohort. Lancet Rheumatol 3:e585– e594 Sbidian E, Penso L, Herlemont P, Botton J, Baricault B, Semenzato L, Drouin J, Weill A, DraySpira R, Zureik M (2020) Comment on ‘Baseline use of hydroxychloroquine in systemic lupus erythematosus does not preclude SARS-CoV-2 infection and severe COVID-19’ by Konig et al. Long-term exposure to hydroxychloroquine or chloroquine and the risk of hospitalisation with COVID-19: a nationwide, observational cohort study in 54 873 exposed individuals and 155 689 matched unexposed individuals in France. Ann Rheum Dis. https://doi.org/10.1136/ annrheumdis-2020-218647 Scharschmidt TC, Fischbach MA (2013) What lives on our skin: ecology, genomics and therapeutic opportunities of the skin microbiome. Drug Discov Today Dis Mech 10:e83–e89 Schioppo T, Argolini LM, Sciascia S, Pregnolato F, Tamborini F, Miraglia P, Roccatello D, Sinico RA, Caporali R, Moroni G, Gerosa M (2021) Clinical and peculiar immunological manifestations of SARS-CoV-2 infection in systemic lupus erythematosus patients. Rheumatology (Oxford) 61:1928–1935 Selber-Hnatiw S, Rukundo B, Ahmadi M, Akoubi H, Al-Bizri H, Aliu AF, Ambeaghen TU, Avetisyan L, Bahar I, Baird A, Begum F, Ben Soussan H, Blondeau-Éthier V, Bordaries R, Bramwell H, Briggs A, Bui R, Carnevale M, Chancharoen M, Chevassus T, Choi JH, Coulombe K, Couvrette F, D'abreau S, Davies M, Desbiens MP, Di Maulo T, Di Paolo SA, Do Ponte S, Dos Santos Ribeiro P, Dubuc-Kanary LA, Duncan PK, Dupuis F, El-Nounou S, Eyangos CN, Ferguson NK, Flores-Chinchilla NR, Fotakis T, Gado Oumarou HDM, Georgiev M, Ghiassy S, Glibetic N, Grégoire Bouchard J, Hassan T, Huseen I, Ibuna Quilatan MF, Iozzo T, Islam S, Jaunky DB, Jeyasegaram A, Johnston MA, Kahler MR, Kaler K, Kamani C, Karimian Rad H, Konidis E, Konieczny F, Kurianowicz S, Lamothe P, Legros K, Leroux S, Li J, Lozano Rodriguez ME, Luponio-Yoffe S, Maalouf Y, Mantha J, Mccormick M, Mondragon P, Narayana T, Neretin E, Nguyen TTT, Niu I, Nkemazem RB, O'Donovan M, Oueis M, Paquette S, Patel N, Pecsi E, Peters J, Pettorelli A, Poirier C, Pompa VR, Rajen H, Ralph RO, Rosales-Vasquez J, Rubinshtein D, Sakr S, Sebai MS, Serravalle L, Sidibe F, Sinnathurai A, Soho D, Sundarakrishnan A, Svistkova V, Ugbeye TE, Vasconcelos MS, Vincelli M, Voitovich O, Vrabel P, Wang L et al (2017) Human gut microbiota: toward an ecology of disease. Front Microbiol 8:1265 Sharma D, Misba L, Khan AU (2019) Antibiotics versus biofilm: an emerging battleground in microbial communities. Antimicrob Resist Infect Control 8:76 Stockinger B, Di Meglio P, Gialitakis M, Duarte JH (2014) The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol 32:403–432 Sun D, Krishnan A, Su J, Lawrence R, Zaman K, Fernandes G (2004) Regulation of immune function by calorie restriction and cyclophosphamide treatment in lupus-prone NZB/NZW F1 mice. Cell Immunol 228:54–65 Szymula A, Rosenthal J, Szczerba BM, Bagavant H, Fu SM, Deshmukh US (2014) T cell epitope mimicry between Sjögren's syndrome antigen A (SSA)/Ro60 and oral, gut, skin and vaginal bacteria. Clin Immunol 152:1–9 Thim-Uam A, Surawut S, Issara-Amphorn J, Jaroonwitchawan T, Hiengrach P, Chatthanathon P, Wilantho A, Somboonna N, Palaga T, Pisitkun P, Leelahavanichkul A (2020) Leaky-gut enhanced lupus progression in the Fc gamma receptor-IIb deficient and pristane-induced mouse models of lupus. Sci Rep 10:777 Toral M, Robles-Vera I, Romero M, De La Visitación N, Sánchez M, O'Valle F, RodriguezNogales A, Gálvez J, Duarte J, Jiménez R (2019) Lactobacillus fermentum CECT5716: a novel alternative for the prevention of vascular disorders in a mouse model of systemic lupus erythematosus. FASEB J 33:10005–10018 Troyer DA, Chandrasekar B, Barnes JL, Fernandes G (1997) Calorie restriction decreases plateletderived growth factor (PDGF)-A and thrombin receptor mRNA expression in autoimmune murine lupus nephritis. Clin Exp Immunol 108:58–62

550

P. Yi et al.

Tsokos GC (2020) Autoimmunity and organ damage in systemic lupus erythematosus. Nat Immunol 21:605–614 Tsokos GC, Lo MS, Costa Reis P, Sullivan KE (2016) New insights into the Immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol 12:716–730 Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI (2006) An obesityassociated gut microbiome with increased capacity for energy harvest. Nature 444:1027–1031 Urao M, Ueda G, Abe M, Kanno K, Hirose S, Shirai T (1995) Food restriction inhibits an autoimmune disease resembling systemic lupus erythematosus in (NZB  NZW) F1 mice. J Nutr 125:2316–2324 Van Der Meulen TA, Harmsen HJM, Vila AV, Kurilshikov A, Liefers SC, Zhernakova A, Fu J, Wijmenga C, Weersma RK, De Leeuw K, Bootsma H, Spijkervet FKL, Vissink A, Kroese FGM (2019) Shared gut, but distinct oral microbiota composition in primary Sjögren's syndrome and systemic lupus erythematosus. J Autoimmun 97:77–87 Vogt NM, Kerby RL, Dill-Mcfarland KA, Harding SJ, Merluzzi AP, Johnson SC, Carlsson CM, Asthana S, Zetterberg H, Blennow K, Bendlin BB, Rey FE (2017) Gut microbiome alterations in Alzheimer's disease. Sci Rep 7:13537 Vorobyev A, Gupta Y, Sezin T, Koga H, Bartsch YC, Belheouane M, Künzel S, Sina C, Schilf P, Körber-Ahrens H, Beltsiou F, Lara Ernst A, Khil'chenko S, Al-Aasam H, Manz RA, Diehl S, Steinhaus M, Jascholt J, Kouki P, Boehncke WH, Mayadas TN, Zillikens D, Sadik CD, Nishi H, Ehlers M, Möller S, Bieber K, Baines JF, Ibrahim SM, Ludwig RJ (2019) Gene-diet interactions associated with complex trait variation in an advanced intercross outbred mouse line. Nat Commun 10:4097 Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT, Serlie MJ, Oozeer R, Derrien M, Druesne A, Van Hylckama Vlieg JE, Bloks VW, Groen AK, Heilig HG, Zoetendal EG, Stroes ES, De Vos WM, Hoekstra JB, Nieuwdorp M (2012) Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143:913–916.e7 Wade WG (2013) The oral microbiome in health and disease. Pharmacol Res 69:137–143 Wang H, Wang G, Banerjee N, Liang Y, Du X, Boor PJ, Hoffman KL, Khan MF (2021) Aberrant gut microbiome contributes to intestinal oxidative stress, barrier dysfunction, inflammation and systemic autoimmune responses in MRL/lpr mice. Front Immunol 12:651191 Wańkowicz P, Szylińska A, Rotter I (2020) Evaluation of mental health factors among people with systemic lupus erythematosus during the SARS-CoV-2 pandemic. J Clin Med 9:2872 Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S (1992) Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356:314–317 Wei F, Xu H, Yan C, Rong C, Liu B, Zhou H (2019) Changes of intestinal flora in patients with systemic lupus erythematosus in Northeast China. PLoS One 14:e0213063 Wells JM, Brummer RJ, Derrien M, Macdonald TT, Troost F, Cani PD, Theodorou V, Dekker J, Méheust A, De Vos WM, Mercenier A, Nauta A, Garcia-Rodenas CL (2017) Homeostasis of the gut barrier and potential biomarkers. Am J Physiol Gastrointest Liver Physiol 312:G171– G193 White CA, Pone EJ, Lam T, Tat C, Hayama KL, Li G, Zan H, Casali P (2014) Histone deacetylase inhibitors upregulate B cell microRNAs that silence aid and Blimp-1 expression for epigenetic modulation of antibody and autoantibody responses. J Immunol 193:5933–5950 Wilson M (2009) Bacteriology of humans: an ecological perspective. Wiley-Blackwell Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, Bewtra M, Knights D, Walters WA, Knight R, Sinha R, Gilroy E, Gupta K, Baldassano R, Nessel L, Li H, Bushman FD, Lewis JD (2011) Linking Long-term dietary patterns with gut microbial enterotypes. Science 334:105– 108 Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, Ståhlman M, Olsson LM, Serino M, Planas-Fèlix M, Xifra G, Mercader JM, Torrents D, Burcelin R, Ricart W, Perkins R, Fernàndez-Real JM, Bäckhed F (2017) Metformin alters the gut microbiome of individuals with

20

Microorganisms in Pathogenesis and Management of Systemic. . .

551

treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med 23: 850–858 Xu R, Tan C, He Y, Wu Q, Wang H, Yin J (2020) Dysbiosis of gut microbiota and short-chain fatty acids in encephalitis: a Chinese pilot study. Front Immunol 11:1994 Yang W, Cong Y (2021) Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases. Cell Mol Immunol 18:866–877 Yazdany J, Kim AHJ (2020) Use of hydroxychloroquine and chloroquine during the COVID-19 pandemic: what every clinician should know. Ann Intern Med 172:754–755 Yoshikawa T, Watanabe T, Kamata K, Hara A, Minaga K, Kudo M (2021) Intestinal dysbiosis and autoimmune pancreatitis. Front Immunol 12:621532 Zegarra-Ruiz DF, El Beidaq A, Iñiguez AJ, Lubrano Di Ricco M, Manfredo Vieira S, Ruff WE, Mubiru D, Fine RL, Sterpka J, Greiling TM, Dehner C, Kriegel MA (2019) A diet-sensitive commensal lactobacillus strain mediates TLR7-dependent systemic autoimmunity. Cell Host Microbe 25:113–127.e6 Zen M, Fuzzi E, Astorri D, Saccon F, Padoan R, Ienna L, Cozzi G, Depascale R, Zanatta E, Gasparotto M, Benvenuti F, Bindoli S, Gatto M, Felicetti M, Ortolan A, Campaniello D, Larosa M, Lorenzin M, Ramonda R, Sfriso P, Schiavon F, Iaccarino L, Doria A (2020) SARS-CoV-2 infection in patients with autoimmune rheumatic diseases in Northeast Italy: a cross-sectional study on 916 patients. J Autoimmun 112:102502 Zhang H, Liao X, Sparks JB, Luo XM (2014) Dynamics of gut microbiota in autoimmune lupus. Appl Environ Microbiol 80:7551–7560 Zhang Y, Wang X, Li H, Ni C, Du Z, Yan F (2018) Human oral microbiota and its modulation for oral health. Biomed Pharmacother 99:883–893 Zhang M, Zhou L, Wang Y, Dorfman RG, Tang D, Xu L, Pan Y, Zhou Q, Li Y, Yin Y, Zhao S, Wu J, Yu C (2019) Faecalibacterium prausnitzii produces butyrate to decrease c-Myc-related metabolism and Th17 differentiation by inhibiting histone deacetylase 3. Int Immunol 31:499– 514 Zhang Y, Liu Q, Yu Y, Wang M, Wen C, He Z (2020) Early and short-term interventions in the gut microbiota affects lupus severity, progression, and treatment in MRL/lpr mice. Front Microbiol 11:628 Zhao Y, Zhang B, Liu C, Ren G (2020) Method for accurate diagnose of lupus erythematosus skin lesions based on microbial Rdna sequencing. Saudi J Biol Sci 27:2111–2115 Zhu W (2018) Alteration of gut microbiome in patients with systemic lupus erythematosus. University of Zhejiang, Zhejiang Zouali M (2021) B lymphocytes, the gastrointestinal tract and autoimmunity. Autoimmun Rev 20: 102777

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

21

Luca Di Bartolomeo, Paolo Custurone, and Fabrizio Guarneri

Abstract

Sjögren’s syndrome (SS) is an autoimmune disease characterized by mononuclear cell infiltration of exocrine glands, leading to loss of function and progressive destruction of lacrimal and salivary glands, with subsequent dryness of the eyes (keratoconjunctivitis sicca) and dryness of the mouth (xerostomia). In addition to these typical clinical signs, SS is associated with multiple systemic manifestations and an increased risk of non-Hodgkin lymphoma. Pathogenesis of SS is not yet fully understood. Aberrant immune responses to environmental factors in genetically predisposed individuals are considered the main cause of disease development. In this context, innate immune system and type I interferon pathways seem particularly involved in the early stages of disease. Infections are probably the most important environmental factor in the pathogenesis of SS. Some viruses, such as EBV, HCV, coxsackievirus, HTLV-1, and HIV, seem to be associated with higher risk of developing SS or SS-like manifestations. Recently, increasing evidences suggest that the microbiota imbalance could also contribute to the development of mucosal inflammation in SS. In this chapter, we explore the pathophysiological mechanisms of SS and their impact on disease management, particularly focusing on the interaction between immune system and microorganisms.

L. Di Bartolomeo · P. Custurone · F. Guarneri (*) Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_21

553

554

L. Di Bartolomeo et al.

Keywords

Sjögren’s syndrome · Xerostomia · Xerophthalmia · Epstein-Barr virus · Hepatitis C virus · Coxsackievirus · Human T-lymphotropic virus type 1 · Human immunodeficiency virus · Helicobacter pylori · Microbiota

21.1

Introduction

Sjögren’s syndrome (SS) is an autoimmune disease characterized by mononuclear cell infiltration of exocrine glands (Jonsson et al. 2018). Lymphoid infiltrations lead to loss of function and progressive destruction of lacrimal and salivary glands, with subsequent dryness of the eyes (keratoconjunctivitis sicca) and dryness of the mouth (xerostomia) (Jonsson et al. 2018; Thorne and Sutcliffe 2017). In addition to these typical clinical signs, SS is associated with multiple systemic manifestations and an increased risk of B cell non-Hodgkin lymphoma (NHL) (Bombardieri et al. 2020). SS is either classified as primary SS (pSS), when occurs in a healthy person, or secondary SS (sSS), which appears in the context of other autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), or dermatomyositis (Thorne and Sutcliffe 2017). The diagnostic criteria for pSS established in 2016 by the American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) take into account 5 objective items, including the presence of xerostomia, xerophthalmia, specific autoantibodies, and histologically evident sialadenitis (Shiboski et al. 2017). The pathogenesis of SS is poorly understood. Autoimmunity appears to play the key role in the induction and progression of this disease, but recent evidences suggest that infections and instability of mucosal microbiota may trigger autoimmune responses. After an epidemiological and clinical overview on SS, this chapter discusses the pathophysiological mechanisms of this complex disease, focusing on the interaction between immune system and microorganisms.

21.2

Epidemiology

21.2.1 Primary SS PSS may affect 0.2–4.0% of the population, with a 9:1 female/male ratio (Pierce et al. 2016; Qin et al. 2015). About the age of pSS patients, Qin et al. (2015) indicated that the pooled age at evaluation was 56.2 years (52.5–59.8 years). Generally, pSS affects people between 40 and 60 years of age (Reksten and Jonsson 2014). Nevertheless, younger individuals may also be affected. The meta-analysis by Qin et al. (2015) gave an overall incidence rate estimate for pSS of 6.92 per 100,000 person-years. Different incidence ratios per 100,000 person-years were reported by many studies: 6.57 by three studies from Asia, 3.9 by a Slovenian study, and 5.3 by a

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

555

Greek study (Alamanos et al. 2006; Plesivcnik Novljan et al. 2004; See et al. 2013; Weng et al. 2011; Yu et al. 2013). According to a prospective population-based study, the incidence ratio in the USA between 1976 and 1992 was 3.9 per 100,000 (Pillemer et al. 2001). Qin et al. (2015) indicated that the pooled incidence ratio for pSS was 12.30 per 100,000 in the female population, while it was 1.47 per 100,000 in the male population. The female/male ratio in the incidence rate for primary SS was 9.29 (Qin et al. 2015). The reported prevalence of pSS varies according to population and gender. A Norwegian population-based study showed that people between 71 and 74 years of age had a higher prevalence than those between 40 and 44 years of age (1.4% vs 0.22%) (Haugen et al. 2008). Another Norwegian study found that the prevalence of pSS was 0.05% in a population mainly composed by females (93%) (Goransson et al. 2011). The meta-analysis of Qin et al. (2015) reported that the pooled prevalence ratio of primary SS in the total population was 60.82 cases per 100,000 inhabitants. The estimated prevalence ratio was 116.72 per 100,000 inhabitants in the female population and 5.53 per 100,000 inhabitants in male population (Qin et al. 2015). The female/male ratio in the prevalence rate for primary SS was 10.72 (Qin et al. 2015).

21.2.2 Secondary SS Prevalence of secondary SS depends on the type of systemic autoimmune disease with which it is associated. According to a recent meta-analysis by Alani et al. (2018), the prevalence is in the range 3.6–55% for RA-sSS, 5–22% for SLE-sSS, 14–60% for SSc-sSS, and 10–23% for myositis-sSS (Alani et al. 2018). In the RA-sSS studies, Greek patients appeared to have the highest reported prevalences (31–39.8%) (Alani et al. 2018). SLE-sSS patients appeared significantly older than those with SLE only, while no significant differences in age between SSc and SSc-sSS patients or RA and RA-sSS patients were described (Alani et al. 2018). Patients with sSS are more frequently females (82–100%) (Alani et al. 2018).

21.3

Clinical Features

21.3.1 Sicca Symptoms SS is characterized by a wide spectrum of clinical features, ranging from exocrine involvement to extraglandular manifestations. Lacrimal and salivary glands are the most affected organs; therefore keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth) are the principal signs of the disease. Symptoms of keratoconjunctivitis sicca are foreign-body sensation, irritation of the eyes, and enhanced sensitivity to light (Stefanski et al. 2017). In addition to dryness of the mouth and hyposalivation, patients with xerostomia have an increased risk of dental diseases, including caries and tooth loss (Stefanski et al. 2017). Other sicca symptoms, such as dry cough in

556

L. Di Bartolomeo et al.

tracheobronchitis sicca or dryness in the nasopharyngeal or genital tract, may be present (Stefanski et al. 2017).

21.3.2 Dermatologic Manifestations Common dermatologic manifestations of SS include xerosis and other manifestations due to cutaneous dryness (eyelid dermatitis, angular cheilitis, vaginal dryness). Cutaneous vasculitis, erythema annulare, livedo reticularis, and Raynaud’s phenomenon may also occur (Kittridge et al. 2011). Cutaneous vasculitis occurs in about 10% of patients with pSS, being the most common dermatologic manifestation in pSS (Ramos-Casals et al. 2004). The most common clinical presentations of cutaneous vasculitis in pSS are palpable and nonpalpable purpura or urticarial vasculitis (Kittridge et al. 2011). The vasculitis of pSS predominantly involves small vessels and rarely also medium-sized vessels (Kittridge et al. 2011). SS patients with cutaneous vasculitis have a higher prevalence of systemic manifestations and cryoglobulins (Ramos-Casals et al. 2004). Cryoglobulinemia has been associated with an increased risk of life-threatening multisystem vasculitis and lymphoma (Ramos-Casals et al. 2004). Therefore, SS patients with purpura or other vasculitic manifestations should be screened for cryoglobulinemia (RamosCasals et al. 2004). Given that some skin manifestations, such as cutaneous vasculitis or Raynaud’s phenomenon, may also be present in connective tissue diseases, a secondary SS should be ruled out in these patients.

21.3.3 Extraglandular Involvement Musculoskeletal symptoms, including myalgia and arthralgia, are the most common extraglandular manifestation of SS, being present in about 90% of patients (Leone et al. 2017). Up to 17% of patients present a nonerosive arthritis (Leone et al. 2017). Respiratory symptoms occur in 9–20% of cases of SS (Flament et al. 2016). The most typical manifestations are chronic interstitial lung disease (ILD) and tracheobronchial disease (Flament et al. 2016). Diffuse ILD is the most alarming form of lung involvement in SS, because it may lead to respiratory failure (Leone et al. 2017). Another common extraglandular manifestation in pSS is pleural effusion that may be associated with pericardial effusion (Leone et al. 2017). The involvement of the cardiovascular system is not frequent in SS; however, chronic inflammation reported in the context of SS is associated with an enhanced risk of atherosclerosis (Melissaropoulos et al. 2020). Only 5% of pSS patients have renal involvement (Aiyegbusi et al. 2021). Kidney disease in pSS is a diagnostic challenge, as it is often subclinical and may precede sicca symptoms (Aiyegbusi et al. 2021). Kidney disease in SS is characterized by lymphocytic infiltration of renal tubules or glomerulopathy due to immune complex deposition (Aiyegbusi et al. 2021). Tubulointerstitial nephritis (TIN) is more frequent than glomerulonephritis (GN), accounting for 85% of cases of renal

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

557

involvement (Aiyegbusi et al. 2021). All SS patients should be checked for symptoms related to renal involvement (oedema, nephrotic/nephritic syndrome, bone pain, muscular weakness, polyuria, polydipsia) and undergo diagnostic tests when needed. Neurologic manifestations of pSS may occur in 8–49% of cases and involve both peripheral and central nervous system (Margaretten 2017). Sensorimotor polyneuropathies are the most common manifestations of peripheral disease, while the central nervous system may be affected by focal central lesions, cerebellar disorders, impairment of frontal cortex functions, or conditions that resemble encephalitis, aseptic meningitis, or multiple sclerosis (Margaretten 2017).

21.3.4 Lymphoma Episodic or chronic enlargement of the parotid gland occurs in up to 34% of patients with SS (Stefanski et al. 2017). In these cases, it is necessary to rule out the development of NHL (Stefanski et al. 2017). Sjögren’s syndrome is associated with the highest lifetime risk of developing lymphoma (5–10%) compared to all autoimmune diseases (Thorne and Sutcliffe 2017). Palpable purpura, lymphopenia, low C4 levels, cryoglobulins, lymphadenopathy, persistent salivary gland enlargement, and cutaneous vasculitis are risk factors for the development of lymphoma (Thorne and Sutcliffe 2017). The most frequent SS-associated lymphoma is MALT lymphoma, but SS patients may also develop follicular lymphoma or diffuse large B cell lymphoma (Talotta et al. 2019).

21.4

Laboratory Findings

A blood test in patients with SS may detect mild anemia, high erythrocyte sedimentation rate, and low C4 and high IgG levels. Autoantibodies are frequently positive, including antinuclear antibody (ANA), rheumatoid factor (RF), Ro, and/or La autoantibodies (Thorne and Sutcliffe 2017). Anti-Ro/SSA and anti-La/SSB antibodies are the most important biomarkers of SS (Jonsson et al. 2018). Ro/SSA and La/SSB include three cellular autoantigens, namely, Ro52, Ro60, and La48, so called according to their molecular weight (Jonsson et al. 2018). Anti-Ro/SSA and anti-La/SSB antibodies are detected in 50–70% of cases of pSS (Fayyaz et al. 2016). Patients with pSS have a higher frequency of anti-Ro/La positivity compared with patients with sSS (HernándezMolina et al. 2010). Anti-Ro/La antibodies may precede the onset of symptoms and are associated with younger age at diagnosis, longer disease duration, more severe dysfunction of the exocrine glands, and systemic disease (Fayyaz et al. 2016).

558

21.5

L. Di Bartolomeo et al.

Diagnosis

Diagnosis of SS is made by a combination of clinical features and laboratory results. The 2016 ACR/EULAR classification criteria are the current diagnostic criteria for SS, applicable to any patient with at least one symptom of ocular or oral dryness for more than 3 months (Shiboski et al. 2017). Diagnosis of primary SS is made if an individual has a score
4 according to the presence/absence of the following items: anti-Ro/SSA positivity and lymphocytic sialoadenitis on biopsy, with a focus score of 1 or more foci/mm2 (each scoring 3 points), and tests for ocular and oral dryness (two ocular tests and an oral test, each scoring 1 point). Exclusion criteria are history of head or neck radiation treatment, active hepatitis C infection, immunodeficiency syndrome, sarcoidosis, amyloidosis, graft-versus-host disease, and IgG4-related diseases (Shiboski et al. 2017). In a recent cohort study, Hernández-Molina et al. demonstrated that the 2016 ACR/EULAR criteria are also applicable for the diagnosis of secondary SS (Hernández-Molina et al. 2020).

21.6

Pathogenesis

The pathogenesis of SS includes dysregulation of cell-mediated and humoral responses (Bombardieri et al. 2018). In this context, environmental factors may play a critical role, interacting with genetic susceptibility to trigger autoimmune responses, which lead to tissue damage and clinical manifestations (Bombardieri et al. 2020). According to a proposed pathogenetic model for SS, microbial triggers initiate disruption of the salivary gland epithelium and activate plasmacytoid dendritic cells (pDCs), which produce type I IFN (IFNα and IFNβ) (Bartoloni et al. 2019; Björk et al. 2020). In this process, the activation of Toll-like receptors (TLR) on epithelial and immune cells appears essential (Bartoloni et al. 2019). Multiple infectious antigens, as well as autoantigens from dying cells, may trigger the TLR pathway and lead to the production of pro-inflammatory cytokines in salivary glands of SS patients, activating innate and adaptative immune cells (Bartoloni et al. 2019). Antigen-presenting cells may process and present viral and self-antigens, leading to the stimulation of autoreactive T and B cells. Autoreactive T cells may secrete cytotoxic granules, causing amplified exposure of autoantigens, while autoreactive B cells produce autoantibodies. Immune complexes composed by autoantibodies and autoantigens bind receptors on pDCs, causing an enhancement of type I IFN and a self-perpetuation of autoimmunity (Björk et al. 2020). Before discussing how the innate and adaptive immune system operate in the pathogenesis of SS, it is important to describe the main predisposing and triggering factors for the onset of the disease, namely, genetic and environmental factors, especially focusing on the role of microorganisms.

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

21.7

559

Genetic Predisposing Factors

Genetic studies have highlighted many risk alleles for SS, but the genetic variants only modestly explain the increased risk (Björk et al. 2020; Bombardieri et al. 2018). Data on concordance rates of SS in twins are scarce, and it is not possible to estimate the genetic contribution to SS based on twin concordance (Harris et al. 2019b). Genetic studies in SS may be divided in four categories: candidate gene, genomewide association, microRNA, and chromosome studies.

21.7.1 Candidate Gene Studies Candidate gene studies have shown that polymorphisms in several genes are associated with an increased risk of SS. Most of these genes encode for proteins involved in inflammation or autoimmunity. The tumor necrosis factor, alphainduced protein 3 (TNFAIP3) gene encodes the A20 protein, an important negative feedback regulator of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway. A TNFAIP3 variant was associated with B cell NHL development in some patients with SS, and its increased prevalence was described in a Greek pSS population (Nezos et al. 2018). A Chinese study found an association between SS and two alleles of the IKAROS family zinc finger 1 (IKZF1) gene, which encodes for a protein involved in lymphocyte development (Qu et al. 2017).

21.7.2 Genome-Wide Association Studies (GWAS) The investigation of the entire genome through GWAS has allowed to study a bigger number of allelic variations compared to candidate gene studies. GWAS confirmed that risk of SS varies according to human leukocyte antigen (HLA) class II alleles on chromosome 6. The most relevant HLA genes involved in susceptibility to primary SS are HLA-DR and HLA-DQ alleles (Cruz-Tapias et al. 2012). Cruz-Tapias et al. (2012) highlighted that SS patients with diverse ethnic origins carry different HLA susceptibility alleles/haplotypes. Nevertheless, in their meta-analysis, the authors found that DQA1*05:01, DQB1*02:01, and DRB1*03:01 were the most important HLA alleles for risk of disease (Cruz-Tapias et al. 2012). HLA class II alleles seem to be linked with autoantibody secretion (Gottenberg et al. 2003). Gottenberg et al. (2003) found an association between HLA and SS only in patients with anti-SSA and/or anti-SSB antibodies. GWAS allowed to increase knowledge about the immune pathways implicated in SS (Harris et al. 2019b). Peripheral blood cells of SS patients overexpressed genes that are inducible by interferons (Emamian et al. 2009). GWAS found many risk alleles for SS in the regions of genes that are associated with the interferon response, including signal transducer and activator of transcription 4 (STAT4), interferon regulatory factor (IRF5), interleukin 12A, and 20 -50 -oligoadenylate synthetase 1 (OAS1) (Lessard et al. 2013; Li et al. 2013, 2017).

560

L. Di Bartolomeo et al.

The presence of these genetic variants in SS patients confirms the relevance of IFN signaling pathways in the pathogenesis of SS (Björk et al. 2020). Moreover, several genes involved in B cell function present risk alleles for SS. GWAS showed associations between SS and some alleles of the aforementioned TNFAIP3, the NF-ĸB pathway, early B cell factor 1 (EBF1), and B lymphocyte kinase (BLK) that are involved in B cell development and B cell signaling (Nordmark et al. 2011; Sun et al. 2013).

21.7.3 microRNA Studies Studies on microRNAs (miRNAs) in the pathogenesis of SS are recently increasing (Harris et al. 2019b). MicroRNAs may influence the expression of Ro and La autoantigens and regulate the immune response (Harris et al. 2019b; Reale et al. 2018). According to a recent review, many studies have reported that specific miRNAs are associated with SS salivary gland tissue inflammation (Reale et al. 2018). MicroRNAs are also involved in activation and maturation of B cells and in regulating the sensitivity of T cell response to antigens (Garo and Murugaiyan 2016; Shi et al. 2014). Moreover, miRNA expression in SS regulates several signaling pathways, such as IFN/STAT, NF-ĸB, TGFβ, and MAPK (Reale et al. 2018).

21.7.4 Chromosome Studies In addition to chromosome 6, which contains HLA class II alleles, the X chromosome is also being investigated for its role in the pathogenesis of SS. In particular, aneuploidy of the X chromosome has been reported among SS patients. Seminog et al. (2015) found that people with Klinefelter’s syndrome (male 47,XXY) had increased risk of some autoimmune diseases, particularly those that are predominant in females, including SS. Harris et al. (2016) confirmed these results, demonstrating that this abnormality of the X chromosome number is statistically more frequent among SS patients compared with controls. Partial triplication of the distal p arm of the X chromosome in SS patients suggests the importance of this portion of the X chromosome in genetic susceptibility to SS (Sharma et al. 2017). Toll-like receptor 7 (TLR7) and CXorf21 are two genes on distal Xp that are involved in the IFN pathway and escape X inactivation in immune cells (Souyris et al. 2018; Tukiainen et al. 2017). In pDCs, TLR7 activation causes robust type I IFN production and is important in the induction of antiviral immune responses (Souyris et al. 2018). CXorf21 mediates specific TLR7 downstream immune responses (Harris et al. 2019a; Odhams et al. 2019). TLR7 and CXorf21 genes seem to play an important role in the X chromosome dose effect in pSS (Harris et al. 2019a).

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

21.8

561

Infections

In a genetically susceptible individual, environmental factors may trigger the development of immune response and influence the severity of the disease (Björk et al. 2020). SS-specific autoantibodies are present on average 4 to 6 years before symptoms (Jonsson et al. 2013). This suggests that some environmental factors may induce the initial development of autoantibodies in serum without the development of clinical manifestations, while other environmental factors have to be added to trigger the disease clinically (Björk et al. 2020). Infections are probably the most important environmental factor in the pathogenesis of SS and may be associated with a higher risk of developing SS or SS-like manifestations (Utomo and Putri 2020). Viruses appear more involved than bacteria. There are many observations that suggest a predominant role of viruses in the pathogenesis of SS. First, some viruses, especially herpesviruses such as CMV or EBV, have an innate tropism for salivary and lacrimal glands. In addition to this, immune defense against viruses shares with SS several signaling pathways, including TLR signaling and the type I IFN system (Björk et al. 2020). We discuss below the infectious agents which appear most frequently implicated in the pathogenesis of SS according to old and recent studies.

21.8.1 Epstein-Barr Virus The Epstein-Barr virus (EBV) is endemic; it is estimated that up to 90% of the population have anti-EBV antibodies (Maślińska 2019). EBV is a double-stranded DNA virus of the human herpes virus (HHV) family and presents tropism for B cells and epithelial cells. An increased level of EBV-DNA was observed in lacrimal and salivary glands from SS patients, and B cell lines from SS patient produced EBV at a higher frequency than other B cell lines (Tateishi et al. 1993; Tsubota et al. 1995). Similarly, the mean antibody titers to EBV antigens, including anti-EBV nuclear antigen (anti-EBNA), anti-early antigen (anti-EA-IgG), and anti-virus capsid antigen (anti-VCA), were found significantly elevated in SS patients compared with controls (Toda et al. 1994). A recent meta-analysis established that the strongest association of SS is with anti-VCA IgM and anti-EA IgG antibodies (Xuan et al. 2020). EBV has two modes of infection: latent, which is predominant, and lytic. The lytic cycle is required for horizontal transmission of EBV among hosts, primary infection, and establishment of latency (McKenzie and El-Guindy 2015). The virus can switch between a latent and a lytic life cycle and may cause chronic infections (Houen and Trier 2021). In genetically predisposed individuals, there is an increased virus uptake by B cells due to several mechanisms, including an increased expression of CD21, the receptor for EBV. Among B cells, autoreactive clones may be infected by EBV, proliferate, and become latently infected memory B cells. The latently infected autoreactive memory B cells may send co-stimulatory survival signals to

562

L. Di Bartolomeo et al.

autoreactive T cells, inhibiting their apoptosis and thus promoting the development of EBV-associated autoimmune diseases (Pender 2003). In addition to this general model, molecular mimicry has been proposed as specific mechanism for the development of autoimmunity by EBV in SS (Maślińska 2019). Since more than three decades, cross-reactivity of SS-associated antibodies with EBV proteins has been investigated. Anti-Ro/La and anti-SSB/La autoantibodies have been shown to precipitate proteins complexed with EBERs (EBV-encoded small RNAs) (Fox et al. 1986; Lerner et al. 1981). Molecular homology has been also proposed between EBV early antigen diffuse component (EAD) and the human proteins α-fodrin and lipocalin. The α-fodrin is a cytoskeleton protein, while lipocalin is a protein expressed in tears and saliva. In SS patients, antibodies against EAD also bind tear lipocalin and α-fodrin. These findings suggest that EBV infection may be associated with the pathogenesis of SS and that tear lipocalin and α-fodrin may be autoantigens in SS such as Ro/La (Navone et al. 2005). Lymphoma may appear in more than 15% of SS patients (Talotta et al. 2019). EBV has been shown to immortalize human B lymphocytes in vitro (Tang et al. 2014). The association of EBV with several neoplasms, such as Burkitt lymphoma, Hodgkin lymphoma, AIDS-related non-Hodgkin lymphoma, post-transplant lymphoproliferative disorders (PTLD), diffuse large B cell lymphoma (DLBCL), NK/T cell lymphoma, nasopharyngeal carcinoma, and EBV-positive gastric cancer, supports its important role in oncogenesis (Yin et al. 2019). EBV promotes oncogenesis and the development of lymphoma by dysregulation of the immune system, B cell immortalization, and induction of B cell proliferation (Maślińska 2019). Despite the well-acknowledged contribution of EBV to lymphomagenesis, its role in the development of SS-associated lymphomas still remains to be completely clarified (Stergiou et al. 2020).

21.8.2 Cytomegalovirus Cytomegalovirus (CMV) is a human herpes virus which infects many individuals in the world, usually without producing apparent symptoms. About 60% of adults in developed countries and 100% in developing countries present CMV antibodies of IgG class, which represent past infection (Griffiths et al. 2015). The association of CMV antibodies with SS is controversial. Barzilai et al. (2007) found elevated titers of CMV IgM antibodies in sera of patients from a wide variety of autoimmune diseases, including SS, but did not demonstrate a significant association of CMV IgG titers with SS. More recently, Kivity et al. (2014) found that prevalence and titers of CMV IgG antibodies were higher in controls than among SS patients, suggesting that the past infection with CMV may have a protective role for SS. Sorgato et al. (2020) evaluated minor salivary glands of SS patients with concomitant RA using immunohistochemistry and did not reveal CMV-DNA in their biopsies.

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

563

Although studies on humans have failed to prove an association between CMV infection and SS, experiments on mice seem to support a role of CMV in the development of SS. In mice with a deficiency of Fas, a surface receptor involved in immune regulation via apoptosis of T cells, murine cytomegalovirus (MCMV) infection induced a chronic inflammatory response in salivary glands that resembles SS. Moreover, the mice developed anti-Ro and anti-La antibodies (Fleck et al. 1998). Further studies on mouse models have obtained similar results. Ohyama et al. (2006) studied the effects of MCMV on an autoimmune-prone mouse strain. After intraperitoneal infection, the authors detected MCMV in the salivary and lacrimal glands of their autoimmune-prone mice, demonstrating acute inflammation in the submandibular gland in association with the presence of MCMV. Despite the subsequent absence of MCMV-DNA in the glands, after a latency period, female mice developed severe chronic periductal inflammation in both submandibular and lacrimal glands (Ohyama et al. 2006). Although CMV exhibits sialotropic characteristics, particularly in mouse models, and therefore represents an interesting candidate as a trigger factor in SS, the evidence on this hypothesis is not satisfactory (Björk et al. 2020).

21.8.3 Hepatitis C Virus Hepatitis C virus (HCV) is a linear, single-stranded RNA virus of the family Flaviviridae. HCV is primary known as the cause of C hepatitis, but HCV infection is also associated with the development of several systemic immune-mediated disorders and malignancies, mainly hepatocellular carcinoma and B cell lymphomas (Ferri et al. 2007). The relationship between SS and HCV was controversial for a long time. In the 2016 ACR/EULAR classification criteria, HCV infection is an exclusion criterion for the diagnosis of pSS (Shiboski et al. 2017). In fact, sicca symptomatology and positive autoantibodies in HCV patients should be considered as extrahepatic manifestations of chronic HCV infection. For that reason, SS in HCV is considered as secondary to HCV (Ramos-Casals et al. 2002, 2008). A recent meta-analysis confirmed that HCV infection is associated with SS/sicca syndrome (Wang et al. 2014). Among HCV-associated autoimmune diseases, SS has the highest prevalence of chronic HCV infection (Ramos-Casals et al. 2005a). Prevalence of HCV infection in SS patients from Southern Europe ranges from 10% to 20%. Compared with patients with pSS, patients with HCV-associated SS (HCV-SS) are epidemiologically, clinically, and immunologically different (RamosCasals et al. 2008). They have a reduced female/male ratio (4:1) and an older age at SS diagnosis (Ramos-Casals et al. 2005b). Moreover, they present specific extraglandular manifestations, such as articular, vasculitic, and neuropathic involvement, namely, the classic triad of the cryoglobulinemic syndrome. The immunologic profile of HCV-SS patients is characterized by predominance of cryoglobulinemicrelated markers (mixed cryoglobulins, rheumatoid factor, hypocomplementemia) and negative anti-Ro/La antibodies (Ramos-Casals et al. 2008). Nevertheless, antiRo/La positivity is found in up to 25% of HCV-SS patients: these patients are often

564

L. Di Bartolomeo et al.

females and have a high prevalence of SS-specific features (Ramos-Casals et al. 2005b). For these reasons, cryoglobulinemia may be considered a marker of HCV-SS (Ramos-Casals et al. 2008). Several studies have added evidence of HCV involvement in pathogenesis of SS. In addition to the well-acknowledged lymphotropism, HCV expresses tropism for lacrimal and salivary epithelial cells, and HCV-RNA is found both in saliva and salivary gland tissue of SS patients (Toussirot et al. 2002). In experimental mice, the envelope proteins of HCV recruited lymphocytes in the salivary glands (Koike et al. 1997). In vitro, the major envelope protein of HCV (HCV-E2) binds with highaffinity CD81 on human B cells, leading to the proliferation of the naïve B cells (Rosa et al. 2005). Moreover, E2-CD81 interaction on B cells was shown to induce double-stranded DNA breaks specifically in the variable region of the immunoglobulin gene locus, leading to hypermutation in the V(H) genes of B cells (Machida et al. 2005). HCV may provide chronic antigen stimulus, which drives clonal expansion of somatically mutated IgM memory B cells. Some of these B cells in HCV-infected patients are autoreactive and, therefore, may be involved in the pathogenesis of SS (Igoe and Scofield 2013). Like EBV, also HCV seems to be involved in the development of lymphoma in SS patients. Both SS and chronic HCV infection are characterized by an underlying B cell hyperactivity that may cause a monoclonal B cell selection and thus the development of a B cell lymphoma (Ramos-Casals et al. 2008). It was proposed that in SS and HCV infection, the first event of lymphomagenesis is the chronic stimulation of polyclonal B cells secreting RF, which may lead to the subsequent isolation of a RF B cell clone (Mariette 2001). Nearly all HCV-SS patients with B cell lymphoma have RF positivity (Ramos-Casals et al. 2007). For that reason, some authors suggest to consider RF positivity as a predictive factor for lymphoma development in HCV-SS patients (Ramos-Casals et al. 2008).

21.8.4 Coxsackievirus Coxsackievirus is a positive-strand RNA virus of the Enterovirus genus of the Picornaviridae family. Coxsackievirus may persistently infect the salivary glands of pSS patients (Triantafyllopoulou and Moutsopoulos 2005). Triantafyllopoulou et al. (2004) studied samples of minor salivary glands by using reverse transcriptasepolymerase chain reaction (rt-PCR) and immunohistochemistry and found a higher coxsackievirus infection rate among patients with pSS compared with patients with sSS or healthy samples. These results were not confirmed by a subsequent study, which highlighted the absence of the coxsackievirus genome in salivary glands of both pSS patients and controls (Gottenberg et al. 2006). The results of these studies are based on small samples and cannot be considered conclusive. A peptide of protein 2B of Coxsackievirus A21 was found to have 87% amino acid homology with a region of the Ro60 autoantigen (pep216–232) (Stathopoulou et al. 2005). Stathopoulou et al. (2005) suggested a possible cross-reaction between antibodies to Ro60 antigen and this Coxsackievirus protein in pSS patients. This

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

565

cross-reaction may play a role in autoantibody formation in patients with Coxsackievirus infection (Stathopoulou et al. 2005).

21.8.5 Human T-Lymphotropic Virus Type 1 Human T-lymphotropic virus type 1 (HTLV-1) is a member of the type C deltaretrovirus family, known primarily as causative agent of adult T cell leukemia/ lymphoma. HTLV-1 infects up to ten million people worldwide but it is not ubiquitous. Southwestern part of Japan, sub-Saharan Africa and South America, the Caribbean area, and foci in Middle East and Australo-Melanesia are the regions with a high endemicity of HTLV-1 (Gessain and Cassar 2012). Since more than three decades, several studies have shown the presence of HTLV-1 in sera or salivary glands from SS patients (Mariette et al. 1993, 2000; Sumida et al. 1994). One of the most specific and important genes of HTLV-1 is the tax gene, a viral transcription factor that is essential for replication of the HTLV-1 genome. In a study by Mariette et al., the tax gene was detected in 30% of SS patients and in 28% of non-SS patients with inflammatory processes of the oral cavity, suggesting that HTLV-1 may also contribute to the development of chronic inflammation in absence of SS (Mariette et al. 2000; Nakamura et al. 2020). Already in 1989, transgenic mice containing the HTLV-1 tax gene were found to develop an SS-like exocrinopathy (Green et al. 1989). In a subsequent study, the introduction of the env-pX gene of HTLV-I in experimental mice caused several autoimmune diseases, including chronic sialoadenitis and dacryoadenitis which resembled human SS (Yamazaki et al. 1997). The presence of HTLV-1 antibodies in SS patients may be considered as a consequence of the endemicity of HTLV-1 in some regions. Terada et al. (1994) found that in Nagasaki, Japan (an endemic area for HTLV-1), the HTLV-1 seroprevalence rate among SS patients (23%) was significantly higher than among blood donors (3%). HTLV-1 seropositive SS patients show a higher frequency of extraglandular manifestations, including uveitis, myopathy, and recurrent high fever (Eguchi et al. 1992). HTLV-1 infection in SS patients appears to be associated with a reduced SS-specific antibody production. HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neurological disease, usually involving the spinal cord, observed in people infected with the HTLV-1 virus. Nakamura et al. (1997) found that HAM patients with SS showed anti-Ro/SSA antibodies, antinuclear antibodies, and RF positivity more rarely than SS patients without HAH. Further studies are necessary to establish whether HTLV1 infection influences the production of SS-specific autoantibodies (Nakamura et al. 2020). Moreover, it is necessary to establish whether HTLV-1 is associated with SS or only with sicca syndrome. Vale et al. (2017) studied prevalence of SS in 129 HTLV-1-infected patients. Of the HTLV-1 patients, 35.7% had xerostomia and 13.95% had xerophthalmia. Only one was positive for autoantibodies (antiSSB), and two met the diagnostic criteria for SS (Vale et al. 2017). Lima et al. (2016) suggested that patients with sicca syndrome associated with HTLV-1 do not have

566

L. Di Bartolomeo et al.

SS. In their group of 272 HTLV-1 seropositive participants, 21.7% of patients had sicca symptoms without anti-Ro/SSA or anti-La/SSB antibodies. Nevertheless, the production of pro-inflammatory cytokines, such as TNFα and IFN-γ, was increased in the group with sicca syndrome (Lima et al. 2016). The authors explained these results assuming that HTLV-1 may induce an exaggerated inflammatory response in salivary and lacrimal glands, leading to their destruction without the development of a SS.

21.8.6 Human Immunodeficiency Viruses The human immunodeficiency viruses (HIV) are two species of Lentivirus, a genus of retrovirus. They infect cells of the human immune system, namely, CD4+ T cells, destroying them and causing the acquired immunodeficiency syndrome (AIDS), a chronic, life-threatening condition characterized by the failure of the immune system. In 2020, 37.7 million people globally were living with HIV, as reported by UNAIDS. Approximately 158 million of new infections occurred in 2020, with about 680,000 global deaths caused by AIDS (UNAIDS 2021). HIV is often associated with an SS-like illness (Meer 2019). The presence of xerostomia and xerophthalmia with lymphocytic infiltration of salivary and lachrymal glands in HIV-infected patients should be considered as a consequence of HIV infection and not as a primary SS. In fact, like the HCV infection, in the 2016 ACR/EULAR classification criteria, the HIV infection is an exclusion criterion for the diagnosis of pSS (Shiboski et al. 2017). The majority of SS-like cases in HIV-infected patients is explained by the presence of a diffuse infiltrative lymphocytosis syndrome (DILS). DILS appears in up to 50% of HIV-infected patients (Vitali 2011). According to Itescu and Winchester (1992), diagnosis of DILS is made when all these signs are present: HIV infection (positive serology), bilateral salivary gland enlargement or xerostomia, persistence of signs/symptoms for 6 months or more, histologic confirmation of salivary or lacrimal gland lymphocytic infiltration without granulomatosis, or neoplastic involvement. In addition to lacrimal and salivary manifestations, DILS shares with SS extraglandular manifestations involving the lungs, nervous system, and kidneys (Ghrenassia et al. 2015). Extraglandular manifestations are more frequent in DILS than in pSS (Vitali 2011). Beyond the clinical similarity with SS, DILS presents distinctive pathophysiologic and serologic features (Itescu and Winchester 1992). DILS is characterized by circulating CD8 lymphocytosis and apparently antigendriven CD8 T cell infiltration of target organs (Itescu and Winchester 1992). A CD8+ T cell expansion characterizes the early stages of HIV infection. This CD8+ T cell expansion is usually transient but may, in some cases, persist and lead to tissue and organ infiltration. The CD8+ T cells in DILS are effector memory cells (Ghrenassia et al. 2015). These lymphocytes present a selective overrepresentation of particular VβJβ combinations of the T cell receptor (TCR), suggesting that an antigen-driven mechanism may select clonally the T cells (Dwyer et al. 1993). Tissue macrophages bordering CD8+ lymphoid aggregates in salivary glands

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

567

contain HIV-encoded proteins (Itescu et al. 1993). The CD8+ T cell lymphocytosis and CD8+ T cell organ infiltration in DILS are opposed to the CD4+ T cell infiltration in SS. The CD4+/CD8+ ratio is usually normal in SS, while in DILS it is lower than 1 (Ghrenassia et al. 2015; Meer 2019). From a serologic point of view, DILS differs from SS by the absence of anti-SSA/SSB antibodies (Ghrenassia et al. 2015).

21.8.7 SARS-CoV-2 and SS The recent pandemic infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with a wide range of new-onset autoimmune diseases. The pathogenesis of coronavirus disease 2019 (COVID-19) shares similarities with autoimmune diseases (Liu et al. 2021). Moreover, reactions of antiSARS-CoV-2 antibodies with some human tissue antigens support the idea that the novel coronavirus may trigger autoimmune responses through a molecular mimicry mechanism (Vojdani and Kharrazian 2020). Nevertheless, further studies are required in this regard. Martelli Júnior et al. (2021) analyzed SS’s incidence from January 2017 to December 2020, in five Brazilian macroregions. They noted an increase of 50% of SS cases in 2020, particularly during the months following the first Brazilian wave of COVID cases (Martelli Júnior et al. 2021). In an early survey on 108 COVID-19 patients in Wuhan (China), Chen et al. (2020) detected dry mouth symptoms in 46.3% of patients. European studies reported similar incidence of SARS-CoV-2-induced xerostomia, ranging from 30% to 46% of cases, with preponderance in females rather than males (Chowdhury et al. 2021). The induction of xerostomia by SARS-CoV-2 may be explained by several mechanisms, including the sialotropism of this virus. SARS-CoV-2 is proven to gain entry into human cells through the angiotensin receptor 2 (ACE2) (Scialo et al. 2020). Xu et al. (2020) observed that ACE2 expression in minor salivary glands was higher than in the lungs, suggesting that salivary gland may be a reservoir for COVID-19 asymptomatic infections. Histological features of minor salivary glands from COVID-19 patients include focal lymphocytic sialadenitis (FLS) with increased B cell infiltration, as in salivary glands of SS patients (Chowdhury et al. 2021). Nevertheless, sialadenitis in COVID19 patients might be just the evidence of glandular repair in response to SARS-CoV2 antigen, not linked to the development of autoimmunity (Chowdhury et al. 2021). Moreover, although several antinuclear antibodies were reported in COVID-19 patients, reports of specific SS autoantibodies are anecdotal (Fujii et al. 2020; Gao et al. 2021; Huang et al. 2020). Despite the observations of increased incidence of SS in the SARS-CoV-2 pandemic period and xerostomia in COVID-19 patients, there is not yet clear evidence of a pathogenetic link between SARS-CoV-2 and SS.

568

L. Di Bartolomeo et al.

21.8.8 Helicobacter pylori The association of SS with bacteria appears weaker than with viruses, and studies on mechanistic links between bacterial infection and SS are scarce (Björk et al. 2020). Helicobacter pylori is one of the most studied bacteria for its possible association with SS. A recent meta-analysis of nine studies with 1958 participants including 619 patients with SS found a significantly higher H. pylori infection rate in patients with SS (Chen et al. 2018). A subsequent case-control study confirmed these results, showing significantly higher serum levels of anti-H. pylori IgM and IgA antibodies in SS patients compared with the control group (Saghafi et al. 2019). H. pylori infection triggers an immune response against bacterial antigens, including the 60 kDa heat-shock protein (HSP60), which is homologous to a human protein (Aragona et al. 1999; Etchegaray-Morales et al. 2021). In a study on 118 persons divided into four groups (primary SS, secondary SS, other autoimmune diseases, and healthy controls), pSS patients presented an increased prevalence of serum antiH. pylori antibodies compared with the remaining groups (Aragona et al. 1999; Etchegaray-Morales et al. 2021). Nevertheless, the role of H. pylori infection in the pathogenesis of SS remains unclear, so further researches are needed to evaluate this association (Etchegaray-Morales et al. 2021).

21.8.9 Mycobacterium tuberculosis and Non-tuberculous Mycobacteria Chao et al. investigated the relationship between SS and tuberculosis (TB) or non-tuberculous mycobacterial (NTM) infection. The authors observed an association between NTM infection and incident SS, but failed to show an association between TB and incident SS (Chao et al. 2017). Mycobacterial infections have been implicated in many autoimmune diseases, and mycobacterial HSPs, particularly HSP65 and HSP70, may interfere with many immune functions, including the differentiation into Th1 and Th2 profiles or the expression of adhesion molecules (Machado Ribeiro and Goldenberg 2015). SS patients were found to have increased Hsp65 antibody levels compared with healthy controls (Zhang et al. 2019b). It remains unclear whether mycobacteria have a causative role in the pathogenesis of SS or, rather, SS patients have an abnormal immune response to mycobacterial infections (Zhang et al. 2019b).

21.8.10 Saccharomyces cerevisiae Saccharomyces cerevisiae is a yeast widely studied for its potential mechanisms of molecular mimicry that may induce anti-Saccharomyces cerevisiae autoantibodies (ASCAs) in several autoimmune diseases (Alunno et al. 2018). ASCA antibodies are frequently detected in patients with Crohn’s disease (Bartoloni et al. 2019). Alunno et al. (2018) detected ASCA IgG and IgA in 4.8% of patients with pSS. In the cohort

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

569

studied by these authors, none of the pSS patients had inflammatory bowel diseases or other autoimmune conditions that could provide an alternative explanation for ASCA positivity. Interestingly, all ASCA positive patients showed anti-SSA/Ro 52/60 and anti-SSB/La autoantibodies together. Moreover, S. cerevisiae mannan showed high similarity with Ro60/SSA protein, suggesting that ASCA may bind autoantigens. All these observations may support the hypothesis that Saccharomyces cerevisiae is associated with SS because of mechanisms of molecular mimicry of its mannan with human autoantigens (Alunno et al. 2018).

21.9

Microbiota

Microbiota is a term to describe the commensal microbes that inhabit the human body. The advent of novel sequence-based technologies such as 16 s rRNA sequencing has allowed to enhance the knowledge about the influence of the microbiota in immune homeostasis (Trujillo-Vargas et al. 2020). Microbiota could act as environmental trigger for SS, but its role in the disease is far from being completely understood. Particularly, dysbiosis, a state of imbalance in bacterial composition, may take part in determining disease states (Björk et al. 2020). Studies about SS have focused on ocular, oral, and intestinal commensal bacteria.

21.9.1 Ocular Microbiota Aerobic cultures from ocular surface reveal most commonly the presence of Staphylococcus epidermidis and Propionibacterium acnes. Nevertheless, it is unclear whether the presence of these organisms is due to transient contamination or not (Trujillo-Vargas et al. 2020). As opposed to the intestinal microbiota, ocular surface microbiota does not appear different in overall composition, richness, or structure between SS patients and controls (de Paiva et al. 2016).

21.9.2 Oral Microbiota The oral cavity presents a higher bacterial richness compared with the ocular surface. Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes, Fusobacteria, TM7, and Spirochaetes represent more than 99% of the core healthy oral microbiota. In SS patients, Firmicutes are increased, while Proteobacteria, TM7, and Spirochaetes are decreased. Similarly, on the genus level, Haemophilus, Neisseria, and Porphyromonas are decreased in SS patients. Dysbiosis of oral microbiota is associated with hyposalivation. SS patients and non-SS sicca patients share similarities in oral microbiota, but have clear differences from healthy controls (Trujillo-Vargas et al. 2020).

570

L. Di Bartolomeo et al.

21.9.3 Intestinal Microbiota The two major commensal bacterial phyla in the gastrointestinal tract are Firmicutes and Bacteroidetes (Stojanov et al. 2020). The ratio between these two phyla (the Firmicutes/Bacteroidetes ratio) appears to have an important influence in maintaining normal intestinal homeostasis and can change with age and the onset of several diseases (Mariat et al. 2009; Stojanov et al. 2020). Fecal microbiota in SS patients is different from that of controls. Primary SS patients are characterized by lower bacterial richness and lower Firmicutes/Bacteroidetes ratio in fecal samples compared with population controls (van der Meulen et al. 2019). De Paiva et al. (2016) described differences in the intestinal microbiota in SS patients compared with healthy controls. SS patients presented a significant reduction in Parabacteroides and Faecalibacterium and an increase in Streptococcus, Blautia, Escherichia, and Pseudobutyrivibrio. Moreover, the authors highlighted that reduced diversity of intestinal taxa in SS patients is associated with the severity of ocular and systemic disease (de Paiva et al. 2016). A subsequent study confirmed these results, showing that severe dysbiosis was significantly more prevalent in SS patients than in controls (21% vs. 3%) and patients with greater dysbiosis had greater clinical severity and increased markers of intestinal inflammation (Mandl et al. 2017).

21.9.4 Microbiota in the Pathogenesis of SS There is increasing evidence that the microbiota has potent immunoregulatory functions. The hypothesis formulated by some authors is that dysbiosis could also contribute to the development of mucosal inflammation in SS. In a pilot study, de Paiva et al. (2016) evaluated the effects of a cocktail of broad-spectrum antibiotics (ABX) on the severity of ocular disease in a mouse dry eye model. ABX-treated mice had a significant worsening of ocular disease, with a decrease in stool microbiota diversity and an increase in potential enteric pathogens, such as Escherichia/Shigella and Enterobacter. The authors postulated that reduced diversity in microbiota may favor the emergence of pathogenic bacteria, with subsequent dysregulation of the intestinal barrier function and production of inflammatory cytokines, particularly IL-17A or IFN-γ (de Paiva et al. 2016). Another interesting study assessed the hypothesis that peptides derived from normal human microbiota can activate Ro60-reactive T cells that are SS-specific T cells. Particularly, a peptide from the von Willebrand factor type A domain protein (vWFA) from the oral microbe Capnocytophaga ochracea was found to be the strongest activator of these T cells (Szymula et al. 2014). The role of bacterial peptides in promoting SS-specific inflammation was also investigated by Yanagisawa et al. (2018). These authors injected bacteria or bacterial cell wall components into immune-deficient mice. Specifically, the authors reproduced mononuclear cell inflammation of the Harderian and salivary glands in mice through repeated injection of recombinant outer membrane protein A of E. coli (Yanagisawa et al. 2018).

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

571

Aquaporin-5 is a major water channel protein of lacrimal and salivary glands, which is involved in tear and saliva secretion. Alam et al. (2016) demonstrated that aquaporin Z or porins from many human-associated bacteria, including members of normal oral flora, such as Enterobacter cloacae, Neisseria subflava, and Streptococcus oralis, had high homology with aquaporin 5. These results suggest another potential mechanism of bacterial mimicry in pathogenesis of SS (Alam et al. 2016). Although several studies seem to support the relationship between SS and microbiota, they could not reveal whether a cause-effect relationship exists nor the mechanisms by which dysbiosis could influence the etiopathogenesis of SS, mostly unknown. Moreover, it is unclear whether reported alterations of the microbiota constitute a risk factor for SS or they are rather the consequences of impaired mucocutaneous barrier function associated with immune dysregulation, a picture typically observed in SS (Björk et al. 2020).

21.10 Innate Immune System 21.10.1 Dendritic Cells and Type I Interferon The contribution of innate immunity in the pathogenesis of SS is demonstrated by the high degree of type I IFN system activation in the majority of patients (Björk et al. 2020). pSS patients have upregulated expression of IFNα in labial salivary glands, plasma, and peripheral blood cells (Zheng et al. 2009). Moreover, expression levels for many IFN-inducible genes correlate positively with titers of anti-Ro/SSA and anti-La/SSB autoantibodies in SS patients (Emamian et al. 2009). Plasmacytoid dendritic cells, a specific dendritic cell subset associated with B cell infiltration in SS salivary tissue, produce 200 to 1000 times more IFN than other blood cells after microbial challenge (Siegal et al. 1999). PDC numbers are decreased in the circulation and increased in the salivary glands of patients with pSS. PDCs are able to produce large amounts of type I IFN after activation by TLRs (Hillen et al. 2019). Type 1 IFN pathways have a central role in autoimmunity and activate B cells and T cells. B cell-derived autoantibodies stimulate dendritic cells to produce type I IFN; thus, a positive feed-forward loop is formed, including both the innate and adaptive systems (Wahren-Herlenius and Dörner 2013).

21.10.2 Toll-Like Receptors Toll-like receptors (TLRs) are components of the innate immune system that respond to exogenous infectious ligands (pathogen-associated molecular patterns, PAMPs) and endogenous molecules that are released during host tissue injury/death (damage-associated molecular patterns, DAMPs). Interaction of TLRs with their ligands leads to activation of downstream signaling pathways that induce an immune response by producing inflammatory cytokines, particularly type I IFN, and other inflammatory mediators. TLR expression is upregulated in salivary tissue and

572

L. Di Bartolomeo et al.

peripheral blood from SS patients and mouse models (Kiripolsky et al. 2017). Davies et al. (2019) studied the effects of TLR7 and TLR9 stimulation on peripheral blood mononuclear cells (PBMC) from 25 pSS patients and 25 matched healthy donors. The authors observed an increase in signaling potentials in peripheral B cells of pSS patients after TLR7 and TLR9 stimulation. TLR7 and TLR9 signals are mediated by STAT3 S727 and NF-κB, which are associated with a type I IFN signature (Davies et al. 2019). In addition to TLR7 and TLR9, TLR3 is also widely investigated for its role in the pathogenesis of SS. TLR-3 is expressed on the surface of activated salivary gland epithelial cells (SGECs). The role of TLR3 signaling in the pathogenesis of SS was proven in a mouse model, where it not only reduced the salivary gland function but also upregulated type I IFN response and recruitment of B cells, dendritic cells, and NK cells in the target organ (Srivastava and Makarenkova 2020).

21.10.3 Salivary Gland Epithelial Cells Interactions between epithelium and immune cells are considered essential for the pathogenesis of SS. Cultured SGECs secrete numerous inflammatory mediators such as B cell activating factor (BAFF); IL-1, IL-6, and IL-18; and TNFα (Kiripolsky et al. 2017). Moreover, disruption of the salivary gland epithelium by microbial triggers may be the initial event of pathogenesis of SS, and in a mouse model, the apoptosis of epithelial cells elicited the activation of self-reactive lymphocytes, causing a SS-like inflammation (Okuma et al. 2013). So, available data suggest that apoptosis and necrosis of SGECs lead to aberrant immune responses that drive the recruitment, activation, and differentiation of B and T cells, thus causing chronic salivary inflammation (Kiripolsky et al. 2017).

21.11 Adaptive Immune System 21.11.1 B Cells The role of adaptive immune system has been widely studied in SS. Abnormal activation of B and T cells was seen in glandular tissue and systemically in SS mouse models and human patients (Kiripolsky et al. 2017). B cell activation in SS is suggested by hypergammaglobulinemia, formation of germinal center-like (GC-like) structures in the glandular tissue, and production of RF and anti-SSA/ SSB antibodies (Srivastava and Makarenkova 2020). B cell infiltration correlates positively with the severity of inflammation in the salivary glands (Sandhya et al. 2017). This B cell infiltrate in salivary glands may be restricted to discrete infiltration or grow until creating organized structures that share morphological features with GCs. pSS patients present GC-like structures within the salivary gland epithelium in 10–30% of cases (Nocturne and Mariette 2018).

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

573

GC-like structures are involved in the pathogenesis of pSS via the promotion of chronic B cell stimulation (Nocturne and Mariette 2018; Sandhya et al. 2017). The chemokine CXC ligand 13 protein (CXCL13), also known as B cell-attracting chemokine-1 or B lymphocyte chemoattractant (BLC), drives the homing of B cells to the salivary gland through interaction with its receptor, CXCR5. CXCL13 is secreted by follicular dendritic cells, stromal cells, and also T cell subsets, such as follicular helper T cells (Tfh). The receptor CXCR5 is located on B cells as well as on Tfh. CXCL13 together with CXCR5 is considered responsible for lymphoid organization seen in salivary gland biopsies of SS patients (Sandhya et al. 2017). Further, BAFF abnormalities determine B cell hyperactivity in SS (Sandhya et al. 2017). BAFF, also known as TNF ligand superfamily member 13B, is essential for homeostasis and antibody production of B cells and represents the connection between the innate immune system and the stimulation of autoreactive B cells (Nocturne and Mariette 2018; Thorlacius et al. 2018). Usually, BAFF is produced by many types of immune cells. In patients with pSS, salivary epithelial cells secrete BAFF after stimulation by viruses or IFNα, supporting the idea that epithelial cells play a critical role in the pathogenesis of pSS, via the stimulation of B cells (Ittah et al. 2006; Nocturne and Mariette 2018). B cells are also involved in the development of lymphoma in pSS. The first step of lymphomagenesis in SS is the formation of immune complexes composed by IgG and an unknown antigen. High concentrations of these immune complexes stimulate the expansion of RF-reactive B cells, first polyclonally and then monoclonally. The stimulation of these autoreactive B cells is enhanced by different factors, including the secretion of BAFF by epithelial cells or other immune cells, the presence of GC-like structures which support the continuous activation of B cells, the presence of immune complexes, and the activation of the NF-κB pathway. Thus, antigendriven mechanism is considered at the base of the lymphomagenesis in pSS patients (Nocturne and Mariette 2018).

21.11.2 T Cells Th1 and Th2 cells are both involved in the pathogenesis of SS, to an extent and with a role which depend on the grade of infiltration and the clinical status of patients. At the beginning of autoimmune response in SS, low affinity autoreactive T cells are recruited and activated in the salivary glands. These low affinity T cells express preferentially a type-2-biased cytokine profile. Locally produced cytokines and chemokines may lead to the redirection from a type-2 to a type-1 immune response (Mitsias et al. 2002). The central role of Th1 cells in the pathogenesis of SS is supported by a study on nonobese diabetic (NOD) mice. NOD mice present an autoimmune exocrinopathy (AEC) that shows numerous similarities with human SS, including cytokine profiles (144). NOD mice that are knockout for IFN-γ and the IFN-γ receptor gene do not show increased acinar cell apoptosis and abnormal salivary protein expression,

574

L. Di Bartolomeo et al.

which are instead typically observed in parental NOD mice in the early stages of AEC (Cha et al. 2004). The Th17 pathway plays an important role in the formation of germinal centers in SS (Sandhya et al. 2017). Minor salivary glands from pSS patients contain IL-17expressing cells within inflammatory lesions. Furthermore, the Th17-centric cytokines IL-17, IL-6, IL-23, and IL-12 are significantly elevated in pSS plasma (Katsifis et al. 2009). In addition to IL-17, some authors found significantly increased levels of IL-22 in the inflamed salivary glands of patients with pSS (Ciccia et al. 2012). Moreover, SS patients showed significantly higher serum levels of IL-22. The serum levels of IL-22 presented statistically significant direct correlations with hyposalivation, anti-SSB, anti-SSA/SSB combined, hypergammaglobulinemia, and RF (Lavoie et al. 2011). IL-22 is produced by Th1, Th17, and Th22 cells at mucosal sites. IL-22 may act either as a protective or as a pro-inflammatory cytokine, depending on the coexpression of IL-17. Demonstration of concomitant IL-22 and IL-17 expression in salivary glands of patients with pSS suggests that IL-22 plays a pro-inflammatory role in the pathogenesis of SS (Ciccia et al. 2012). Follicular helper T cells mediate interactions between antigen-specific B cells, CD4+ T helper cells, and dendritic cells in response to microbial antigens, leading to the formation of germinal centers (Ma et al. 2012). SS patients present a higher frequency of Tfh cells in blood and glandular tissues compared with healthy controls (Srivastava and Makarenkova 2020). SGECs drive the differentiation of CD4+ naïve T cells into Tfh cells via upregulation of inducible T cell costimulator ligand (ICOSL) and IL-6 (Gong et al. 2014). The expression of CXCR5 and CXCL13 promotes the organization of GC-like structures by involving Tfh cells and B cells (Nocturne and Mariette 2018). Therefore, Tfh cells may play a key role in the formation of lymphoid follicles and GC-like structures in salivary glands of SS patients (Sandhya et al. 2017). Tfh cells express IL-21, which is considered the most potent inducer of terminal B cell differentiation in humans (Moens and Tangye 2014). SS patients present higher expression of IL-21 in serum and salivary glands, and these measures of IL-21 correlate positively with serum immunoglobulin levels and lymphocytic infiltration (Sandhya et al. 2017). The presence of the increased IL-21 levels in pSS patients further support the key role of Tfh cells in the pathogenesis of SS (Srivastava and Makarenkova 2020).

21.12 Management The therapeutic management of SS is commonly based on symptomatic treatment of sicca symptomatology and broad-spectrum immunosuppression for systemic disease. Despite the significant knowledge about pathogenesis and comorbidities of SS, there is a paucity of scientific evidence on the efficacy of treatments, and recommendations are mostly based on expert opinions or uncontrolled studies. Moreover, currently available therapies are far from reaching the goal of “disease modification” (Ramos-Casals et al. 2020).

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

575

The 2020 EULAR recommendations for the management of SS advise that the first approach to dryness should be the use of topical therapies, while systemic therapies may be considered for the treatment of active systemic disease. In patients with glandular dysfunction, non-pharmacological (xylitol, sugar-free chewing gum) or pharmacological (muscarinic agonists) stimulation should be weighted according to salivary gland function. In case of severe dysfunction, saliva substitutes are recommended. The first-line therapeutic approach to ocular dryness includes artificial tears and ocular gels/ointments, while, in refractory cases, topical application of drops containing nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or cyclosporine may be used. NSAIDs and oral corticosteroids have also a role in managing acute musculoskeletal pain. Finally, for the treatment of systemic disease, a progressive use of corticosteroids, immunosuppressive agents, and biologics is recommended according to the organ-specific severity (Ramos-Casals et al. 2020).

21.12.1 Therapies Against Predisposing Infections A fascinating hypothesis is that therapies against predisposing infections could change the course of the disease or prevent SS onset. About patients with HCV-SS, some authors suggest that the use of antiviral agents may help to eradicate the virus as the main causative agent of this B cell hyperactivity (Ramos-Casals et al. 2008). Few studies have assessed the role of treatment of HCV in HCV-SS patients (Sherman and Sherman 2015). Doffoël-Hantz et al. (2005) treated 12 HCV-SS patients with interferon or interferon/ribavirin for their chronic hepatitis C. Improvement of sicca symptoms was observed in the patients treated with the association (Doffoël-Hantz et al. 2005). So, evidence about the effects of antivirals in SS patients is scarce (Flores-Chávez et al. 2017). The effects of HAART on HIV-associated salivary gland disease are still controversial (Ghrenassia et al. 2015; Meer 2019). Some reports showed a reduction of oral manifestations of HIV infection following HAART, but other reports described an increase in HIV-related salivary gland disease (Meer 2019). Currently, first-line treatment for DILS is HAART (Ghrenassia et al. 2015). In addition to antimicrobial therapies, an interesting strategy for decreasing the global disease burden of SS is the development of vaccines against microbial agents involved in the pathogenesis of SS. To date, vaccines against the majority of the microbial agents associated with SS (EBV, HCV, coxsackievirus, HTLV-1, HIV, H. pylori) are not yet commercially available, although some of them are in development (Alam et al. 2020; Sun et al. 2021; Sutton and Boag 2019). The advent of a new generation of vaccines based on mRNA technology seems to provide an alternative to conventional vaccines (Zhang et al. 2019a).

576

L. Di Bartolomeo et al.

21.12.2 Management of SS by Probiotics The management of mucosal dysbiosis in SS patients is another prospect for future treatments. A study investigated the role of commensal bacteria by comparing SS-prone mice (CD25 knockout) raised in conventional or germ-free conditions. The authors observed a greater degree of corneal barrier dysfunction and total lymphocytic infiltration score among germ-free mice compared with conventionally raised mice. Intestinal microbiota reconstitution of germ-free mice through fecal transplant reversed the spontaneous dry eye, suggesting that manipulation of the gut microbiota may be a potential therapy for severe forms of SS (Zaheer et al. 2018). In another mouse model of SS, the fecal microbiota transplant reverted the dry eye phenotype in germ-free (GF) mice and lowered CD4+ T cell infiltration in the lacrimal glands (Wang et al. 2018). Choi et al. (2020) administered a probiotic mixture of five strains, including Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus reuteri, and Streptococcus thermophiles, to mice with autoimmune dry eye. The authors observed that probiotic treatment improved clinical manifestations of dry eye, downregulated antigen presentation by immune cells, and modulated cytokine expression, lowering IL-1β levels and increasing IL-10 levels in the conjunctiva and cornea (Choi et al. 2020). The effect of probiotics and prebiotics in SS patients has also been investigated. Chisari et al. (2017a) found that administration of probiotics strains of Enterococcus faecium and Saccharomyces boulardii was effective in reducing symptoms in patients with dry eye. Kamal et al. (2020) conducted a double-blinded, placebocontrolled, randomized trial to investigate the efficacy of probiotics in preventing candidiasis in SS patients. They administered orally a mixture of probiotics, including Lactobacillus acidophilus, Lactobacillus bulgaricus, Streptococcus thermophilus, and Bifidobacterium bifidum, to SS patients for 5 weeks. At the end of treatment, they noted a significant reduction of the candidal load of oral samples from these patients (Kamal et al. 2020). Nevertheless, the small number of participants and the short duration of the trial did not provide conclusive evidence on probiotics efficacy in reducing the risk of developing oral candidiasis in SS patients (Brignardello-Petersen 2020). Also synbiotics, i.e., mixtures of probiotics and prebiotics, have shown efficacy in studies on mice and humans, improving clinical symptoms and reducing the damage of the ocular surface in keratoconjunctivitis sicca (Chisari et al. 2017b; Kawashima et al. 2016). Nevertheless, the efficacy of prebiotics and probiotics in SS needs to be confirmed by larger, placebo-controlled, randomized clinical trials.

21.13 Conclusions Sjögren’s syndrome is a complex autoimmune disease, whose pathogenesis is mostly still obscure. Interaction between microbial trigger factors and immune system is recently emerging as a key element to understand the mechanisms underlying the initiation of the disease. Some viruses appear more involved than bacteria

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

577

in the pathogenesis, and the prevention of viral infections by vaccines might decrease the global disease burden of SS. The differences in oral and gut microbiota in SS patients compared to healthy controls have stimulated research on the role of dysbiosis in mucosal inflammation in SS. Preliminary studies on probiotic therapies in SS patients and mouse models seem to be encouraging. Therefore, further studies, focusing on the possible link between SS and microorganisms, might open new horizons on prevention of SS and disease modifying therapies.

References Aiyegbusi O, McGregor L, McGeoch L et al (2021) Renal disease in primary Sjögren's syndrome. Rheumatol Ther 8:63–80 Alam J, Koh JH, Kim N et al (2016) Detection of autoantibodies against aquaporin-5 in the sera of patients with primary Sjögren's syndrome. Immunol Res 64:848–856 Alam S, Hasan MK, Manjur OHB et al (2020) Predicting and designing epitope ensemble vaccines against HTLV-1. J Integr Bioinform 16:20180051 Alamanos Y, Tsifetaki N, Voulgari PV et al (2006) Epidemiology of primary Sjogren’s syndrome in north-west Greece, 1982–2003. Rheumatology (Oxford) 45:187–191 Alani H, Henty JR, Thompson NL et al (2018) Systematic review and meta-analysis of the epidemiology of polyautoimmunity in Sjögren's syndrome (secondary Sjögren's syndrome) focusing on autoimmune rheumatic diseases. Scand J Rheumatol 47:141–154 Alunno A, Bistoni O, Carubbi F et al (2018) Prevalence and significance of anti-Saccharomyces cerevisiae antibodies in primary Sjögren's syndrome. Clin Exp Rheumatol 36:73–79 Aragona P, Magazzù G, Macchia G et al (1999) Presence of antibodies against Helicobacter pylori and its heat-shock protein 60 in the serum of patients with Sjögren's syndrome. J Rheumatol 26: 1306–1311 Bartoloni E, Alunno A, Gerli R (2019) The dark side of Sjögren's syndrome: the possible pathogenic role of infections. Curr Opin Rheumatol 3:505–511 Barzilai O, Sherer Y, Ram M et al (2007) Epstein-Barr virus and cytomegalovirus in autoimmune diseases: are they truly notorious? A preliminary report. Ann N Y Acad Sci 1108:567–577 Björk A, Mofors J, Wahren-Herlenius M (2020) Environmental factors in the pathogenesis of primary Sjögren's syndrome. J Intern Med 287:475–492 Bombardieri M, Baldini C, Alevizos I et al (2018) Highlights of the 14th International Symposium in Sjögren's syndrome. Clin Exp Rheumatol 36:3–13 Bombardieri M, Argyropoulou OD, Ferro F et al (2020) One year in review 2020: pathogenesis of primary Sjögren's syndrome. Clin Exp Rheumatol 38:3–9 Brignardello-Petersen R (2020) Small trial with short duration does not provide evidence that probiotics reduce the risk of developing oral candidiasis in patients with Sjögren syndrome. J Am Dent Assoc 151:e92 Cha S, Brayer J, Gao J et al (2004) A dual role for interferon-gamma in the pathogenesis of Sjogren's syndrome-like autoimmune exocrinopathy in the nonobese diabetic mouse. Scand J Immunol 60:552–565 Chao WC, Lin CH, Liao TL et al (2017) Association between a history of mycobacterial infection and the risk of newly diagnosed Sjögren's syndrome: a nationwide, population-based casecontrol study. PLoS One 12:e0176549 Chen Q, Zhou X, Tan W et al (2018) Association between Helicobacter pylori infection and Sjögren syndrome: a meta-analysis. Medicine (Baltimore) 97:e13528 Chen L, Zhao J, Peng J, Li X, Deng X, Geng Z, Shen Z, Guo F, Zhang Q, Jin Y, Wang L, Wang S (2020) Detection of SARS-CoV-2 in saliva and characterization of oral symptoms in COVID-19 patients. Cell Prolif 53:e12923

578

L. Di Bartolomeo et al.

Chisari G, Chisari EM, Borzi AM et al (2017a) Aging eye microbiota in dry eye syndrome in patients treated with Enterococcus faecium and Saccharomyces boulardii. Curr Clin Pharmacol 12:99–105 Chisari G, Chisari EM, Francaviglia A et al (2017b) The mixture of bifidobacterium associated with fructo-oligosaccharides reduces the damage of the ocular surface. Clin Ter 168:e181–e185 Choi SH, Oh JW, Ryu JS, Kim HM, Im SH, Kim KP, Kim MK (2020) IRT5 probiotics changes immune modulatory protein expression in the extraorbital lacrimal glands of an autoimmune dry eye mouse model. Invest Ophthalmol Vis Sci 61:42 Chowdhury F, Grigoriadou S, Bombardieri M (2021) Severity of COVID-19 infection in primary Sjögren's syndrome and the emerging evidence of COVID-19-induced xerostomia. Clin Exp Rheumatol 39(Suppl 133):215–222 Ciccia F, Guggino G, Rizzo A et al (2012) Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands of patients with Sjogren's syndrome. Ann Rheum Dis 71: 295–301 Cruz-Tapias P, Rojas-Villarraga A, Maier-Moore S et al (2012) HLA and Sjögren's syndrome susceptibility. A meta-analysis of worldwide studies. Autoimmun Rev 11:281–287 Davies R, Sarkar I, Hammenfors D et al (2019) Single cell based phosphorylation profiling identifies alterations in Toll-Like Receptor 7 and 9 signaling in patients with primary Sjögren's syndrome. Front Immunol 10:281 de Paiva CS, Jones DB, Stern ME et al (2016) Altered mucosal microbiome diversity and disease severity in Sjögren syndrome. Sci Rep 6:23561 Doffoël-Hantz V, Loustaud-Ratti V, Ramos-Casals M et al (2005) Evolution des syndromes de Gougerot-Sjögren associés au virus de l'hépatite C sous interféron et l'association interféronribavirine. Rev Med Interne 26:88–94 Dwyer E, Itescu S, Winchester R (1993) Characterization of the primary structure of T cell receptor beta chains in cells infiltrating the salivary gland in the sicca syndrome of HIV-1 infection. Evidence of antigen-driven clonal selection suggested by restricted combinations of V beta J beta gene segment usage and shared somatically encoded amino acid residues. J Clin Invest 92: 495–502 Eguchi K, Matsuoka N, Ida H et al (1992) Primary Sjögren's syndrome with antibodies to HTLV-I: clinical and laboratory features. Ann Rheum Dis 51:769–776 Emamian ES, Leon JM, Lessard CJ et al (2009) Peripheral blood gene expression profiling in Sjögren's syndrome. Genes Immun 10:285–296 Etchegaray-Morales I, Jiménez-Herrera EA, Mendoza-Pinto C et al (2021) Helicobacter pylori and its association with autoimmune diseases: systemic lupus erythematosus, rheumatoid arthritis and Sjögren syndrome. J Transl Autoimmun 4:100135 Fayyaz A, Kurien BT, Scofield RH (2016) Autoantibodies in Sjögren's syndrome. Rheum Dis Clin N Am 42:419–434 Ferri C, Antonelli A, Mascia MT et al (2007) HCV-related autoimmune and neoplastic disorders: the HCV syndrome. Dig Liver Dis 39:S13–S21 Flament T, Bigot A, Chaigne B et al (2016) Pulmonary manifestations of Sjögren's syndrome. Eur Respir Rev 25:110–123 Fleck M, Kern ER, Zhou T et al (1998) Murine cytomegalovirus induces a Sjögren's syndrome-like disease in C57Bl/6-lpr/lpr mice. Arthritis Rheum 41:2175–2184 Flores-Chávez A, Carrion JA, Forns X et al (2017) Extrahepatic manifestations associated with chronic hepatitis C virus infection. Rev Esp Sanid Penit 19:87–97 Fox RJ, Pearson G, Vaughan JH (1986) Detection of Epstein-Barr virus associated antigens and DNA in salivary gland biopsies from patients with Sjogren’s syndrome. J Immunol 137:3162– 3168 Fujii H, Tsuji T, Yuba T, Tanaka S, Suga Y, Matsuyama A, Omura A, Shiotsu S, Takumi C, Ono S, Horiguchi M, Hiraoka N (2020) High levels of anti-SSA/Ro antibodies in COVID-19 patients with severe respiratory failure: a case-based review: high levels of anti-SSA/Ro antibodies in COVID-19. Clin Rheumatol 39:3171–3175

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

579

Gao ZW, Zhang HZ, Liu C, Dong K (2021) Autoantibodies in COVID-19: frequency and function. Autoimmun Rev 20:102754 Garo LP, Murugaiyan G (2016) Contribution of microRNAs to autoimmune diseases. Cell Mol Life Sci 73:2041–2051 Gessain A, Cassar O (2012) Epidemiological aspects and world distribution of HTLV-1 infection. Front Microbiol 3:388 Ghrenassia E, Martis N, Boyer J et al (2015) The diffuse infiltrative lymphocytosis syndrome (DILS). A comprehensive review. J Autoimmun 59:19–25 Gong YZ, Nititham J, Taylor K et al (2014) Differentiation of follicular helper T cells by salivary gland epithelial cells in primary Sjögren's syndrome. J Autoimmun 51:57–66 Goransson LG, Haldorsen K, Brun JG et al (2011) The point prevalence of clinically relevant primary Sjogren’s syndrome in two Norwegian counties. Scand J Rheumatol 40:221–224 Gottenberg JE, Busson M, Loiseau P et al (2003) In primary Sjögren's syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response. Arthritis Rheum 48:2240–2245 Gottenberg JE, Pallier C, Ittah M et al (2006) Failure to confirm coxsackievirus infection in primary Sjögren's syndrome. Arthritis Rheum 54:2026–2028 Green JE, Hinrichs SH, Vogel J et al (1989) Exocrinopathy resembling Sjögren's syndrome in HTLV-1 tax transgenic mice. Nature 341:72–74 Griffiths P, Baraniak I, Reeves M (2015) The pathogenesis of human cytomegalovirus. J Pathol 235:288–297 Harris VM, Sharma R, Cavett J et al (2016) Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome. Clin Immunol 168:25–29 Harris VM, Koelsch KA, Kurien BT et al (2019a) Characterization of cxorf21 provides molecular insight into female-bias immune response in SLE pathogenesis. Front Immunol 10:2160 Harris VM, Scofield RH, Sivils KL (2019b) Genetics in Sjögren's syndrome: where we are and where we go. Clin Exp Rheumatol 37:234–239 Haugen AJ, Peen E, Hulten B et al (2008) Estimation of the prevalence of primary Sjogren’s syndrome in two age-different community-based populations using two sets of classification criteria: the Hordaland Health Study. Scand J Rheumatol 37:30–34 Hernández-Molina G, Avila-Casado C, Cárdenas-Velázquez F et al (2010) Similarities and differences between primary and secondary Sjogren’s syndrome. J Rheumatol 37:800–808 Hernández-Molina G, Ávila-Casado C, Hernández-Hernández C et al (2020) Performance of the 2016 ACR/EULAR SS classification criteria in patients with secondary Sjögren's syndrome. Clin Exp Rheumatol 38:130–133 Hillen MR, Chouri E, Wang M et al (2019) Dysregulated miRNome of plasmacytoid dendritic cells from patients with Sjögren's syndrome is associated with processes at the centre of their function. Rheumatology (Oxford) 58:2305–2314 Houen G, Trier NH (2021) Epstein-Barr virus and systemic autoimmune diseases. Front Immunol 11:587380 Huang PI, Lin TC, Liu FC, Ho YJ, Lu JW, Lin TY (2020) Positive anti-SSA/Ro antibody in a woman with SARS-CoV-2 infection using immunophenotyping: a case report. Medicina (Kaunas) 56:521 Igoe A, Scofield RH (2013) Autoimmunity and infection in Sjögren's syndrome. Curr Opin Rheumatol 25:480–487 Itescu S, Winchester R (1992) Diffuse infiltrative lymphocytosis syndrome: a disorder occurring in human immunodeficiency virus-1 infection that may present as a sicca syndrome. Rheum Dis Clin N Am 18:683–697 Itescu S, Dalton J, Zhang HZ et al (1993) Tissue infiltration in a CD8 lymphocytosis syndrome associated with human immunodeficiency virus-1 infection has the phenotypic appearance of an antigenically driven response. J Clin Invest 91:2216–2225

580

L. Di Bartolomeo et al.

Ittah M, Miceli-Richard C, Eric Gottenberg J (2006) B cell-activating factor of the tumor necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjögren's syndrome. Arthritis Res Ther 8:R51 Jonsson R, Theander E, Sjöström B et al (2013) Autoantibodies present before symptom onset in primary Sjögren syndrome. JAMA 310:1854–1855 Jonsson R, Brokstad KA, Jonsson MV et al (2018) Current concepts on Sjögren's syndrome classification criteria and biomarkers. Eur J Oral Sci 126:37–48 Kamal Y, Kandil M, Eissa M, Yousef R, Elsaadany B (2020) Probiotics as a prophylaxis to prevent oral candidiasis in patients with Sjogren's syndrome: a double-blinded, placebo-controlled, randomized trial. Rheumatol Int 40:873–879 Katsifis GE, Rekka S, Moutsopoulos NM et al (2009) Systemic and local interleukin-17 and linked cytokines associated with Sjögren's syndrome immunopathogenesis. Am J Pathol 175:1167– 1177 Kawashima M, Nakamura S, Izuta Y et al (2016) Dietary supplementation with a combination of lactoferrin, fish oil, and Enterococcus faecium WB2000 for treating dry eye: a rat model and human clinical study. Ocul Surf 14:255–263 Kiripolsky J, McCabe LG, Kramer JM (2017) Innate immunity in Sjögren's syndrome. Clin Immunol 182:4–13 Kittridge A, Routhouska SB, Korman NJ (2011) Dermatologic manifestations of Sjögren syndrome. J Cutan Med Surg 15:8–14 Kivity S, Arango MT, Ehrenfeld M et al (2014) Infection and autoimmunity in Sjogren's syndrome: a clinical study and comprehensive review. J Autoimmun 51:17–22 Koike K, Moriya K, Ishibashi K et al (1997) Sialadenitis histologically resembling Sjogren syndrome in mice transgenic for hepatitis C virus envelope genes. Proc Natl Acad Sci U S A 94:233–236 Lavoie TN, Stewart CM, Berg KM et al (2011) Expression of interleukin-22 in Sjögren's syndrome: significant correlation with disease parameters. Scand J Immunol 74:377–382 Leone MC, Alunno A, Cafaro G et al (2017) The clinical spectrum of primary Sjögren's syndrome: beyond exocrine glands. Reumatismo 69:93–100 Lerner MR, Andrews NC, Miller G et al (1981) Two small RNAs encoded by Epstein-Barr virus and complexed with protein are precipitated by antibodies from patients with systemic lupus erythematosus. Proc Natl Acad Sci U S A 78:805–809 Lessard CJ, Li H, Adrianto I et al (2013) Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome. Nat Genet 45:1284–1292 Li Y, Zhang K, Chen H et al (2013) A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren’s syndrome at 7q11.23. Nat Genet 45:1361–1365 Li H, Reksten TR, Ice JA et al (2017) Identification of a Sjögren’s syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. PLoS Genet 13:e1006820 Lima CM, Santos S, Dourado A et al (2016) Association of sicca syndrome with proviral load and proinflammatory cytokines in HTLV-1 infection. J Immunol Res 2016:8402059 Liu Y, Sawalha AH, Lu Q (2021) COVID-19 and autoimmune diseases. Curr Opin Rheumatol 33: 155–162 Ma CS, Deenick EK, Batten M et al (2012) The origins, function, and regulation of T follicular helper cells. J Exp Med 209:1241–1253 Machado Ribeiro F, Goldenberg T (2015) Mycobacteria and autoimmunity. Lupus 24:374–381 Machida K, Cheng KT, Pavio N et al (2005) Hepatitis C virus E2-CD81 interaction induces hypermutation of the immunoglobulin gene in B cells. J Virol 79:8079–8089 Mandl T, Marsal J, Olsson P et al (2017) Severe intestinal dysbiosis is prevalent in primary Sjogren’s syndrome and is associated with systemic disease activity. Arthritis Res Ther 19:237 Margaretten M (2017) Neurologic manifestations of primary Sjögren syndrome. Rheum Dis Clin N Am 43:519–529

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

581

Mariat D, Firmesse O, Levenez F et al (2009) The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol 9:123 Mariette X (2001) Lymphomas complicating Sjögren's syndrome and hepatitis C virus infection may share a common pathogenesis: chronic stimulation of rheumatoid factor B cells. Ann Rheum Dis 60:1007–1010 Mariette X, Agbalika F, Daniel M-T et al (1993) Detection of human T lymphotropic virus type I tax gene in salivary gland epithelium from two patients with Sjögren's syndrome. Arthritis Rheum 36:1423–1428 Mariette X, Agbalika F, Zucker-Franklin D et al (2000) Detection of the tax gene of HTLV-I in labial salivary glands from patients with Sjögren's syndrome and other diseases of the oral cavity. Clin Exp Rheumatol 18:341–347 Martelli Júnior H, Gueiros LA, de Lucena EG, Coletta RD (2021) Increase in the number of Sjögren's syndrome cases in Brazil in the COVID-19 Era [published online ahead of print, 2021 May 27]. Oral Dis. https://doi.org/10.1111/odi.13925 Maślińska M (2019) The role of Epstein-Barr virus infection in primary Sjögren's syndrome. Curr Opin Rheumatol 31:475–483 McKenzie J, El-Guindy A (2015) Epstein-Barr virus lytic cycle reactivation. Curr Top Microbiol Immunol 391:237–261 Meer S (2019) Human immunodeficiency virus and salivary gland pathology: an update. Oral Surg Oral Med Oral Pathol Oral Radiol 128:52–59 Melissaropoulos K, Bogdanos D, Dimitroulas T et al (2020) Primary Sjögren's syndrome and cardiovascular disease. Curr Vasc Pharmacol 18:447–454 Mitsias DI, Tzioufas AG, Veiopoulou C et al (2002) The Th1/Th2 cytokine balance changes with the progress of the immunopathological lesion of Sjogren's syndrome. Clin Exp Immunol 128: 562–568 Moens L, Tangye SG (2014) Cytokine-mediated regulation of plasma cell generation: IL-21 takes center stage. Front Immunol 5:65 Nakamura H, Eguchi K, Nakamura T et al (1997) High prevalence of Sjögren's syndrome in patients with HTLV-I associated myelopathy. Ann Rheum Dis 56:167–172 Nakamura H, Shimizu T, Kawakami A (2020) Role of viral infections in the pathogenesis of Sjögren's syndrome: different characteristics of Epstein-Barr virus and HTLV-1. J Clin Med 9: 1459 Navone R, Lunardi C, Gerli R et al (2005) Identification of tear lipocalin as a novel autoantigen target in Sjögren's syndrome. J Autoimmun 25:229–234 Nezos A, Gkioka E, Koutsilieris M et al (2018) TNFAIP3 F127C coding variation in Greek primary Sjogren's syndrome patients. J Immunol Res 2018:6923213 Nocturne G, Mariette X (2018) B cells in the pathogenesis of primary Sjögren syndrome. Nat Rev Rheumatol 14:133–145 Nordmark G, Kristjansdottir G, Theander E et al (2011) Association of EBF1, FAM167A (C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren’s syndrome. Genes Immun 12:100–109 Odhams CA, Roberts AL, Vester SK et al (2019) Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in systemic lupus erythematosus. Nat Commun 10:2164 Ohyama Y, Carroll VA, Deshmukh U et al (2006) Severe focal sialadenitis and dacryoadenitis in NZM2328 mice induced by MCMV: a novel model for human Sjögren's syndrome. J Immunol 177:7391–7397 Okuma A, Hoshino K, Ohba T et al (2013) Enhanced apoptosis by disruption of the STAT3-IκB-ζ signaling pathway in epithelial cells induces Sjögren's syndrome-like autoimmune disease. Immunity 38:450–460 Pender MP (2003) Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol 24:584–588 Pierce JL, Tanner K, Merrill RM et al (2016) Swallowing disorders in Sjögren's syndrome: prevalence, risk factors, and effects on quality of life. Dysphagia 31:49–59

582

L. Di Bartolomeo et al.

Pillemer SR, Matteson EL, Jacobsson LT et al (2001) Incidence of physician-diagnosed primary Sjogren syndrome in residents of Olmsted County, Minnesota. Mayo Clin Proc 76:593–599 Plesivcnik Novljan M, Rozman B et al (2004) Incidence of primary Sjogren’s syndrome in Slovenia. Ann Rheum Dis 63:874–876 Qin B, Wang J, Yang Z et al (2015) Epidemiology of primary Sjögren's syndrome: a systematic review and meta-analysis. Ann Rheum Dis 74:1983–1989 Qu S, Du Y, Chang S et al (2017) Common variants near IKZF1 are associated with primary Sjögren's syndrome in Han Chinese. PLoS One 12:e0177320 Ramos-Casals M, García-Carrasco M, Brito Zerón MP et al (2002) Viral etiopathogenesis of Sjögren's syndrome: role of the hepatitis C virus. Autoimmun Rev 1:238–243 Ramos-Casals M, Anaya JM, García-Carrasco M et al (2004) Cutaneous vasculitis in primary Sjögren syndrome: classification and clinical significance of 52 patients. Medicine (Baltimore) 83:96–106 Ramos-Casals M, De Vita S, Tzioufas AG (2005a) Hepatitis C virus, Sjögren's syndrome and B-cell lymphoma: linking infection, autoimmunity and cancer. Autoimmun Rev 4:8–15 Ramos-Casals M, Loustaud-Ratti V, De Vita S et al (2005b) Sjogren syndrome associated with hepatitis C virus: a multicenter analysis of 137 cases. Medicine (Baltimore) 84:81–89 Ramos-Casals M, la Civita L, de Vita S et al (2007) Characterization of B cell lymphoma in patients with Sjogren’s syndrome and hepatitis C virus infection. Arthritis Rheum 57:161–170 Ramos-Casals M, Muñoz S, Zerón PB (2008) Hepatitis C virus and Sjögren's syndrome: trigger or mimic? Rheum Dis Clin N Am 34:869–884 Ramos-Casals M, Brito-Zerón P, Bombardieri S et al (2020) EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies. Ann Rheum Dis 79:3– 18 Reale M, D'Angelo C, Costantini E et al (2018) MicroRNA in Sjögren's syndrome: their potential roles in pathogenesis and diagnosis. J Immunol Res 2018:7510174 Reksten TR, Jonsson MV (2014) Sjögren's syndrome: an update on epidemiology and current insights on pathophysiology. Oral Maxillofac Surg Clin North Am 26:1–12 Rosa D, Saletti G, De Gregorio E et al (2005) Activation of naïve B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders. Proc Natl Acad Sci U S A 102:18544–18549 Saghafi M, Abdolahi N, Orang R et al (2019) Helicobacter pylori infection in Sjögren's syndrome: co-incidence or causality? Curr Rheumatol Rev 15:238–241 Sandhya P, Kurien BT, Danda D et al (2017) Update on pathogenesis of Sjogren's syndrome. Curr Rheumatol Rev 13:5–22 Scialo F, Daniele A, Amato F et al (2020) ACE2: the major cell entry receptor for SARS-CoV-2. Lung 198:867–877 See LC, Kuo CF, Chou IJ et al (2013) Sex- and age-specific incidence of autoimmune rheumatic diseases in the Chinese population: a Taiwan population-based study. Semin Arthritis Rheum 43:381–386 Seminog OO, Seminog AB, Yeates D et al (2015) Associations between Klinefelter's syndrome and autoimmune diseases: English national record linkage studies. Autoimmunity 48:125–128 Sharma R, Harris VM, Cavett J et al (2017) Rare X chromosome abnormalities in systemic lupus erythematosus and Sjögren's syndrome. Arthritis Rheumatol 69:2187–2192 Sherman AC, Sherman KE (2015) Extrahepatic manifestations of hepatitis C infection: navigating CHASM. Curr HIV/AIDS Rep 12:353–361 Shi H, Zheng LY, Zhang P et al (2014) miR-146a and miR-155 expression in PBMCs from patients with Sjögren’s syndrome. J Oral Pathol Med 43:792–797 Shiboski CH, Shiboski SC, Seror R et al (2017) 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol 69:35–45

21

Microorganisms in Pathogenesis and Management of Sjögren’s Syndrome

583

Siegal FP, Kadowaki N, Shodell M et al (1999) The nature of the principal type 1 interferonproducing cells in human blood. Science 284:1835–1837 Sorgato CC, Lins-E-Silva M, Leão JC et al (2020) EBV and CMV viral load in rheumatoid arthritis and their role in associated Sjögren's syndrome. J Oral Pathol Med 49:693–700 Souyris M, Cenac C, Azar P et al (2018) TLR7 escapes X chromosome inactivation in immune cells. Sci Immunol 3:eaap8855 Srivastava A, Makarenkova HP (2020) Innate immunity and biological therapies for the treatment of Sjögren's syndrome. Int J Mol Sci 21:9172 Stathopoulou EA, Routsias JG, Stea EA et al (2005) Cross-reaction between antibodies to the major epitope of Ro60 kD autoantigen and a homologous peptide of Coxsackie virus 2B protein. Clin Exp Immunol 141:148–154 Stefanski AL, Tomiak C, Pleyer U et al (2017) The diagnosis and treatment of Sjögren's syndrome. Dtsch Arztebl Int 114:354–361 Stergiou IE, Papageorgiou A, Chatzis LG et al (2020) T cell lymphoma in the setting of Sjögren's syndrome: T cells gone bad? Report of five cases from a single centre cohort. Clin Exp Rheumatol 38:125–129 Stojanov S, Berlec A, Štrukelj B (2020) The influence of probiotics on the Firmicutes/Bacteroidetes ratio in the treatment of obesity and inflammatory bowel disease. Microorganisms 8:1715 Sumida T, Yonaha F, Maeda T et al (1994) Expression of sequences homologous to HTLV-I tax gene in the labial salivary glands of Japanese patients with Sjögren's syndrome. Arthritis Rheum 37:545–550 Sun F, Li P, Chen H et al (2013) Association studies of TNFSF4, TNFAIP3 and FAM167ABLK polymorphisms with primary Sjögren’s syndrome in Han Chinese. J Hum Genet 58:475–479 Sun C, Chen XC, Kang YF et al (2021) The status and prospects of Epstein-Barr virus prophylactic vaccine development. Front Immunol 12:677027 Sutton P, Boag JM (2019) Status of vaccine research and development for Helicobacter pylori. Vaccine 37:7295–7299 Szymula A, Rosenthal J, Szczerba BM et al (2014) T cell epitope mimicry between Sjögren's syndrome Antigen A (SSA)/Ro60 and oral, gut, skin and vaginal bacteria. Clin Immunol 152:1– 9 Talotta R, Sarzi-Puttini P, Atzeni F (2019) Microbial agents as putative inducers of B cell lymphoma in Sjögren's syndrome through an impaired epigenetic control: the state-of-the-art. J Immunol Res 2019:8567364 Tang Y, Luo C, Cheng A et al (2014) Expression of latent membrane proteins in Epstein-Barr virustransformed lymphocytes in vitro. Mol Med Rep 10:1117–1121 Tateishi M, Saito I, Yamamoto K et al (1993) Spontaneous production of Epstein-Barr virus by B lymphoblastoid cell lines obtained from patients with Sjögren's syndrome. Possible involvement of a novel strain of Epstein-Barr virus in disease pathogenesis. Arthritis Rheum 36:827–835 Terada K, Katamine S, Eguchi K et al (1994) Prevalence of serum and salivary antibodies to HTLV1 in Sjögren's syndrome. Lancet 344:1116–1119 Thorlacius GE, Wahren-Herlenius M, Rönnblom L (2018) An update on the role of type I interferons in systemic lupus erythematosus and Sjögren's syndrome. Curr Opin Rheumatol 30:471–481 Thorne I, Sutcliffe N (2017) Sjögren's syndrome. Br J Hosp Med (Lond) 78:438–442 Toda I, Ono M, Fujishima H et al (1994) Sjögren's syndrome (SS) and Epstein-Barr virus (EBV) reactivation. Ocul Immunol Inflamm 2:101–109 Toussirot E, Le Huédé G, Mougin C et al (2002) Presence of hepatitis C virus RNA in the salivary glands of patients with Sjögren’s syndrome and hepatitis C virus infection. J Rheumatol 29: 2382–2385 Triantafyllopoulou A, Moutsopoulos HM (2005) Autoimmunity and coxsackievirus infection in primary Sjogren's syndrome. Ann N Y Acad Sci 1050:389–396 Triantafyllopoulou A, Tapinos N, Moutsopoulos HM (2004) Evidence for coxsackievirus infection in primary Sjögren's syndrome. Arthritis Rheum 50:2897–2902

584

L. Di Bartolomeo et al.

Trujillo-Vargas CM, Schaefer L, Alam J et al (2020) The gut-eye-lacrimal gland-microbiome axis in Sjögren syndrome. Ocul Surf 18:335–344 Tsubota K, Fujishima H, Toda I et al (1995) Increased levels of Epstein-Barr virus DNA in lacrimal glands of Sjögren's syndrome patients. Acta Ophthalmol Scand 73:425–430 Tukiainen T, Villani AC, Yen A et al (2017) Landscape of X chromosome inactivation across human tissues. Nature 550:244–248 UNAIDS (2021). https://www.unaids.org. Accessed 06 December 2021 Utomo SW, Putri JF (2020) Infections as risk factor of Sjögren’s syndrome. Open Access Rheumatol 12:257–266 Vale DAD, Casseb J, de Oliveira ACP et al (2017) Prevalence of Sjögren's syndrome in Brazilian patients infected with human T-cell lymphotropic virus. J Oral Pathol Med 46:543–548 van der Meulen TA, Harmsen HJM, Vila AV et al (2019) Shared gut, but distinct oral microbiota composition in primary Sjögren's syndrome and systemic lupus erythematosus. J Autoimmun 97:77–87 Vitali C (2011) Immunopathologic differences of Sjögren's syndrome versus sicca syndrome in HCV and HIV infection. Arthritis Res Ther 13:233 Vojdani A, Kharrazian D (2020) Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin Immunol 217: 108480 Wahren-Herlenius M, Dörner T (2013) Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 382:819–831 Wang Y, Dou H, Liu G et al (2014) Hepatitis C virus infection and the risk of Sjögren or sicca syndrome: a meta-analysis. Microbiol Immunol 58:675–687 Wang C, Zaheer M, Bian F, Quach D, Swennes AG, Britton RA, Pflugfelder SC, de Paiva CS (2018) Sjögren-like lacrimal keratoconjunctivitis in germ-free mice. Int J Mol Sci 19:565 Weng MY, Huang YT, Liu MF et al (2011) Incidence and mortality of treated primary Sjogren’s syndrome in Taiwan: a population-based study. J Rheumatol 38:706–708 Xu J, Li Y, Gan F, Du Y, Yao Y (2020) Salivary glands: potential reservoirs for COVID-19 asymptomatic infection. J Dent Res 99:989 Xuan J, Ji Z, Wang B et al (2020) Serological evidence for the association between Epstein-Barr virus infection and Sjögren's syndrome. Front Immunol 11:590444 Yamazaki H, Ikeda H, Ishizu A et al (1997) A wide spectrum of collagen vascular and autoimmune diseases in transgenic rats carrying the env-pX gene of human T lymphocyte virus type I. Int Immunol 9:339–346 Yanagisawa N, Ueshiba H, Abe Y et al (2018) Outer membrane protein of gut commensal microorganism induces autoantibody production and extra-intestinal gland inflammation in mice. Int J Mol Sci 19:3241 Yin H, Qu J, Peng Q et al (2019) Molecular mechanisms of EBV-driven cell cycle progression and oncogenesis. Med Microbiol Immunol 208:573–583 Yu KH, See LC, Kuo CF et al (2013) Prevalence and incidence in patients with autoimmune rheumatic diseases: a nationwide population-based study in Taiwan. Arthritis Care Res (Hoboken) 65:244–250 Zaheer M, Wang C, Bian F et al (2018) Protective role of commensal bacteria in Sjögren syndrome. J Autoimmun 93:45–56 Zhang C, Maruggi G, Shan H (2019a) Advances in mRNA vaccines for infectious diseases. Front Immunol 10:594 Zhang P, Minardi LM, Kuenstner JT et al (2019b) Serological testing for mycobacterial heat shock protein Hsp65 antibody in health and diseases. Microorganisms 8:47 Zheng L, Zhang Z, Yu C et al (2009) Association between IFN-alpha and primary Sjogren’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 107:e12–e18

Autoimmune Diseases Associated with Chikungunya Infection

22

Jozélio Freire de Carvalho, Mitesh Kumar Dwivedi, Luisa Rodrigues Cordeiro, Thelma Larocca Skare, and Yehuda Shoenfeld

Abstract

Chikungunya virus infection (CKV) is an arbovirosis transmitted by Aedes aegypti and Aedes albopictus mosquito. It is now an established infection in the tropical areas of the world, and it has emerged as a significant public health concern in the last 10–15 years. Several autoimmune manifestations have been linked to this viral infection. Rheumatoid arthritis is one of the most recognized, but several others such as Guillain-Barré, psoriasis, vitiligo, uveitis, myocarditis, and Addison’s disease have also been documented. This chapter aims to review the main autoimmune manifestations associated with CKV infection.

J. F. de Carvalho (*) Institute for Health Sciences from Federal University of Bahia, Salvador, Bahia, Brazil M. K. Dwivedi C. G. Bhakta Institute of Biotechnology, Faculty of Science, Uka Tarsadia University, Barodli, Gujarat, India L. R. Cordeiro Escola Bahiana de Medicina, Salvador, Bahia, Brazil T. L. Skare Unit of Rheumatology, Hospital Evangélico Mackenzie, Curitiba, PR, Brazil Y. Shoenfeld Zabludowizc Center for Autoimmunity, Sheba Medical Center, Tel-Hashomer, Israel # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_22

585

586

J. F. de Carvalho et al.

Keywords

Chikungunya infection · Arboviruses · Autoimmunity · Autoantibodies · Viral infection

22.1

Introduction

Chikungunya virus infection (CKV) is an arbovirus transmitted by Aedes aegypti and Aedes albopictus mosquito. It leads to acute clinical pictures characterized by fever, headache, macular rash, and arthralgia in the short term (Tanay 2016). Chikungunya infection is divided into an acute, viremic, and subacute post-viremic phase. In the subacute and chronic phases, some patients may present diseases mainly characterized by musculoskeletal disorders (Krishnamurthy 2008). Several autoimmune pathologies were described during CKV infection, and the most common manifestation is rheumatoid arthritis (Bouquillard and Combe 2009). However, several systems were described to be involved in the clinical alterations of CKV, such as skin (psoriasis exacerbation) and neurological impairment such as Guillain-Barré syndrome (Mathew et al. 2011). Nevertheless, there are several literature descriptions and case reports about different autoimmune manifestations after subacute and chronic chikungunya virus infection. Therefore, it is essential to assess whether autoimmunity is a cause or a consequence of developing these diseases.

22.2

Pathophysiology

The pathophysiology of CKV infection has not yet been fully elucidated, but it is known that the infection begins with an intradermal inoculation of the virus after the female Aedes aegypti mosquito bite. Then, viral replication begins in fibroblasts, endothelial cells, and macrophages (Petitdemange et al. 2015). The initial immune response is carried out via IFN-α, which activates the TH1 response to fight the pathogen. It has been shown that the virus’s persistence in “immune privileged” sites such as the synovial cavity faced directly an autoimmune response mediated by IFN-α, IL-10, and CCL2 (Petitdemange et al. 2015). In turn, the activation of innate immunity by natural killer cells infiltrates the cavity and contributes to arthralgia development. Monocytes and macrophages continuously migrate towards the joint cavity, further increasing joint infection. As for autoimmunity, CD4+ T cells were detected mainly in chronic stages of the disease and, along with regulatory T cells (Treg), maintain immune tolerance and seem to be associated with the autoimmunity carried by the viral infection (Macêdo 2018). In summary, the intracellular viral behavior macroscopically tends to stimulate inflammatory dysregulation in both phases of the disease. After the acute phase of the disease, the infected individual has chances to progress to the chronic phase and express autoimmunity patterns (mainly arthralgia) due to the dysregulation of the immune response triggered by the chikungunya virus (Burt et al. 2017).

22

Autoimmune Diseases Associated with Chikungunya Infection

22.3

587

Autoimmune Manifestations Associated with CKV Infection

This chapter aims to review and summarize the articles published concerning autoimmune manifestations linked to CKV infection. A research of articles published in PubMed/MEDLINE, Web of Science, LILACS, and Scielo dating from 1966 to August 2020 was performed. All the researched articles are based on “Chikungunya” and “rheumatic disease” or “autoimmune disease,” “Guillain-Barré syndrome,” “uveitis,” “psoriasis,” “myocarditis,” “rheumatoid arthritis,” “ankylosing spondylitis,” “spondyloarthritis,” “psoriatic arthritis,” “systemic lupus erythematosus,” “antiphospholipid syndrome,” “vasculitis,” “Addison disease,” “vitiligo,” “Still disease,” “myositis,” and “Sjögren syndrome.” No restriction on languages was applied. The following parameters were screened for the published cases of SS and autoimmune condition association: demographic characteristics (gender, age), autoimmune disease diagnosis, disease duration, treatment, autoantibodies, laboratory test which diagnosed CKV, and outcomes. Duplicate articles, insufficiently detailed or not informative enough, were excluded. This review found 44 articles in 18 autoimmune diseases associated with CKV. The number of patients included varied from 1 to 56 individuals, age varied from 4 months to 77 years, and female gender predominance varied from 0 to 100% of the articles. The most common study design was case report (n ¼ 19), followed by retrospective study (n ¼ 12), prospective study (n ¼ 5), case series (n ¼ 5), observational using questionnaires (n ¼ 5), and one case-control study. Regarding autoimmune disorders, Guillain-Barré syndrome was the most published disease (n ¼ 10), followed by uveitis (n ¼ 8), psoriasis (n ¼ 6), myocarditis (n ¼ 6), rheumatoid arthritis (n ¼ 3), ankylosing spondylitis (n ¼ 1), spondyloarthritis (n ¼ 1), undifferentiated spondyloarthritis (n ¼ 2), undifferentiated polyarthritis (n ¼ 2), psoriatic arthritis (n ¼ 2), and lupus that evolved with catastrophic antiphospholipid syndrome (n ¼ 1), Kawasaki-like disease (n ¼ 1), Addison’s disease (n ¼ 1), vitiligo (n ¼ 1), Still (n ¼ 1), polymyositis (n ¼ 1), and Sjögren syndrome (n ¼ 1). Concerning the clinical form of duration, most cases were in the acute phase of CKV (n ¼ 20), followed by subacute (n ¼ 13) and chronic phases in 11 articles. This data was not described in four articles. Disease duration between CKV onset and autoimmunity varied from 0 to 27.5 months. Serology IgM and/or IgG for CKV was performed in 40 articles, RT-PCR for CKV in 15, and not described, meaning an epidemiological and clinical diagnosis, in 2. Treatment included intravenous immunoglobulin in 8/44, followed by topical or systemic steroids in 10/44, methotrexate in 5/44, and biologicals in 2/44. This datum was not described in 9/44; no therapy was present in 2/44 and symptomatic in 7/44. The outcome with total or partial recovery was observed in most studies (n ¼ 38); in one study patient worsened (uveitis needing several ocular surgeries), and in another study, the patient died (lupus that evolved to catastrophic antiphospholipid syndrome). This datum was not available in five studies.

588

22.4

J. F. de Carvalho et al.

Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy caused by viral molecule mimicry, and later research has shown in epidemiological studies a clear correlation between both diseases. After an arbovirus outbreak in French Polynesia, the Pan American Health Organization/World Health Organization (PAHO/WHO) released an epidemiological update to its member states, presenting the correlation of neurological syndromes (SN) or autoimmune syndromes (SA) and Guillain-Barré syndrome, alerting to all countries favorable to the proliferation of the virus, for a possible increase in cases of this syndrome resulting from the CKV infection (Pinheiro et al. 2016). Table 22.1 shows the data obtained on Guillain-Barré disease. This table shows that most of the cases occurred in acute and subacute phases, were treated with immunoglobulin, and had, at least, a partial recovery.

22.5

Rheumatic Manifestations

In Table 22.2 the articles on rheumatic manifestations are displayed. This table demonstrates that a wide range of rheumatological manifestations is seen in this context. It also shows that rheumatic manifestations that appear at the chronic phase of the disease are mainly rheumatoid arthritis, spondyloarthritis, and undifferentiated arthritis, while cases associated with macrophage activation syndrome or catastrophic antiphospholipid antibodies syndrome appear in the acute phase. Females seem to predominate in this type of complication.

22.6

Uveitis

Table 22.3 shows the information on uveitis in CHV infection. Anterior uveitis was the most common form of uveitis seen in this review, and CHV uveitis was found to be both: granulomatous and non-granulomatous. Both bilateral and unilateral ocular involvements are described in Table 22.3.

22.7

Other Autoimmune Diseases

Table 22.4 shows the association of CKV infection with skin diseases (psoriasis and vitiligo), myocarditis, and Addison’s disease.

Hameed and Khan (2019)

Author, year Agarwal et al. (2017a, b)

Case report

Study design Case report

1, 100%

N, female sex 2, males

36

Age 18, 30.

Suspect CKV, 4 weeks

CKV test and disease duration IgM CKV in one case, the other was suspect CKV, 20 and 25 days

Subacute

CKV phase Subacute

Clinical symptoms Swelling and weakness of distal upper limbs which gradually spread proximally and then progressed to dysphagia, neck weakness, and tachypnea, mechanical ventilation Rare variant pharyngeal– cervical– brachial GBS N/A

Autoantibodies N/A

Table 22.1 Literature review on Guillain-Barré syndrome (GBS) after Chikungunya virus (CKV) infection

Intravenous immunoglobulin Mechanical ventilation

Treatment Plasmapheresis: 5 cycles

(continued)

She improved and was discharged after 10 days. She had normal bulbar function with MRC grade 4+/5 power in the left upper limb after 6 months

Outcome Partial recovery

22 Autoimmune Diseases Associated with Chikungunya Infection 589

13, 23%

Study design Case report

Retrospective

24, 37.5%

N, female sex 1, 100%

Stegmann- Case-control Planchard study et al. (2020)

Balavoine et al. (2017)12

Author, year VillamilGómez et al. (2016)

Table 22.1 (continued)

61

61

Age 77

RT-PCR, IgM and IgG antibodies, 54.2% up to 8 days

IgM CKV, and RT-PCR, 9 days

CKV test and disease duration RT-PCR and IgM and IgG CKV, 1 day

Acute

Acute

CKV phase Acute

Clinical symptoms

N/A

N/A

Autoantibodies Not done

N/A

Intravenous immunoglobulin

Treatment Intravenous immunoglobulin

Outcome She recovered and was discharged on day 30 postadmission. Eight weeks after the onset of symptoms, the patient reported a satisfactory full recovery. She was able to walk, and her sensory disturbances rapidly disappeared 9 improved within 7 days. 5/13 required mechanical ventilation. 2 with severe GBS died. At 6 months of follow-up, 7/13 achieved a good functional recovery with no or minor residual symptoms N/A

590 J. F. de Carvalho et al.

2, 100%

6, 28%

3, 66%

Case series

Retrospective

Case series

Lebrun et al. (2009) Crosby et al. (2016) Wielanek et al. (2007)

49, 51, 60

60

48, 51

47

48

IV, intravenous; N/A, not available; pos., positive

9, 34%

Prospective observational

de Matos et al. (2020)

9, 33%

Retrospective

Oehler et al. (2015)

IgM CKV and RT-PCR IgM CKV and/or RT-PCR

IgM and IgG CKV

IgM and/or IgG CKV and RT-PCR

8 had IgM and IgG and 1 RT-PCR

Acute

N/A

Acute

N/A

Acute

N/A

N/A

N/A

N/A

N/A

Intravenous immunoglobulin in 2/3

N/A

Intravenous immunoglobulin

N/A

Intravenous immunoglobulin

Improvement after 1 month

N/A

6/9 were discharged to a functional rehabilitation center for a median stay of 28 days (range: 19–60 days). For all patients, electrophysiological parameters quickly returned to almost normal levels within 3 months Recovery after 6 months was complete for 33%, whereas 67% remained with minor signs or symptoms After 2 months, complete recovery

22 Autoimmune Diseases Associated with Chikungunya Infection 591

Autoimmune disease

Rheumatoid arthritis

Rheumatoid arthritis

Rheumatoid arthritis

Ankylosing spondylitis

Author, year

Mathew et al. (2011)

Javelle et al. (2015)

Bouquillard and Combe (2009)

Mathew et al. (2011)

Observational based on a questionnaire house-tohouse survey

Prospective

Retrospective

Observational based on a questionnaire house-tohouse survey

Study design

1 out of 1396, 71.6%

21, 62%

40, 75%

6 out of 1396, 71.6%

N, female sex

IgM and/or CKV or RT-PCR IgM and/or IgG CKV, 10 months

IgM CKV, 15 months after epidemics

57  12

48.37  13.62 years

IgM CKV, 15 months after epidemics

49

48.37  13.62 years

Age

CKV test and disease duration

Chronic

Chronic

Chronic

Chronic

CKV phase Clinical symptoms

Table 22.2 Literature review on rheumatic manifestations after Chikungunya virus (CKV) infection

RF 57.1%, antiCCP 28.6%, and HLA-DRB1*04 or 01 alleles 66.6%

12 RF or antiCCP

2 RF and 4 antiCCP

Autoantibodies

Treatment

N/A

Methotrexate 91% Anti-TNF 29%

Methotrexate in 100% Biologicals23%

N/A

Outcome

After the initial flare of symptoms, most of the patients were in the remission phase, requiring minimal analgesic support

After 27.6  6.4 months, X-rays showed 5 additional patients with joint space narrowing and 12 more with erosions, despite DMARDs 19% had normal X-ray of hands and feet 33% continued steroid use.

75% response to methotrexate

After the initial flare of symptoms, most of the patients were in the remission phase, requiring minimal analgesic support

592 J. F. de Carvalho et al.

Case report

Undifferentiated polyarthritis

Symmetrical polyarthritis

Psoriatic arthritis

Javelle et al. (2015)

Blettery et al. (2016)

Chen and Sehra (2019)

40

Retrospective

Undifferentiated spondyloarthritis

Mathew et al. (2011)

Retrospective

Observational based on a questionnaire house-tohouse survey

Retrospective

Undifferentiated spondyloarthritis

Javelle et al. (2015)

Observational based on a questionnaire

Spondyloarthritis

Essackjee et al. (2013)

1, male

27 out of 147

21, 75%

5 out of 1396, 71.6%

33, 70%

10 out of 173, 100%

34 years

62.5

RT-PCR and IgM and IgG CKV

42% has positive serology CKV, 8 months

IgM and/or CKV or RT-PCR

IgM CKV, 15 months after epidemics

48.37  13.62 years

59

IgM and/or CKV or RT-PCR

Suspected CKV, 27.5 months

49

60.4

Subacute

Chronic

Chronic

Chronic

Chronic

Chronic

Past of mild psoriasis. On day 35, a rash developed and subsequently extensive psoriasis exacerbation, polyarthritis

Symmetrical polyarthritis and synovitis 27/27 Inflammatory back pain in 17/27 Rheumatoid arthritis 1/27

Negative rheumatoid factor and antiCCP

Nonsteroidal antiinflammatory drugs, steroid cream, and phototherapy

Methotrexate in 100% Anti-TNF in 22%

Methotrexate in 29%

–

Negative ANA, anti-ENA, RF, and anti-CCP

N/A

Methotrexate in 79% Biologicals ion 9%

Methotrexate Anti-TNF (n ¼ 13)

No

2 HLA-B27

N/A

(continued)

Responded after 4–6 months

Good MTX response in 78%

75% response to methotrexate

After the initial flare of symptoms, most of the patients were in the remission phase, requiring minimal analgesic support

75% response to methotrexate

Good response

22 Autoimmune Diseases Associated with Chikungunya Infection 593

Psoriatic arthritis

SLE evolved to catastrophic antiphospholipid syndrome

Mathew et al. (2011)

Betancur et al. (2015)

Author, year

Autoimmune disease

Table 22.2 (continued)

Case report

Observational based on a questionnaire house-tohouse survey

Study design

1, 100%

6 out of 1396, 71.6%

N, female sex

21

48.37  13.62 years

Age

RT-PCR, 4 days

IgM CKV, 15 months after epidemics

CKV test and disease duration

Acute

Chronic

CKV phase

SLE was diagnosed 5 years before. Multi-organ compromise (renal, heart, hematologic, hypotension, acute respiratory distress syndrome with mechanical ventilation required, skin lesions progressing to livedoid vasculitis, digital necrotic lesions, and splenic infarction)

Clinical symptoms

Lupus anticoagulant and anticardiolipin antibody

No

Autoantibodies

Treatment

Steroids and intravenous immunoglobulin

N/A

Outcome

Patient died

After the initial flare of symptoms, most of the patients were in the remission phase, requiring minimal analgesic support

594 J. F. de Carvalho et al.

Kawasaki-like disease

Still disease and macrophagic activation syndrome, concomitant hepatitis E virus

Probable polymyositis

Lee et al. (2010)

Jindal et al. (2018)

Maek-anantawat and Silachamroon (2009)

Case report

Case report

Case report

1, 100%

1, 100%

1, male

21

18

4 months

IgM and IgG CKV, 3–45 days

IgM CKV and IgM hepatitis E, 2 months

RT-PCR and IgM CKV

Acute and subacute

Subacute

Acute

Puffy hands and feet, polyarthralgia, polymyalgia, proximal muscle weakness in both upper and lower extremities, creatinine kinase 16.35 (normal range 0.17–1.17μkat/L). No electromyography or muscle biopsy was done

Rash, polyarthritis which evolved to anemia, leukopenia, thrombocytopenia, rising ferritin levels, and ESR decrease. Bone marrow examination revealed increased macrophages and hemophagocytosis

Tonic seizure, fever Maculopapular rash over the trunk and limbs, hepatomegaly, swollen hands and feet with intense redness, involving the palms and soles, lymphopenia, high CRP. Normal echocardiogram

Positive ANA 1: 320, speckled, negative antidsDNA anti-Sm, anti-Jo-1, and RF

Negative ANA and RF

N/A

Dexamethasone 20 mg/day and then prednisolone 0.8 mg/kg/day

Naproxen IVIg Subsequently, prednisolone (15 mg/d) and methotrexate (7.5 mg/wk)

Spontaneous resolution

Autoimmune Diseases Associated with Chikungunya Infection (continued)

4–6 weeks later, the patient improved markedly and resumed her normal activities. Steroid dosage was tapered off and stopped at 10 weeks. ANA became negative after 3 months

Improvement. Corticoid was stopped after 6 months, MTX continues

Improvement in 11 days

22 595

Sjögren syndrome

Case report

Study design

1, 100%

N, female sex

49

Age IgM CKV, 0

CKV test and disease duration Acute

CKV phase Clinical symptoms Positive ANA and anti-Ro/SSA

Autoantibodies

Treatment Prednisone, azathioprine, HCQ

Outcome Good response

ANA, antinuclear antibodies; AZA, azathioprine; HCQ, hydroxychloroquine; IV, intravenous; N/A, not available; pos., positive; NSAID, the nonsteroidal antiinflammatory drug

de Carvalho et al. (2021) (submitted)

Author, year

Autoimmune disease

Table 22.2 (continued)

596 J. F. de Carvalho et al.

Study design Case series

Retrospective

Author, year Mittal et al. (2007)

Kharel et al. (2018)

1 out of 100, 48%

N, female sex 15, 46.7%

39.2  15.4

Age 53.6  12.1

Ocular fluid RT-PCR

CKV test and disease duration IgM CKV, 3– 42 days

N/A

CKV phase Acute and subacute

Table 22.3 Literature review on uveitis after Chikungunya virus (CKV) infection

Clinical symptoms Uveitis was seen in 18 eyes; 3 individuals (20%) had bilateral involvement. 9/15 (60.0%) developed ocular symptoms during the course of CKV. The remaining 6/16, within 6 weeks after CKV Uveitis was unilateral in 82% and granulomatous in 40%. PCR was performed in 100 patients with infectious diseases Not done

Auto antibodies Not done

N/A

Treatment Topical steroid eye drops (prednisolone acetate 0.2%, 8 times per day) on a 5-day tapering dose schedule and cyclopentolate 1.0% twice daily

(continued)

N/A

Outcome The uveitis was transient and resolved within 1 week of treatment in all eyes

22 Autoimmune Diseases Associated with Chikungunya Infection 597

Study design Case report

Case report

Author, year Chanana et al. (2007) 21

Scripsema et al. (2015)

Table 22.3 (continued)

1, 100%

N, female sex 1, male

47

Age 16

IgM and IgG CKV, 10 days

CKV test and disease duration IgM CKV, 1 month

Acute

CKV phase Subacute

After 15 days of CKV symptoms, bilateral decreased vision and photophobia were noted

Clinical symptoms

Not done

Auto antibodies Not done

Prednisolone acetate 1% cyclopentolate 1%, oral prednisone (1 mg/kg), mycophenolate mofetil

Treatment Prednisolone 1 mg/kg/day

Outcome Visual acuity improved, and the fundus showed resolving choroiditis bilaterally. y. CMT decreased to 156 m OD and 181 m OS (Fig. 22.1b). Inflammation resolved within 6 weeks of treatment, but the vision did not improve further After 6 weeks, her best-corrected visual acuity had improved to 20/20 in both eyes, and the inflammation had resolved

598 J. F. de Carvalho et al.

Case report

Case report

Babu and Murthy (2012)

Lin et al. (2018)

1, 100%

1, male

44

37

IgM and IgG CKV, 1 month

RT-PCR, uveitis for 6 months, and CKV 1 month ago

Subacute

Subacute

Intermediate uveitis for 10 days after 30 days of CKV infection

Flare of recurrent non-granulomatous anterior uveitis with secondary glaucoma after 3 months of CKV

Not done

Negative ANA, RF, and HLA-B27

Topical steroids, antiglaucoma medications, and trabeculectomy with mitomycin C, Ahmed valve implant Prednisone 60 mg, topical steroids, and cycloplegia

(continued)

The patient had a final visual acuity of 20/20 that was stable without residual signs of inflammation at 1.5 years follow-up after discontinuing the medication

Bad, the patient needed 2 surgical procedures

22 Autoimmune Diseases Associated with Chikungunya Infection 599

Retrospective

Mahendradas et al. (2008) 2

9, 44.4%

N, female sex 16/37, 43.2%

55

Age 44.17

IgM CKV, 6 weeks

CKV test and disease duration IgM CKV, 42.1 DAYS

ANA, antinuclear antibodies; RF, rheumatoid factor; N/A, not available

Study design Retrospective, observational case series

Author, year Lalitha et al. (2007)

Table 22.3 (continued)

Subacute

CKV phase Subacute

1 had nodular episcleritis, 5 presented with acute iridocyclitis, and 3 had retinitis

Clinical symptoms 10 non-granulomatous anterior uveitis 5 pan uveitis 1 granulomatous anterior uveitis

Negative ANA and RF

Auto antibodies Not done

1% prednisolone, 2% homatropine hydrobromide, and 0.1% diclofenac sodium ophthalmic solutions

Treatment Topical and systemic steroids

Outcome After 3 months, the visual acuity improved in 11/26, remained the same in 12/26 patients, and worsened in 3/26 (none of this group had uveitis) All patients recovered from the infection with relatively good vision

600 J. F. de Carvalho et al.

Psoriasis

Psoriasis

Psoriasis

Psoriasis

Prashant et al. (2009)

Riyaz et al. (2010)

Seetharam and Sridevi (2011)

Autoimmune disease

Kumar et al. (2017)

Author, year

Case series

Prospective

Prospective

Prospective

Study design

Age

7, 33%

25.4

14 out of 34.25 162, 61.1%

6 out of N/A 115, 44.6%

2 out 30.18 112, 44.6%

N, female sex

IgM CKV, 5–14 days

IgM CKV

Not done

IgM CKV

CKV test and disease duration

Acute

2 cases of exacerbation (1 generalized and 1 erythroderma) and 5 of new-onset psoriasis (4 guttate and 1 pustular). All were biopsied,

N/A

Conservative (moisturizers and topical steroids) or methotrexate or phototherapy

N/A

Flare of psoriasis N/A 74.2% of all case were subacute

Flare of psoriasis. Cases were suspected CKV; the authors did not confirm by laboratory tests the CKV diagnosis

N/A

N/A

N/A

Autoantibodies Treatment N/A

Clinical symptoms

Flare of psoriasis N/A 80.3% of all cases were subacute

CKV phase

Table 22.4 Literature review on other autoimmune diseases associated with Chikungunya virus (CKV) infection Outcome

Autoimmune Diseases Associated with Chikungunya Infection (continued)

All improved from 4–6 weeks to 4 months

N/A

N/A

N/A

22 601

Psoriasis

Psoriasis

Myocarditis

Inamadar et al. (2008)

Simon et al. (2008)

Autoimmune disease

Araujo et al. (2020)

Author, year

Table 22.4 (continued)

N, female sex

Case report

1, 100%

Retrospective 2/145, 35.9%

Retrospective 56, 51%

Study design

CKV test and disease duration

CKV phase

21

34.71

IgM CKV, 10 days

IgM CKV

Acute

N/A

N/A 52.2  13.8 Arbovirosis (zika, dengue, or CKV), N/A

Age

Psoriasis exacerbation

6 (10.1%) had concomitant arbovirosis. Presence of arbovirus correlated with the exacerbation of psoriasis (r ¼ 0.21, p < 0.01)

and psoriasis was confirmed

Clinical symptoms

Not performed

N/A

N/A

No treatment

All patients were treated symptomatically

75% was managed conservatively

Autoantibodies Treatment

1 year after she was asymptomatic, Holter was normal, but MRI showed persisting subepicardial delayed enhancement without segmental wall

Good response. None developed long-term sequelae

Good

Outcome

602 J. F. de Carvalho et al.

Myocarditis and cardiomyopathy

Myocarditis and Case report severe thrombocytopenia

Obeyesekere and Hermon (1972)

Totadri et al. (2016)

Case series

Case report

Myocarditis

Mirabel et al. (2007)

Case report

Myocarditis

Farias et al. (2019a, b)

1, 100%

10,

1, male

1, male

12

40, 43, 44

19

28

IgM CKV, 10 days

Acute

Acute

The patient also had osteosarcoma

Negative ANA

Negative tests for SLE

Not done

Acute Positive antibodies at 1: 512 (determination by neutralization of the cytopathogenic effect of fibroblastic cells), 4 days Positive serology

Not done

Acute

IgM CKV, 5 days

Dobutamine and noradrenaline, platelet transfusions, and thiamine

Symptomatic

Symptomatic and cardiovascular drugs

Dobutamine (2.9 mcg/Kg/ min) IV was initiated and maintained for 4 days and a single dose of 400 mg of hydrocortisone IV was administered

Autoimmune Diseases Associated with Chikungunya Infection (continued)

Cardiac function and platelet count gradually recovered over 3 weeks

1/3 recovered, 2/3 evolved with cardiac heart failure

After 1 year, he was asymptomatic, without arrhythmias

Improved. After 11 days, the last echocardiogram showed an EF of 70% and persistence of pericardial effusion

motion abnormalities

22 603

N/A, not available

Addison’s disease Case report

Chung and Chlebicki (2013)

Case report

Vitiligo

Farias et al. (2019a, b)

Case report

Study design

Myocarditis

Autoimmune disease

Menon et al. (2010)

Author, year

Table 22.4 (continued)

1, male

1, N/A

1, male

N, female sex

54

53

5

Age

RT-PCR, 0

IgG, 6 months

IgM CKV, 4 days

CKV test and disease duration

Acute

Chronic

Acute

CKV phase Not done

Addison’s disease was initiated 21 years before. He evolved with CKV and Addison’s crisis and demyelinating polyneuropathy

–

IVIg for polyneuropathy Steroids were increased for Addison’s crisis

Topical tacrolimus (0.1%)

Symptomatic (dopamine, dobutamine, losartan), carnitine

Autoantibodies Treatment

N/A 5 days after CKV onset, the patient developed hypochromic and achromic lesions throughout the malar region and glabella. A biopsy confirmed vitiligo

Clinical symptoms Outcome

Vitiligo improvement was noted

After 2 months, he was asymptomatic

604 J. F. de Carvalho et al.

22

Autoimmune Diseases Associated with Chikungunya Infection

22.8

605

Conclusions

In summary, this chapter reviewed the literature for the most relevant published cases of autoimmune disease that emerged on CKV infection. Guillain-Barré syndrome, uveitis, several rheumatic manifestations, psoriasis, vitiligo, and myocarditis were some of the complications found. Therefore, neurologists, ophthalmologists, rheumatologists, and general practice physicians need to be aware of these complications during CKV epidemics, especially in endemic regions.

References Agarwal A, Vibha D, Srivastava A, Shukla G, Prasad K (2017a) Síndrome de Guillain-Barré complicando a infecção pelo vírus Chikungunya. J Neurovirol 23:504–507 Agarwal A, Vibha D, Srivastava AK, Shukla G, Prasad K (2017b) Guillain-Barré syndrome complicating chikungunya virus infection. J Neurovirol 23(3):504–507 Araujo KM, Bressan AL, Azulay-Abulafia L (2020) Zika, chikungunya, and dengue infections as exacerbating factors of psoriasis in patients receiving biological therapy. Int J Dermatol 59(6): e209–e211 Babu K, Murthy GJ (2012) Chikungunya virus iridocyclitis in Fuchs heterochromic iridocyclitis. Indian J Ophthalmol 60(1):73–74 Balavoine S, Pircher M, Hoen B, Herrmann-Storck C, Najioullah F, Madeux B et al (2017) Guillain-Barré syndrome and Chikungunya: Description of all cases diagnosed during the 2014 outbreak in the French West Indies. Am J Trop Med Hyg. 97(2):356–360 Betancur JF, Navarro EP, Echeverry A, Moncada PA, Cañas CA, Tobón GJ (2015) Hyperferritinemic syndrome: Still’s disease and catastrophic antiphospholipid syndrome triggered by fulminant Chikungunya infection: a case report of two patients. Clin Rheumatol 11: 1989–1992 Blettery M, Brunier L, Polomat K, Moinet F, Deligny C, Arfi S, Jean-Baptiste G, De Bandt M (2016) Brief report: management of chronic post-chikungunya rheumatic disease: the martinican experience. Arthritis Rheumatol 68(11):2817–2824. https://doi.org/10.1002/art. 39775. Epub 2016 Oct 9. PMID: 27273928 Bouquillard É, Combe B (2009) A report of 21 cases of rheumatoid arthritis following Chikungunya fever. A mean follow-up of two years. Jt Bone Spine 76(6):654–657 Burt FJ, Chen W, Miner JJ, Lenschow DJ, Merits A, Schnettler E et al (2017) Chikungunya virus: an update on the biology and pathogenesis of this emerging pathogen. Lancet Infect Dis 17(4): e107–e117 Chanana B, Azad RV, Nair S (2007) Bilateral macular choroiditis following Chikungunya virus infection. Eye (Lond) 21(7):1020–1021. https://doi.org/10.1038/sj.eye.6702863. Epub 2007 May 4. PMID: 17479113 Chen LH, Sehra ST (2019) Chikungunya virus infection–associated psoriatic arthritis? Mayo Clin Proc 94(7):1384–1386 Chung SJ, Chlebicki MP (2013) A case of Addisonian crisis, acute renal failure, vesiculobullous rash, rhabdomyolysis, neurological disturbances and prolonged viraemia in a patient on long term steroids. J Clin Virol 57(3):187–190 Crosby L, Perreau C, Madeux B, Cossic J, Armand C, Herrmann-Storke C et al (2016) Severe manifestations of Chikungunya virus in critically ill patients during the 2013–2014 Caribbean outbreak. Int J Infect Dis 48:78–80 de Carvalho JF, Kanduc D, da Silva FF, Tanay A, Lucchese A, Shoenfeld Y (2021) Sjögren’s syndrome associated with Chikungunya infection: a case report. Rheumatol Ther 8(1):631–637.

606

J. F. de Carvalho et al.

https://doi.org/10.1007/s40744-021-00281-4. Epub 2021 Feb 1. PMID: 33527325; PMCID: PMC7991050 de Matos AMB, Maia Carvalho FM, Malta DL, Rodrigues CL, Félix AC, Pannuti CS et al (2020) High proportion of Guillain-Barré syndrome associated with chikungunya in Northeast Brazil. Neurol Neuroimmunol Neuroinflammation 7(5):e833 Essackjee K, Goorah S, Ramchurn SK, Cheeneebash J, Walker-Bone K (2013) Prevalence of and risk factors for chronic arthralgia and rheumatoid-like polyarthritis more than 2 years after infection with chikungunya virus. Postgrad Med J 1054:440–447 Farias LABG, Beserra FLCN, Fernandes L, Teixeira AAR, Ferragut JM, Girão ES et al (2019a) Myocarditis following recent chikungunya and dengue virus coinfection: a case report. Arq Bras Cardiol 113(4):783–786 Farias LABG, Bezerra KRF, de Albuquerque MMS, da Pires Neto RJ, Accioly Filho JWA (2019b) Association between vitiligo lesions and acute chikungunya infection: is there a causal relationship? Rev Soc Bras Med Trop 52(52):e20190238 Hameed S, Khan S (2019) Rare variant of Guillain-Barré syndrome after chikungunya viral fever. BMJ Case Rep 12(4):2018–2020 Inamadar AC, Palit A, Sampagavi VV, Raghunath S, Deshmukh NS (2008) Cutaneous manifestations of chikungunya fever: observations made during a recent outbreak in south India. Int J Dermatol 47(2):154–159 Javelle E, Ribera A, Degasne I, Gaüzère BA, Marimoutou C, Simon F (2015) Specific Management of post-Chikungunya rheumatic disorders: A retrospective study of 159 cases in Reunion Island from 2006–2012. PLoS Negl Trop Dis 9(3):1–18 Jindal AK, Agarwal A, Guleria S, Suri D, Singh MP, Sharma S, Naseem S, Ratho RK (2018) Adultonset still disease and macrophage activation syndrome following chikungunya and Hepatitis E coinfection. J Clin Rheumatol 24(7):413–416. https://doi.org/10.1097/RHU. 0000000000000714. PMID: 29485548 Kharel R, Janani MK, Madhavan HN, Biswas J (2018) Outcome of polymerase chain reaction (PCR) analysis in 100 suspected cases of infectious uveitis. J Ophthalmic Inflamm Infect 8(1): 1–8 Krishnamurthy V (2008) Chikungunya arthritis. Indian J Rheumatol 3(3):91–92 Kumar R, Sharma MK, Jain SK, Yadav SK, Singhal AK (2017) Cutaneous manifestations of chikungunya fever: observations from an outbreak at a tertiary care hospital in Southeast Rajasthan, India. Indian Dermatol Online J 8(5):336–342. https://doi.org/10.4103/idoj.IDOJ_ 429_16. PMID: 28979866; PMCID: PMC5621193 Lalitha P, Rathinam S, Banushree K, Maheshkumar S, Vijayakumar R, Sathe P (2007) Ocular involvement associated with an epidemic outbreak of Chikungunya virus infection. Am J Ophthalmol 144(4):552–556 Lee YS, Quek SC, Koay ES, Tang JW (2010) Chikungunya mimicking atypical Kawasaki disease in an infant. Pediatr Infect Dis J 29(3):275–277. https://doi.org/10.1097/INF. 0b013e3181bce34d. PMID: 19935121 Lebrun G, Chadda K, Reboux AH, Martinet O, Gaüzère BA (2009) Guillain-Barré syndrome after chikungunya infection. Emerg Infect Dis 15(3):495–496 Lin J, Chen RWS, Hazan A, Weiss M (2018) Chikungunya virus infection manifesting as intermediate uveitis. Ocul Immunol Inflamm 26(5):680–682 Macêdo BG (2018) Avaliação das respostas de células T reguladoras (Treg) em fases aguda e crônica da Chikungunya em humanos. Thesis. Centro de Biotecnologia. Universidade Federal da Paraíba-Brazil Maek-a-nantawat W, Silachamroon U (2009) Presence of Autoimmune antibody in Chikungunya infection. Case Rep Med 2009:840183 Mahendradas P, Ranganna SK, Shetty R, Balu R, Narayana KM, Babu RB et al (2008) Ocular manifestations associated with Chikungunya. Ophthalmology 115(2):287–291 Mathew AJ, Goyal V, George E, Thekkemuriyil DV, Jayakumar B, Chopra A (2011) Rheumaticmusculoskeletal pain and disorders in a naïve group of individuals 15 months following a

22

Autoimmune Diseases Associated with Chikungunya Infection

607

Chikungunya viral epidemic in south India: a population based observational study. Int J Clin Pract 65(12):1306–1312 Menon PR, Krishnan C, Sankar J, Gopinathan KM, Mohan G (2010) A child with serious chikungunya virus (CHIKV) infection requiring intensive care, after an outbreak. Indian J Pediatr 77(11):1326–1328 Mirabel M, Vignaux O, Lebon P, Legmann P, Weber S, Meune C (2007) Acute myocarditis due to Chikungunya virus assessed by contrast-enhanced MRI. Int J Cardiol 121(1):7–8 Mittal A, Mittal S, Bharathi JM, Ramakrishnan R, Sathe P, S. (2007) Uveitis during Outbreak of Chikungunya fever. Ophthalmology 114(9):2005–2008 Obeyesekere I, Hermon Y (1972) Myocarditis and cardiomyopathy after arbovirus infections (dengue and chikungunya fever). Heart 34(8):821–827 Oehler E, Fournier E, Leparc-Goffart I, Larre P, Cubizolle S, Sookhareea C et al (2015) Increase in cases of Guillain-Barré syndrome during a Chikungunya outbreak, French Polynesia, 2014 to 2015. Eur Secur 20(48):5–6 Petitdemange C, Wauquier N, Vieillard V (2015) Control of immunopathology during chikungunya virus infection. J Allergy Clin 135(4):846–855 Pinheiro TJ, Guimarães LF, Silva MT, Soares CN (2016) Neurological manifestations of Chikungunya and Zika infections. Arq Neuropsiquiatr 74(11):937–943. https://doi.org/10. 1590/0004-282X20160138 Prashant S, Kumar A, Mohammed Basheeruddin D, Chowdhary T, Madhu B (2009) Cutaneous manifestations in patients suspected of chikungunya disease. Indian J Dermatol 54(2):128–131 Riyaz N, Riyaz AR, Abdul Latheef E, Anitha P, Aravindan K et al (2010) Cutaneous manifestations of chikungunya during a recent epidemic in Calicut, north Kerala, South India. Indian J Dermatol Venereol Leprol 76(6):671–676 Scripsema NK, Sharifi E, Samson CM, Kedhar S, Rosen RB (2015) Chikungunya-associated uveitis and exudative retinal detachment: a case report. Retin Cases Br Rep 9(4):352–356 Seetharam KA, Sridevi K (2011) Chikungunya infection: a new trigger for psoriasis. J Dermatol 38(10):1033–1034 Simon F, Paule P, Oliver M (2008) Case report: Chikungunya virus-induced myopericarditis: toward an increase of dilated cardiomyopathy in countries with epidemics? Am J Trop Med Hyg 78(2):212–213 Stegmann-Planchard S, Gallian P, Tressières B, Leparc-Goffart I, Lannuzel A, Signaté A, Laouénan C, Cabié A, Hoen B (2020) Chikungunya, a risk factor for Guillain-Barré syndrome. Clin Infect Dis 70(6):1233–1235. https://doi.org/10.1093/cid/ciz625. PMID: 31290540 Tanay A (2016) Chikungunya fever presenting as a systemic disease with fever, arthritis and rash: our experience in Israel. Isr Med Assoc J 18(3–4):162–163 Totadri S, Radhakrishnan V, Raja A, Sagar TG (2016) Chikungunya fever with seizures, myocarditis, and severe thrombocytopenia in a child with osteosarcoma. Pediatr Blood Cancer 63(9): 1687 Villamil-Gómez W, Silvera LA, Páez-Castellanos J, Rodriguez-Morales AJ (2016) Guillain-Barré syndrome after Chikungunya infection: a case in Colombia. Enferm Infecc Microbiol Clin 34(2):140–141 Wielanek AC, Monredon JD, Amrani ME, Roger JC, Serveaux JP (2007) Guillain-Barré syndrome complicating a Chikungunya virus infection. Neurology 69(22):2105–2107. https://doi.org/10. 1212/01.wnl.0000277267.07220.88. PMID: 18040016

Part VI Microorganisms in Pathogenesis & Management of Idiopathic Inflammatory Myopathies

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM) and Polymyositis (PM) Maria Giovanna Danieli and Eleonora Longhi

, Alberto Paladini, Luca Passantino

,

Abstract

As with most autoimmune diseases, the etiology and especially the prime mover of idiopathic inflammatory myopathies are not well defined. It is assumed that the disease is related to a chronic immune impairment, following exposure to environmental agents in genetically predisposed individuals. In this chapter we discuss the role of microorganisms in pathogenesis of myopathies, especially polymyositis and dermatomyositis. We focused on interaction between immune response and biological and molecular networks created by host characteristics and most common pathogens as described in the literature on the topic. Infectious agents proved a strong connection with autoimmune myositis in several animal

M. G. Danieli (*) Clinica Medica, Dipartimento di Medicina Interna, Ospedali Riuniti di Ancona e DISCLIMO, Università Politecnica delle Marche, Ancona, Italy School of Specialisation in Allergology and Clinical Immunology, Dipartimento di Medicina Interna, Ospedali Riuniti di Ancona e DISCLIMO, Università Politecnica delle Marche, Ancona, Italy e-mail: [email protected] A. Paladini School of Specialisation in Internal Medicine, Dipartimento di Medicina Interna, Ospedali Riuniti di Ancona e DISCLIMO, Università Politecnica delle Marche, Ancona, Italy L. Passantino School of Specialisation in Allergology and Clinical Immunology, Dipartimento di Medicina Interna, Ospedali Riuniti di Ancona e DISCLIMO, Università Politecnica delle Marche, Ancona, Italy E. Longhi Scuola di Medicina e Chirurgia, Alma Mater Studiorum, Università degli Studi di Bologna, Bologna, Italy # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_23

611

612

M. G. Danieli et al.

models, and, learning from the infamous recent zoonosis which started the SARSCoV-2 (“the autoimmune virus”) pandemic, new challenges and discoveries are around the corner. Keywords

COVID-19 · Dermatomyositis · Long COVID syndrome · Microbiome · Microorganisms · Myositis · Polymyositis

23.1

Introduction: Genetic and Environmental Factors in Idiopathic Inflammatory Myopathies

As with most autoimmune diseases, the etiology and especially the prime mover of idiopathic inflammatory myopathies (IIM) are not well defined. It is assumed that the disease is related to a chronic immune impairment, following exposure to environmental agents in genetically predisposed individuals. Immune system changes could also anticipate clinical manifestations by years, making it difficult to establish the relationship between exposure to certain environmental agents and disease development. IIMs are divided into subtypes: dermatomyositis (DM), polymyositis (PM), necrotizing autoimmune myositis (NAM), anti-synthetase syndrome-overlap myositis (anti-SS-OM), and inclusion body myositis (IBM) (Dalakas, 2020, 2015). Other clinical pictures are juvenile dermatomyositis, paraneoplastic myositis, and myositis-connective tissue disease [CTD] overlap. In addition to clinical differences, various subtypes are characterized by distinct autoantibodies, classified into specific myositis (MSA) and associated myositis antibodies (MAA). The various clinical characteristics of the subtypes could be due to the heterogeneity of genetic, environmental, and infectious factors involved in pathogenic processes: different input could lead to different phenotypes. In patients with IIM the most relevant predisposing genetic factor, identified by case-control studies, is the major histocompatibility complex (MHC) region on chromosome 6 (Rothwell et al. 2019). Some examples are the association between HLA-DRB1*0301 and HLA-B*0801 haplotype and anti-Jo-1 antibody; between HLADRB1*0301/0101 and IBM; and between HLA-DRB1*11 and the development of anti-HMGCR antibody after statin administration. Other genetic variants have been found in the PTPN22, STAT4, and UBE2L3 genes (Rothwell et al. 2017, 2019). The most important environmental factors are exposure to UV rays, related with DM and anti-MI-2 antibody (Love et al. 2009); cigarette smoking, related with antiJo1 antibody in predisposed patients (Chinoy et al. 2012); statin administration and the development of anti-HMGCR (Dalakas 2015). Another issue is the relationship with different types of cancer (Giat et al. 2017) at the diagnosis or few years later since patients with DM have a 30% greater risk of developing cancer than general population in the first 5 years after diagnosis (Dalakas 2020). The boundary between

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

613

the two concepts is often fleeting, and it is not easy to understand whether myositis is an early paraneoplastic manifestation of a cancer that is not yet manifest. Antibodies to transcription intermediary factor 1-gamma (TIF1-γ) are also associated with paraneoplastic myositis in adults.

Table 23.1 Antibodies in IIM and clinical phenotypes associated Antibody Anti-aminoacyltRNA synthetases (anti-ARS) Histidyl-tRNA synthetase (Jo-1) Threonyl-tRNA synthetase (PL-7) Alanyl-tRNA synthetase (PL-12) Glycyl-tRNA synthetase (EJ) Isoleucyl-tRNA synthetase (OJ) Asparaginyl-tRNA synthetase (KS) PhenylalanyltRNA synthetase (ZO) Tyrosyl-tRNA synthetase (HA) Anti-helicase protein (Mi2) Anti-melanoma differentiationassociated gene 5 (MDA5) Anti-TIF1γ Anti-signal recognition particle (SRP) Anti-SUMO-1 activating enzyme (SAE) Anti-NXP2 Anti-HMGCoAR

Clinical phenotype associated Anti-synthetase syndrome (myositis, ILD, polyarthritis, Raynaud’s phenomenon, fever, mechanic’s hands)

Relationship with microorganism Amino acid correspondence between: • Anti-Jo-1 and ECRF4 protein from EBV • Anti-PL-12 and: – Exon associated protein (IIIA) from adenovirus 2 – BPLF1 protein from EBV – Hemagglutinin molecules from two strains of influenza viruses

DM DM/CADM/rapidly progressive ILD

Clinical and radiological elements in common with COVID-19 infection (Saud et al. 2021)

Cancer-related DM in adults/JDM IMNM

DM

DM/JDM INMN statin associated

CADM, clinically amyopathic dermatomyositis; IMNM, immune-mediated necrotizing myopathy; DM, dermatomyositis; PM, polymyositis; JDM, juvenile dermatomyositis; ILD, interstitial lung disease; EBV, Epstein-Barr virus; HMGCoA-R, hydroxy-methylglutaryl coenzyme A reductase

614

M. G. Danieli et al.

Infectious triggers leading to autoimmunity are described in myositis, and although there is no concrete evidence of correlation between infections and the onset of disease, several pathogenetic hypotheses have been proposed.

23.2

Microorganisms in Myositis Immune-Pathogenic Process

23.2.1 Seasonal Variation Manta et al. (1989) were the first to notice an epidemiological evidence related to seasonal variations and the onset of polymyositis (PM) and dermatomyositis (DM). They described a higher rate of disease onset or first hospitalization in the spring months. These findings were subsequently confirmed and implemented: not only the onset of symptoms but also disease exacerbations have a seasonal pattern, with peaks in the spring season and in March to April (Sarkar et al. 2005). The seasonal trend of anti-Jo1 patients also confirmed the peak in April, while patients with antiSRP seem to have a peak in the autumn season (November) (Leff et al. 1991). These seasonal variations could indicate a correlation with different environmental factors including the role of a bacterial or viral infection. An infectious trigger preceding the onset of the disease was sought in a juvenile DM population, and in a substantial number of patients (38%), there was a sign of a probable infection, in most cases a respiratory tract infection (Manlhiot et al. 2008). A similar study was also performed in an adult population with IIM, in which a higher rate of infection before disease onset in comparison to control population was detected. Moreover, there was an increased risk of IIM after respiratory and gastrointestinal tract infections (Svensson et al. 2017).

23.2.2 Virus Myotropism: Latent Infection or Autoimmunity? The association between IIM and infections was initially focused on viruses with marked myotropism, such as Coxsackie virus B and lymphotropic T-cell virus (HTLV-1). The evidence showed a higher rate of antibodies against Coxsackie B virus and HTLV-1 in patients with IIM (Morgan et al. 1989, Bowles et al. 1987) and juvenile DM (Christensen et al. 1986). Furthermore, Coxsackie B virus was used successfully to induce disease in animal models (Ray et al. 1979). The presence of viral DNA is found only in some muscle biopsies (Bowles et al. 1987), not confirmed in other studies (Leff et al. 1992). Moreover, it was not confirmed in a second specimen collected in the same previously positive patient during a relapse of the disease (Chevrel et al. 2003). These findings dismissed the possibility of a latent viral infection underlying the IIM and together with other evidence, such as the response to immunosuppressive therapy and the presence of specific antibodies, advanced different pathogenic hypotheses on autoimmunity. So far, the only virus, which could directly infect the muscle, is SARS-CoV-2 (see below).

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

615

23.2.3 Autoantibodies in IIM Although it is yet unclear whether antibodies detected in IIM represent an epiphenomenon of the disease or have a pathogenetic role, it is now well established that different autoantibodies are associated with different clinical pictures. Autoantibodies are classified into specific myositis (MSA) present in PM/DM, PM/DM-overlap syndrome, and associated myositis (MAA), detected in CTD and overlap syndromes (PM/DM, PM/DM-overlap syndrome, SSc, SLE). Among the MSAs, anti-aminoacyl-tRNA synthetases (anti-ARS) are related to anti-synthetase syndrome (myositis, interstitial lung disease [ILD], polyarthritis, Raynaud’s phenomenon, fever, mechanic’s hands). Anti-histidyl-tRNA synthetase (Jo-1) is present in 15–30% of patients and was the first autoantibody reported in literature. Antihelicase protein (Mi2) is present in 10% of cases and is associated with the typical DM. Anti-MDA5 (melanoma differentiation-associated gene 5) is found in 15–20% and is associated with amyopathic DM with severe skin manifestations or rapidly progressive ILD. Anti-TIF1γ is associated with adult cancer-related DM; anti-SRP is present in approximately 5% of patients and can be associated with necrotizing myositis (Dalakas 2015).

23.2.4 IIM Pathogenesis Both the cell-mediated immune response and the humoral response are involved in the pathogenesis of IIM. A complex interaction between the two responses contributes to the chronicity of the disease. The genes identified in predisposed subjects are mainly HLA gene haplotypes encoding the MHC complex (Chinoy et al. 2012; Rothwell et al. 2017, 2019). In PM, the presentation of muscle antigens by dendritic cells, macrophages, and muscle fibers presenting MHC-I (normally not expressed) activates TCD8 + lymphocytes. The rearrangement of the TCR gene of endomysial T cells, the presence of costimulatory molecules, and the upregulation of cytokines and chemokines also contribute to immune inflammation. Muscle specimens from PM reveal T-cell infiltrate, with a high CD8+/CD4+ ratio, in the endomysium and a widespread expression of MHC-I (Dalakas 2020, 2015). In DM, the target is the vascular endothelium of the endomysial capillaries, and the inflammation is mediated by complement activation, pro-inflammatory cytokines, and an increased expression of type I interferon-inducible proteins whose significance is not yet fully understood (Dalakas 2020, 2015). The biopsy shows a perivascular, perimysial, and perifascicular lymphocytic infiltrate with CD4+ and B lymphocytes and dendritic cells, necrotic fibers, and perifascicular atrophy with reduction of capillaries (Dalakas 2020, 2015). In IBM, lymphocytic infiltrates with CD8+/MHC-I complex are found together with B cells and typically vacuolar infiltrates with beta-amyloid protein deposits (Dalakas 2020, 2015). There is therefore a degenerative process associated with the

616

M. G. Danieli et al.

concomitant immune process, which makes the pathogenetic process even more complex. Other mechanisms have been proposed in the pathogenesis of IIM and in the maintenance of the disease. A further mechanism not yet fully understood concerns the role of CD4 + CD25 high FoxP3+ regulatory T cells (Tregs), capable of regulating the response to self / non-self-antigens, thus playing a critical role in the regulation of immune response. In response to infections and other pathological insults, muscle cells respond to pro-inflammatory cytokines by upregulating MHC molecules and pro-inflammatory cytokines. These immune responses must be tightly regulated to prevent immunemediated tissue damage, and Tregs have been proposed to limit immunopathology during the acute phase of the infection (Wohlfert, Blader, and Wilson 2017). Treg alterations are found in several autoimmune diseases and have been shown to influence the development of IIM in animal models (Allenbach et al. 2009). Non-immune-mediated mechanisms, including tissue hypoxia and mitochondrial dysfunction with increased stress on the endoplasmic reticulum (ER stress), certainly deserve observation. Mitochondrial dysfunction could play an important role especially for the induction of autophagy and the maintenance of inflammatory state with the release of pro-inflammatory molecules and damage-associated molecular patterns (DAMPs). The role of mitochondrial dysfunction appears to be important in IBM (De Paepe 2019). New mechanisms could arise from the latest evidence on the onset of myositis in cancer patients under treatment with immune checkpoint inhibitors (ICPIs). In particular, involved ICPIs have as activity markers CTLA-4, PD-1, and PD-L1. These markers expressed on neoplastic cells co-stimulate inhibition signals on T cells, which do not attack neoplastic cells. ICPIs delete the molecules’ signals and promote an immune response against cancer cells. Some patients developed inflammatory myositis, especially DM and NAM, which had a good response to steroid and intravenous immunoglobulin (IVIg) therapy. It seems therefore ICPIs could stimulate an uncontrolled activation of T lymphocytes with loss of immune tolerance (Dalakas 2020, 2015).

23.2.5 Hypothesis on the Role of Microorganisms in Induction of Autoimmunity in IMM Several mechanisms have been proposed to explain the role of infectious agents in IIM pathogenesis. • Molecular mimicry could play an important role. The likeness between exogenous protein and human protein structures could promote autoimmunity. Amino acid sequencing of histidyl-tRNA (anti-Jo-1) and alanyl-tRNA (anti-PL-12) demonstrated correspondence between anti-Jo-1 and ECRF4 protein from Epstein-Barr virus and between anti-PL-12 and three different viral proteins: exon associated protein (IIIA) from adenovirus 2, BPLF1 protein from Epstein-

23

•

• • • •

•

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

617

Barr virus, and hemagglutinin in molecules from two strains of influenza viruses. Another model of molecular mimicry has been proposed for juvenile DM: group A streptococcal 5 M protein and human skeletal muscle myosin have a homologous sequence that is the target of immune responses (Adler and ChristopherStine 2018). The development of anti-tRNA synthetase antibodies could be due to the interaction between the virus and tRNA synthetase. tRNA synthetase is used to produce viral proteins, and the complex is not recognized as self-inducing autoimmunity (Adler and Christopher-Stine 2018). Infectious agents can modify conformation of endogenous proteins, exposing cryptic epitopes that are usually hidden, making them recognizable by the immune system (Adler and Christopher-Stine 2018). Induction of human antibodies carrying pathogenic idiotypes (anti-idiotypic antibodies) (Shoenfeld 2004). Superantigens produced by bacteria- or virus-infected cells are potent activators of the immune system and T lymphocytes, inducing cross-reactive antibodies (Emmer et al. 2019). Apoptotic processes also play an important role. Initial damage (even infectious) can lead to the physiological apoptosis of muscle cells. If this mechanism fails, it can progress to secondary necrosis which leads to perpetuating muscle damage by releasing DAMPs (Nagaraju et al. 2000). Accumulation of nuclear material could occur because of necrosis and could lead to autoimmunity (Schulze et al. 2008). In this regard, a dysregulation of the apoptotic system has been proposed in patients with PM. Proapoptotic proteins (particularly HRK) may be overexpressed and unable to respond to muscle damage, leading to subsequent mitochondrial dysfunction, necrosis, release of TLR ligands, and production of pro-inflammatory cytokines that increase muscle damage (Boehler et al. 2019). Influence of Treg cells mediates damage to muscle and triggers a reparative program that ensures the efficacious activation and differentiation of stem cells (satellite cells) to intermediary myoblasts and terminally differentiated myotubes. Skeletal muscle repair steps through an inflammatory phase mediated by monocyte/pro-inflammatory macrophages (IM/M1), followed by a shift in macrophage polarization to a pro-regenerative (M2) phenotype. Tregs act as controllers for each step, and their inability to limit the number of IM/M1 cells or a block in M1– M2 conversion leads to muscle damage (Rayavarapu et al. 2013). In animal autoimmune myositis models, the reduction of Tregs causes a worsening of myositis (with PM-like infiltrates) (Allenbach et al. 2009). An evaluation on mice depleted of Tregs affected by chronic toxoplasmosis showed a reduction in skeletal muscle damage. Moreover, Treg depletion led to an increase in the numbers of M2 cells in the parasite-infected samples. Altered functional Tregs may also limit the ability for IM/M1 cells to remove skeletal muscle debris from a damaged nerve fiber or for M2 cells to promote regeneration (Jin et al. 2017). The presence of a microorganism could therefore modify the distribution of Treg lymphocytes and be one of the predisposing factors for the disease.

618

M. G. Danieli et al.

• MDA-5 gene encodes for RNA helicase involved in innate immune response against viruses. It appears to stimulate type I interferon (IFNs) production that suppresses viral replication. During viral infection, innate defense mechanisms are overactivated, and MDA-5 gene is upregulated. The persistent innate immune response could lead to cytotoxic processes and infected cell apoptosis, releasing proteolytic fragments of MDA-5 and viral protein complexes. Fragments recognized as non-self could trigger autoimmune response to MDA-5 (Saud et al. 2021). In this way, the clinical similarity described between clinically amyopathic dermatomyositis (CADM) and COVID-19 infection is interesting. Rapidly progressive ILD (different from other types of myositis) with similar radiological signs, fever, rash, arthralgias, myalgias, and the cytokine storm are all similar elements (Giannini et al. 2020). As purposed for other RNA viruses implicated in DM, also COVID-19 could act on MDA-5 gene and give similar clinical picture.

23.3

Evidence on Bacteria, Virus, Fungi, and Parasites Implicated in Myositis

23.3.1 Bacteria and Myositis There is few evidence of immune-mediated myositis following bacterial infections or exposure. The most important finding is the presence of homologous amino acid sequences between group A streptococcal 5 M protein and human skeletal muscle myosin (Martini et al. 1992), focusing attention on the relationship between DM and Streptococcus pyogenes. In this regard, Martini et al. (1992) also described a case of JDM overlapping polyarteritis nodosa (PAN) followed for years and with a rise of serum antistreptococcal antibodies during the seven recurrences evaluated. Patient was treated with penicillin prophylaxis and corticosteroids during relapses. Other M protein streptococcal serotypes were also evaluated, and serum titer of antibodies against streptococcal recombinant M12 protein was higher in DM patients than controls, proving a strong humoral response to M12 streptococcal protein (Ichimiya et al. 1998). In this way, molecular mimicry was proposed as one of the mechanisms involved in DM pathogenesis; it could be considered also the M streptococcal protein as a superantigen inducing the production of cross-reactive autoantigens. Bacteria are more frequently the cause of infectious myositis, having penetrating trauma, hematogenous dissemination, contiguous focus, and vascular insufficiency as favoring factors. The most common bacteria involved is Staphylococcus aureus (60–90% of infections), followed by group A Streptococcus and other Streptococci types. Less common are gram-negative, anaerobes, and Mycobacterium (CrumCianflone 2008).

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

619

23.3.2 Viruses and Myositis The most common muscle manifestations caused by viral infections are myalgias, polymyositis, or rhabdomyolysis: luckily, such nonspecific symptoms appear always after some more suggestive ones, easily attributable to the causative viral pathogen.

23.3.2.1 Influenza A and B Viruses Benign acute childhood myositis (BACM) is a common self-limited condition, which raises concern in both parents and healthcare professionals. Frequently misdiagnosed, BACM is also known as influenza-associated myositis, viral myositis, and acute myositis. Myalgias are a common feature of the well-known seasonal flu and may be often an initial complaint along with, or even before, the onset of classical symptoms such as fever, headache, cough and rhinorrhea. Most cases can be complicated by upper respiratory infections or pneumonia. Rare complications are myocarditis and meningoencephalitis. First described in the 1950s as myalgias cruris epidemica (Lundberg 1957; Morgensen 1974), BACM can be differentiated by myalgias for the late onset, focal location, and intensity. The major prevalence of myositis presents in virus B infections (34%) than in virus A ones (6%). This difference is attributed to a protein called “NB,” necessary for viral entry, which may make virus B more myotrophic than A (Hu et al. 2004). BACM is a common finding in children because they are more susceptible to muscle involvement: an explanation could be the influenza virus’s tropism toward more immature muscle cells (Davis and Kornfeld 2001), albeit some cases have been described in adults and elderly patients. Differential diagnosis is the key for a diagnosis of BACM, mainly in adults: mandatory is the exclusion of trauma or non-accidental injury, Guillain-Barré syndrome, rhabdomyolysis, osteomyelitis deep vein thrombosis, malignancy, dermatomyositis and polymyositis, muscular dystrophy, and intracranial pathology. In children it is important to exclude juvenile rheumatoid arthritis too (Magee and Goldman 2017). Muscle involvement usually begins approximately 3 days (0–18) after the onset of fever and respiratory symptoms (Agyeman et al. 2004). Boys are most affected (2: 1 ratio). Calf muscles are often interested alone: clinical examination can reveal tenderness on palpation and gait difficulties. Laboratory tests with elevated CK are always present, with an AST and LDH possible increase. Though EMG is not necessary for diagnosis, and not even recommended, it can show typical myopathic changes. Muscle biopsies, even if not indicated, can show muscle fiber degeneration and necrosis with little inflammatory infiltrates. Diagnosis is made by clinical history, anamnesis, and the detection of viruses in nasopharyngeal specimens. Treatment is symptomatic: BACM is self-limited and can resolve in a mean time of 3 days. The efficacy of antiviral treatment is unknown and is not currently

620

M. G. Danieli et al.

recommended for myositis only, finding a ratio only if severe respiratory involvement is present and within 36 hours from the symptom’s onset. Even rhabdomyolysis has been described, and, among all viruses causing it (HIV, enteroviruses, etc.), influenza virus accounts for 42% of cases observed (Singh and Scheld 1996). Influenza A virus is more often associated with rhabdomyolysis than type B, and it is more frequent in girls, contrary to the findings observed for myositis. The complications described for rhabdomyolysis are renal failure and compartment syndrome (Agyeman et al. 2004; Hu et al. 2004).

23.3.2.2 Enteroviruses Coxsackieviruses (A and B) and echoviruses can cause myositis with peculiar features. Most common are the Coxsackievirus B myositis, symptomatic as pleurodynia (Bornholm disease) (Warin et al. 1953). These infections are usually observed in children with severe and sharp chest pains for costochondral involvement; muscles in this region can result tender on palpation. Usually, these symptoms occur paroxysmally in summer or fall. Rhabdomyolysis with pleurodynia, with recurrences, has been reported by several studies (es. Fodili and Van Bommel 2003) with a male/female ratio of 0.6, in both children and adults. Muscle biopsies have shown degenerative necrosis of fibers and picornavirus-like structures. Though pathogenesis is still unclear, animal models proved a direct virusmediated muscle damage for coxsackievirus infections. Diagnosis can be made by clinical features, but stool samples and serologic testing (with four-fold increased titer) can suggest an acute infection. 23.3.2.3 Hepatitis B and C Viruses Well known for having a role in a variety of musculoskeletal syndromes, including polyarthritis, cryoglobulinemia, and polymyalgia rheumatica, hepatitis B and C viruses have also been associated, in case reports, with the development of polymyositis. The pathogenic process seems to be immune-related, even if not well studied: as a logical conclusion, glucocorticoids seem to have a ratio for treatment. Usually, symptoms include myalgias and proximal muscle weakness. In one case described, severity of myositis appeared to be associated with hepatitis flare (Crum-Cianflone 2008). 23.3.2.4 HIV HIV infection has been described as a cause of a wide range of musculoskeletal disorders such as ocular myopathy (Fabricius et al. 1991), rhabdomyolysis (Chariot et al. 1994), and polymyositis, first described in 1983 (Dalakas et al. 1986). HIV-infected lymphoid cells have been found in muscular biopsies, surrounding the tissue, but the virus has not been found directly in muscle cells. Although physiopathology of PM during HIV infection remains poorly understood, the loss of CD4+ T lymphocytes during HIV infection may contribute to an immune dysregulation leading to generation of autoreactive CD8+ T lymphocytes, which

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

621

might increase T CD8+ cell-mediated autoimmune diseases, as polymyositis (Zandman-Goddard and Shoenfeld 2002). HIV-positive patients may present with some characteristic polymyositis features including young age at onset, very high CK levels, or proximal weakness, which improves during treatment. However, all HIV-positive patients with myositis eventually develop features most consistent with IBM, including finger and wrist flexor weakness, rimmed vacuoles on biopsy, or anti-NT5C1A autoantibodies (Lloyd et al. 2017). Muscular disease can occur anytime during HIV infection: diagnosis is made by exclusion. Old-generation antiretrovirals, such as zidovudine, didanosine, and stavudine, opportunistic infections and wasting syndromes are often addressed as myopathy causes. To differentiate HIV-associated myositis from toxic myopathy is compelling, especially when symptoms recede at the end of antiretroviral treatment and muscle biopsy reveals ragged red fibers (Cupler et al. 1995). Dermatomyositis has been observed too (Gresh et al. 1989). Clinical course, laboratory, and EMG findings have no difference with the idiopathic form (Cuellar 1998). Management includes NSAIDs, supportive care, and even immunosuppressants. Some cases can improve without any immunosuppressive therapy (Johnson et al. 2003).

23.3.2.5 HTLV-1 Human T-cell leukemia/lymphoma virus 1 has been associated in areas of endemicity (Caribbean, Africa, Japan, southern USA) with polymyositis. Like HIV, the pathogenesis is thought to be immune-mediated, through the action of viral protein Tax-1 (Ozden et al. 2005). 23.3.2.6 Other Viruses Acute myositis and/or rhabdomyolysis have been associated with other viruses, such as parainfluenza virus (Crum-Cianflone 2008), adenovirus, and respiratory syncytial virus (Sakata et al. 1998). A case-control study (Chen et al. 2010) showed evidence for higher frequencies of anti-Epstein-Barr nuclear antigen 1 (EBNA1) antibodies at the onset of dermatomyositis/polymyositis: EBV genome was detected with a higher frequency in patients than in matched healthy controls. A single case of dermatomyositis after EBV infection and antibiotic treatment has been recently described (Peravali et al. 2020). Diagnosis is usually supported and suggested by serologic studies or cultures from nasopharyngeal or stool specimens. Myositis caused by most of these viruses is accountable to direct infection of muscle tissue, but some immune-mediated phenomena, such as cross-reactivity, have been suggested: several muscle biopsies support this scenario in place of a direct damage mechanism. Recently, a case-control study (Gergely Jr et al. 2005) detected the infection of a novel virus, Torque teno virus (TTV), in both IIM patients and healthy controls.

622

M. G. Danieli et al.

Although no clear association between the viral infection and the development of IIM has been observed, a higher frequency of myopathies in severe TTV infection versus mild ones suggests a more severe disease when viral infection occurs. Other viruses variously linked to myositis are CMV, HSV, VZV, and dengue, the last one cited with a growing number of cases described (Crum-Cianflone 2008). The possible role of other viruses in IIM development has been described in animal models, such as Chikungunya virus (Morrison et al. 2011) and Ross River virus (Lidbury et al. 2008).

23.3.3 Fungi and Myositis Several species of fungi can infect muscles, giving pictures suggestive of myositis. Most of them interest immune-compromised patients and are mediated by Microsporidia spp., Aspergillus spp., and Candida spp. Furthermore, no data or studies are available about immune dysregulation mediated by fungal infections. Further studies are needed to clarify their role in creating an immune milieu in muscles during acute and/chronic infections and if this milieu can be the cradle of aberrant immune responses or autoimmunity phenomena.

23.3.4 Parasites and Myositis A variety of parasitic infections may encyst in the musculature and give rise to phenomena related to immune system activation, from immunomodulation to aberrant responses, mostly in patients with immune deficits. Eosinophilia is often linked to a parasitic etiology in myositis. Helminthic infections of Trichinella spp. (trichinosis) and Taenia solium (cysticercosis) are the most frequent. Protozoa such as Toxoplasma gondii (toxoplasmosis), as well as Microsporidia spp., are also causative agents of nonbacterial myositis. The clinical course can be differentiated into acute, subacute, or chronic. The clinical presentation depends on the number and the location(s) of muscles involved as well as host characteristics.

23.3.4.1 Trichinella spp. Animal model studies suggest that T. spiralis can build an immunomodulatory network (which encompasses Th2- and Treg-type responses) that may allow the host to deal with various hyperimmune-associated disorders (Sofronic-Milosavljevic et al. 2015). Most cases of infections by Trichinella spp. are subclinical. The number of larvae ingested drives severity of clinical symptoms related to host characteristics, such as age, size, and comorbidities. Gastrointestinal symptoms may occur during the first week (days 2–7) after ingestion and include nausea, abdominal pains, anorexia, vomiting, and either diarrhea or constipation. Systemic manifestations occur from days 9 to 28 as the

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

623

larvae disseminate throughout the body, causing systemic symptoms such as fevers, myalgias, conjunctival and splinter hemorrhages, and periorbital edema. Muscle invasion features are myalgias, swelling, and weakness; levels of 50 larvae/g of muscle are usually associated with muscular symptoms. Myositis initially occurs in the extraocular muscles, followed by the masseters and muscles of the diaphragm, neck, and larynx as well as the limbs; any striated muscle can be involved (Capo and Despommier 1996). Severe proximal muscle weakness simulating polymyositis is rare but has been described (Santos Durán-Ortiz et al. 1992). Symptoms and signs of myositis peak at 5–6 weeks after infection and then begin to wane after encapsulation and calcification of larvae within the muscles. The degree of myositis may correlate with the level of eosinophilia (Ferraccioli et al. 1988). Some patients experience muscle aches, headaches, and mental apathy for weeks to months after infection. Peripheral eosinophil count is elevated in the second week of illness and may reach very high levels (Pozio et al. 2001). Depending on the different Trichinella species responsible for infection, differences in the level of myositis are observed: non-encapsulating species feature an inflammatory response significantly lower. Such a difference is present not only around the parasite-NC (nurse cell) complex but also in noninfected muscles (Bruschi et al. 2009). Laboratory tests may also show leukocytosis, elevated immunoglobulin E, and increased muscle enzymes. Making the diagnosis through serologic testing such as enzyme-linked immunofluorescence assay and fluorescent antibody tests defines the best practice in a hospital setting. Antibodies are usually detectable by 2–4 weeks after infection; a rising titer is highly suggested for the disease. Diagnosis can also be confirmed by biopsy of a swollen, tender superficial skeletal muscle, often the deltoid or gastrocnemius, near its insertion site (CrumCianflone 2010). Therapy in early infection is preferable to reduce the number of larvae in the gastrointestinal tract that may invade the muscles. One study showed that anthelmintic medications have little effect on the larvae within muscles (Pozio et al. 2001). However, some studies have shown that muscle symptoms, enzyme levels, and residual larval infestation resolve more rapidly when treatment is administered (Fourestié et al. 1988; Watt et al. 2000). To notice, viable larvae may be present despite therapy. The drug of choice is albendazole or alternatively mebendazole; thiabendazole is also active but is less tolerable. Rest is the best advice for patients and myalgias may be treated with analgesics. Severe forms of trichinosis, such as severe myositis, myocarditis, and neurologic complications, are often treated with albendazole in combination with corticosteroids (e.g., prednisone) (Edoardo Pozio et al. 2003).

23.3.4.2 Toxoplasma gondii Toxoplasma gondii is a widespread parasitic pathogen that infects over a third of the world’s population. After acute infection, the parasite can persist within its host as intraneuronal or intramuscular cysts. Cysts could occasionally reactivate, and

624

M. G. Danieli et al.

depending on the host’s immune status and site of reactivation, encephalitis or myositis can develop (Wohlfert et al. 2017). In AIDS patients acute infections and reactivated infections can cause myositis (Plonquet et al. 2003). Despite its clinical significance and importance in Toxoplasma’s life cycle, Toxoplasma-skeletal muscle interactions need further studies. Immune responses to Toxoplasma in the brain and skeletal muscle were originally believed to be quite similar. IFN-γ has a critical role in control of Toxoplasma in skeletal muscle which appears to interact with immune cells by activating IFN-γ-stimulated GTPases and nitric oxide (Takács et al. 2012). For the role of Tregs in T. gondii chronic infection, we refer to Sect. 23.2.5, previous in this chapter. Two forms of polymyositis following toxoplasmosis are known: an acute form, which is responsive to antiprotozoal therapy, and a chronic one manifested by altered immune response and requiring treatment with steroids (Cuturic et al. 1997). Infection is usually self-limited, so treatment is generally not warranted. In severe cases, including progressive myositis, sulfadiazine, and pyrimethamine are indicated (Stanford and Gilbert 2009). A single case of dermatomyositis-like syndrome following acute toxoplasmosis has been described (Saberin et al. 2004).

23.3.4.3 Trypanosoma cruzi T. cruzi isolates are distributed in non-phagocytic muscle cells and can evade the immune system, so smooth and striated muscles can be heavily parasitized. In striated heart and skeletal muscle, amastigotes form large niches in the absence of inflammation (El-Beshbishi et al. 2012). At muscle biopsies degenerative features of parasite-free muscle cells can be associated with inflammatory infiltrates. Skeletal muscle after being infected is characterized by spotty inflammation, target cell lysis, and degeneration. Similar aspects are present in smooth muscle cells all throughout the digestive tract (Teixeira et al. 2006). Most data on T. cruzi infections causing myositis are experimental and based on animal models (Maldonado et al. 2004). Few data exist among human cases, the occurrence of myositis is described both in acute and chronic stages of Chagas disease (Cossermelli et al. 1978), human infections are often subclinical, and the muscular complaints are usually overshadowed by other symptoms (ibid.). Myositis of the lower and upper extremities, ocular myositis, and polymyositis have been reported (dos Santos et al. 1999). Reactivation of Chagas disease occurs at a higher rate among AIDS patients, and these cases may present with myositis (Ferreira et al. 1997). 23.3.4.4 Sarcocystis spp. Sarcocystosis is a protozoan infection commonly seen in southeastern Asia but described worldwide. Myositis develops when cysts break (“sarcosporidiosis”) (Arness et al. 1999). Most sarcocystis infections are subclinical, and sarcocysts could be or not be associated with inflammatory response (Lindsay et al. 1995). Symptoms typically include painful swellings on the trunk, upper and lower extremities, and on the plantar surface of the feet. At the beginning, subcutaneous

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

625

masses are associated with overlying erythema and recede spontaneously in 2 weeks (Fayer 2004). Myalgias, weakness, tenderness, and fasciculations are commonly described. Symptoms of myositis may be chronic and relapsing in nature and may be due to both direct parasitic activity and immune-mediated responses: different manifestations of disease pledge the last hypothesis (Van den Enden et al. 1995; Arness et al. 1999). Recurrent or persistent symptoms of myositis may occur. Treatment is largely symptomatic; corticosteroids are often used. Some reports have suggested symptomatic benefit from albendazole or cotrimoxazole therapy, but controlled trials are lacking. Th2 cytokine polarization in infected patients and an overall cytokine production decrease in the early phase of the disease, suggestive of initial immunosuppression, have been described along with elevated levels of pro-inflammatory and chemotactic cytokines in the later myositic phase. An immune-dependent two-phase process seems to be the driver of the symptomatic shift, as happens for trichinellosis (Tappe et al. 2015).

23.3.4.5 Leishmania spp. There are few reports on muscular pathology induced by Leishmania spp. among humans. Leishmania spp. infection is associated with inflammatory myopathy (IM) in dogs. The mechanism underlying this disorder is still unclear: the pattern of cellular infiltration and MHC-I and MHC-II upregulation indicate an immunemediated myositis. The major antigen involved in molecular mimicry has been identified as the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1 (SERCA1): canine SERCA1 presents several identical traits to the calcium-translocating P-type ATPase of Leishmania infantum (Prisco et al. 2021). An IIM model infecting Syrian hamster with Leishmania infantum has been proposed. This animal model resembled some of the most characteristic histopathologic features of polymyositis: infiltrating inflammatory cells consisting mainly of T cells and CD8+ T cells present in non-necrotic muscle fibers expressing MHC class I on the sarcolemma. In addition to T cells, several macrophages were present (Paciello et al. 2010). Three patients with leishmaniasis and AIDS have been described, with cutaneous lesions mimicking dermatomyositis (Dauden et al. 1996), and one case with fever and severe muscle pain (Punda-Polic et al. 1997). Antimony remains the best therapeutic choice for visceral leishmaniasis. Although the cure rate is about 90% with antimony, many patients can now receive liposomal amphotericin B treatment, with high-level efficacy in a short-term course (Murray 2004). Paromomycin shows high-level efficacy, minimum toxicity, and low cost (Guerin et al. 2002). Miltefosine is the first effective oral treatment for antimony-resistant infection with visceral involvement (Bhattacharya et al. 2004).

626

M. G. Danieli et al.

23.3.4.6 Other Parasites Microsporidia spp. Microsporidia spp. are obligate intracellular eukaryotes. They are a rising cause of chronic diarrheal syndromes in patients with human immunodeficiency virus (HIV) infection. A single case of myositis caused by B. algerae, isolated for the first time from deep tissue in a person, in treatment with anti-TNF-α (Infliximab), has been reported (Coyle et al. 2004). Onchocerca volvulus Onchocerca volvulus is known for causing river blindness in Africa and Central/ South America, after a person is bitten by an infected host, the Simulium black fly. Most common symptoms are skin manifestation, nodules over bony prominences, and eye disease. It was reported that O. volvulus can occasionally cause eosinophilic myositis that presents with mass swelling, tenderness, pain, and weakness, associated with cutaneous lesions with peripheral and/or tissue eosinophilia (Dourmishev and Dourmishev 2009). These symptoms, as described, could mimic dermatomyositis (Crum-Cianflone 2010).

23.4

Coronavirus (and New Pathogenic Hypothesis)

In reporting on the link between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and myositis, we can distinguish two situations: 1. Myositis as a disease induced by SARS-CoV-2 infection or vaccination. 2. The impact of COVID-19 in patients already suffering from inflammatory myopathies.

23.4.1 SARS-CoV-2-Induced Myositis Recent case reports have revealed new clinical manifestations of SARS-CoV2 infection, resulting in rarer and unusual displays in multiple organs. The musculoskeletal system involvement is no exception, with signs and symptoms varying from mild weakness and/or creatine kinase (CK) increase to rhabdomyolysis, sometimes followed by patient exitus. An increasing number of cases with muscle involvement has been reported directly linked to COVID-19. Etiopathogenesis: • Direct entry of the virus in myocytes. In this regard, SARS-CoV-2 could be the first virus that can directly infect the myocyte entering through angiotensinconverting enzyme 2 (ACE2) receptor. Once penetrated the muscle cell, the virus would possibly activate both innate and adaptive immune systems, with subsequent muscle damage.

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

627

• Virus-antibody complex deposition might indirectly cause skeletal muscle damage; meanwhile direct harm seems to be mediated by viral toxins in blood (Veyseh et al. 2021). • The activation of innate immune system triggered by the virus leads to autoinflammation. A recent paper revised the role of toll-like receptor 4 (TLR4) on the inflammation during COVID-19. TLR4 is expressed on circulating and in tissue-resident cells of the immune system. Once activated by SARS-CoV-2, TLR4 induces the synthesis of type I interferons and pro-inflammatory cytokines thus promoting inflammation. Moreover, TLR4 can lead to an increase of ACE2 expression on lung cells, thus increasing the viral burden. • Activation of adaptive immune system: T-cell-mediated response to SARS-CoV2 induces antiviral T-cell clonal expansion in muscle. In addition, a macrophagemediated reaction might be responsible for fiber invasion with elevated proinflammatory cytokines (Dalakas 2020). The main phenomenon considered responsible for adaptive response is molecular mimicry, which explains the various manifestations of signs and symptoms. In support of this mechanism, several autoimmune pathological sequelae have been associated with SARSCoV-2 infection, in both previously healthy people and patients with pre-existing autoimmune rheumatic diseases (Ehrenfeld et al. 2020). In addition, here are summarized the further hypotheses previously discussed in the preceding chapters: anti-tRNA synthetase antibodies, infectious agents exposing cryptic epitopes of endogenous proteins, anti-idiotypic antibodies, superantigens produced by bacteria- or virus-infected cells, apoptotic processes, and influence on Treg cells. Although not yet directly linked to SARS-CoV-2, latest studies are on work to evaluate these mechanisms’ involvement. In this regard, a recent research discovered a strong resemblance between COVID-19 and anti-MDA5 myositis, which needs to be further investigated, to find therapeutic approaches from a shared etiopathogenesis. Myalgia is common in COVID-19 infection, in the early stages of the infection with up to 50% of cases involved. Myositis induced by SARS-CoV-2 may have variable presentations, ranging from chronic back pain or marked fatigue to classical dermatomyositis with heliotrope rashes to acute rhabdomyolysis. Gokhale et al. (2020) reported four cases of DM, all presenting with proximal muscle weakness (no myalgias) and classic rashes (heliotrope, malar, or diffuse facial rashes). Laboratory investigations showed high serum CK levels (from 150 to 8000 U/L) and positivity to myositis-specific antibodies (MSA: anti-MDA5 (antimelanoma differentiation-associated gene 5), anti-Mi-2, anti-SAE-1 (anti-small ubiquitin-like modifier-1 activating enzyme) and to antinuclear autoantibodies (ANA, one case)). Three patients recovered, while one had died. Heterogeneous outcomes have been described, ranging from a milder variant with full strength return in 1 week to long-lasting sequelae with strength restitutio longer than 3 months. Fatal or severe disease with severe lung involvement occurs rarely, with evident relation to anti-MDA5 antibodies (Gokhale et al. 2020).

628

M. G. Danieli et al.

As for rhabdomyolysis, the nine cases described presented with intense myalgias and profound muscle weakness, with very high serum CK levels (from 4000 to 42,000 U/L), in one case with myoglobinuria and renal impairment. MSA or ANA were negative. They are generally patients recovered in intensive care units with ventilatory support. The prognosis is poor with 45% mortality. The elevated serum CK levels observed in these patients with DM and rhabdomyolysis can help to distinguish between these two conditions. However, it should be reminded that higher CK levels did not correlate directly, as far as we know from published cases, with a more severe prognosis. An additional clue to differentiate myositis from rhabdomyolysis is the magnetic resonance imaging (MRI) findings of intramuscular hemorrhage, reported in the proximal muscles from this latter condition (rhabdomyolysis). Recently, Veyseh et al. (2021) described a case of a 57-year-old woman who developed a necrotizing autoimmune myositis (NAM) 1 month after the recovery of a mild COVID-19 infection. As in other cases of NAM, she had a subacute onset with severe proximal muscle weakness, elevated serum CK levels (>15,000 U/L) with positive ANA (1:320, speckled pattern), and negative MSA. Histological pattern with scarce necrotic myofibers and few inflammatory cells infiltrating the muscle confirmed the diagnosis of NAM. The treatment with glucocorticoids (at the onset with high-dose predniso(lo)ne with slow tapering) and methotrexate led her to remission in the following months. Other rarer muscle manifestations linked to COVID-19 have been described in sporadic cases and comprise paraspinal myositis, axonal neuropathy, cachexia, and myofascial compartment syndrome due to inflammation of an isolated group of muscles. Lastly, 16–33% patients exhibited elevated CK levels and/or loss in strength or rashes (Guan et al. 2020). Some studies refer an association high level of CK with higher morbidity and mortality, making it reasonable to evaluate serum CK levels in COVID-19 patients with myalgias (Rivas-García et al. 2020). Conversely, due to its short half-life and high false-negative results, myoglobin levels are not required to evaluate rhabdomyolysis (Bach et al. 2021). The manifestations listed above also recurred in few patients as an adverse effect of SARS-CoV-2 vaccination; here are brought some cases. First, a 21-year-old male lamented progressive pain with lower back swelling and radiation to his left lateral thigh 1 day after the first Pfizer/BioNTech injection. Darker urine was also signaled. A first inspection revealed transient high blood pressure and tenderness to palpation in the pain site. Laboratory exams revealed a severe elevation in CK (>22,000 U/L). ANA, anti-ENA, and MSA, including antiMDA5, resulted negative (Nassar et al. 2021). The second case regards an 80-year-old male with severe strength loss, generalized myalgia, and negative COVID-19 PCR, with LDH and CK elevation (>6000 U/L) 2 days after the second injection of Moderna vaccine. Other than that, no significant clinical, laboratory, or instrumental findings are described. A 3-month prior SARS-CoV-2 infection required a 13-day hospital stay. Apart from that, history is only interested by diabetes mellitus type 2 (Mack et al. 2021).

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

629

Finally, a 34-year-old male developed rhabdomyolysis after the Oxford/ AstraZeneca vaccination; additional symptoms were myalgia, weakness, hematuria, and pyrexia. CK is referred 250,000 U/L. No prior SARS-CoV-2 infection was described, though the patient was affected by carnitine palmitoyl transferase II (CPT II) deficiency (Tan et al. 2021), a neuromuscular condition that predisposes to rhabdomyolysis. What needs to be finally addressed is the difference between Oxford/AstraZeneca, an adenoviral vector vaccine, and mRNA vaccines such as Pfizer/BioNTech injection and Moderna. Regarding myositis, a case report describes a 56-year-old woman developing pain and progressive decrease in strength and range of motion localized in the deltoid muscle, after 8 days from the second dose of an mRNA vaccine. The site presented tenderness to palpation and edema to imaging. CK increase is also reported. As stated by the authors, all the above symptoms vanished in 6 weeks with no sequelae. However, MRI outcomes persisted for 2 additional months (Theodorou et al. 2021). In conclusion, this generalized myositis should be considered capable of evolving into rhabdomyolysis such as in the second case. The first hypothetical explanation for these adverse effects could be ASIAShoendfeld’s syndrome. The acronym stands for autoimmune/inflammatory syndrome induced by adjuvants, whose mechanism depends on an amplified immune response to external elements with adjuvant purpose (Shoenfeld and Agmon-Levin 2011). ASIA-Shoenfeld’s syndrome can possibly lead to rhabdomyolysis and other inflammatory complications (Watad et al. 2017). Ultimately, the previous SARSCoV-2 infection of the second case could have influenced this inflammatory reaction, thus the patient’s response to vaccination. Secondly, mRNA vaccines could promote the activation of specific toll-like receptors (TLRs), through RNA molecules stimulating the immune system. Previous studies show an increased T-cell and antibody response in patients with prior SARSCoV-2 infection (Manisty et al. 2021) which might emphasize the reaction to the vaccine. Although being a rare adverse effect, the connection between rhabdomyolysis, myositis, and vaccine has been already described in literature, especially concerning flu vaccination (Urayoshi et al. 2015). To date, over 120 rhabdomyolysis and 80 myositis events result after a search on the Vaccine Adverse Event Reporting System (VAERS) database. SARS-CoV-2 infection might mimic rhabdomyolysis as both share similar symptoms and signs, especially fever, myalgia, elevated AST/ALT, and LDH. Lack of diagnosis raises the risk of morbidity and mortality, as it has shown how rhabdomyolysis in SARS-CoV-2 patients increases ICU admission (90.9% vs 5.3%) and the need for assisted ventilation (86.4% vs 2.7%) (Geng et al. 2021). CK monitoring, however, makes a perfect screening for rhabdomyolysis in these patients. Ultimately, growing evidence suggests that nearly half of COVID-19 patients still suffer from chronic and in some cases debilitating symptoms, once resolved the acute phase of the infection. These cases are included in the definition of post-acute

630

M. G. Danieli et al.

COVID or long COVID syndrome. Among these symptoms there are myalgias, weakness, fatigue, or other neurological problems.

23.4.2 Patients with Pre-existing Myositis (and Our Center Experience) The COVID-19 pandemic resulted in increased disease flares, disrupted treatments, and logistic impasses, finally leading to reduced quality care. The new SARS-CoV-2 that caused the COVID19 pandemic has high morbidity and mortality especially in high-risk patients, such as those with rheumatic diseases and treated with glucocorticoids and/or immunosuppressants. Few data are still available on the impact of COVID-19 in inflammatory myopathies. In our series of 78 patients with inflammatory myopathies (IIM), only two patients contracted SARS-CoV-2 infection. This may be due to the increased focus on prevention measures. The two cases are different: the first was an 87-year-old woman at high risk due to old age, high cardiovascular risk, chronic obstructive pulmonary disease (COPD), and intraductal papillary mucinous neoplasms. In April 2020 she contracted SARS-CoV-2 infection. About a week after the first positive swab test, she developed severe ILD which led to respiratory failure and death, 25 days after the SARS-CoV-2 positivity. The second patient was a 45-year-old man with DM. In March 2020, while in remission with low-dose predniso(lo)ne, he presented a mild SARS-CoV-2 infection for which he received home treatment with paracetamol and NSAIDs for 2 days until sudden death. The autopsy identified acute myocardial ischemia in COVID-19 interstitial pneumonia as the cause of death. A previous echocardiogram performed in January 2020 was negative. Apparently, the man was not a high-risk patient since he did not have comorbidities and was in long-lasting stable remission. However, he had an acute thrombotic event during COVID-19. All our patients continued with their current treatment, mainly based on low-dose predniso(lo)ne, hydroxychloroquine, mycophenolate mofetil, intravenous (IVIg), and subcutaneous immunoglobulin (20%SCIg) (Danieli et al. 2020). It is important to remind the difficult balance in immunosuppressive therapy that can be necessary for myositis but can negatively impact on COVID-19 disease. However, more recent data has shown that some drugs such as tocilizumab or IVIg/SCIg, acting as immunomodulatory agents, can be helpful for both diseases. As for vaccination against COVID-19, all patients have received both doses of Pfizer vaccine, with no problems. Due to COVID-19 restrictions, we used to send an email with updates on the infection and the vaccinations. Moreover, in spring 2021, to provide a stronger link with patients, we started teleconsultations, with their great satisfaction.

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

23.5

631

The Role of Microbiome in Myositis

Few and scarce data are currently available about the microbial composition or pathogenic role of the microbiome in autoimmune myositis. There is very little evidence supporting a pathogenic role of dysbiosis in the onset of inflammatory myopathies. A high-fat diet seems to have a role on intestinal microbial composition: the possibility of an effect on adipose and skeletal muscle has been considered (Bleau et al. 2015). Enterobacteriaceae and other bacterial species, characterized by the presence of LPS, seem to have a selective vantage versus Bacteroidetes, through activation of TLRs in macrophages, adipose, and skeletal muscle tissue. Some evidence about a direct activation of TLR2 and TLR4 by saturated fatty acids has been produced: this may favor chronic pro-inflammation with release of TNF-α, IL-6, and several chemokines. The subsequent reduction in protein synthesis and the induction of insulin resistance and oxidative stress can trigger inflammation in the skeletal muscle. Some studies have stressed the potential development of inflammatory myopathies after infections or vaccinations (Limaye et al. 2017), but no study has yet investigated the differences in microbial taxonomic composition in autoimmune myopathies (Talotta et al. 2017). In recent years, the use of probiotics has also proposed for the treatment of autoimmune diseases. In several studies probiotics seem to reduce inflammatory state, in particular inducing Tregs. Mechanisms proposed involve the modulation of DC cells, the stimulation of TLRs, and the increasing of TGF-b and IL-10. Moreover, probiotics lead to the production of immunomodulatory short-chain fatty acids (SCFAs) that could induce Tregs and improve its functions trough G-protein pathways, inhibiting histone deacetylases (HDACs) and modulating prostaglandin E2 (PGE2). All mechanisms seem to increase the function of Tregs that suppress CD8+ and Th17 cells (Dwivedi et al. 2016). Studies in animal models could support probiotics in autoimmune diseases: some strains of probiotics in mouse model of systemic lupus erythematosus (SLE) reduced inflammation and shifted the balance of Treg-Th17 toward Treg cells (Mu et al. 2017). Evidence in vitro and in animal models, however, is found with different strains of probiotics that make difficult to find specific microorganisms to use in specific disease. Moreover, studies on IIM models are not yet available.

23.6

Infectious Complications and Risk in Myositis Patients

Patients with IIM have an increased infectious risk due to different factors, related to disease and chronic immunosuppression therapy. Infectious complications are described with a rate between 25 and 40% in outpatients (Marie 2012; Nuño-Nuño et al. 2017) and between 30 and 60% in hospitalized patients (Murray et al. 2015; Peng et al. 2016). Infections are a major risk factor in morbidity and mortality in patients with IIM. The lung is the most common site, and opportunistic infections are common (Mecoli and Danoff 2020). Bacterial infections are more frequent in hospitalized patients and

632

M. G. Danieli et al.

related to clinical outcome, whereas opportunistic infections in almost all studies did not correlate with mortality. Factors which could favor infectious processes are represented by immunosuppressive treatments (Marie 2012), esophageal involvement, the presence of respiratory failure, malignancy, and lymphopenia (Mecoli and Danoff 2020; Marie 2012). In a study of 279 patients (Marie 2012) with IIM, 37% developed an infection in a median follow-up of 36 months. Pyogenic infections are described in 68% (aspiration pneumonia and calcinosis skin infections) and non-pyogenic and opportunistic infections in 32%, most commonly due to fungi (P. jirovecii and Candida albicans). Additionally, methotrexate, azathioprine, infliximab, and higher daily doses of glucocorticoids increase susceptibility to infections. A retrospective study evaluated the causes of death in 467 patients with IIM (Nuño-Nuño et al. 2017). Twenty-four percent of patients died in a mean follow-up of 9.7 years. Twenty-five percent of patients developed severe infections (requiring hospitalization or resulting in death); the most frequent infectious site was the lung (63%). Severe infection led to death in 30% of patients. Opportunistic infections were evaluated in 204 patients with IIM (RedondoBenito et al. 2018). The prevalence of opportunistic infections was 6.4% (44% viruses, 22% bacteria, 17% fungi, 17% parasites); most affected sites were lung and soft tissues. More than half of opportunistic infections (about 55%) occurred in the first year after diagnosis and were significantly associated with high-dose glucocorticoid use. Regarding hospital infections, a retrospective study (Peng et al. 2016) evaluated 102 Chinese patients with IIM admitted to intensive care unit over a period of 8 years. An infection was the most common reason for hospitalization and was found in 67% of patients. The lung was the most affected organ and represented the site of infection in 85% of cases. Most of the infections were due to opportunistic germs (Aspergillus, P. jirovecii, CMV). However, it is important to keep in mind that 85% of patients were on high-dose steroid therapy (0.5 mg/kg/day) before hospitalization. Another study examined the causes of mortality in 676 patients with IIM hospitalized over a period of 14 years (Xiao et al. 2016). Out of 49 (7.2%) deaths, 34 (69% of all deaths) were associated with infections, most frequently involving the lungs and blood. The most isolated bacteria were Klebsiella pneumoniae, Acinetobacter baumannii, Streptococcus pneumoniae, Staphylococcus aureus, and Candida spp. Co-infections, opportunistic infections, invasive fungal infections, and viral infections were common. A US study (Murray et al. 2015) on 15,000 admissions of patients with DM and PM documented a hospital mortality of about 5%. Twenty-eight percent of hospitalized patients had an infection, usually bacterial, and the most common sites were the lung and blood. Infections were the strongest predictor of mortality among hospitalized individuals with IIM, with a 4.2-fold increase in the odds of death. Pneumonia, bacteremia, and opportunistic fungal infections were significantly associated with mortality.

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

633

The weight of infections on mortality in patients with IIM requires particular attention, especially during hospitalizations. It could be important to exclude viral and fungal infections, in view of the heterogeneity of the infectious processes. Another fundamental factor is immunosuppressive therapy. Steroid therapy appears to favor some infections (Mecoli and Danoff 2020), while the role of other drugs is not entirely clear. In this regard, it is important that IVIg could be useful in reducing the infectious risk by playing a steroid- and immunosuppressantsparing role (Wang et al. 2012; Danieli et al. 2014).

23.7

Conclusions

Microorganisms certainly represent one of the possible agents involved in the development of PM and DM. However, evidence described are few and mainly concern viruses. Further studies are therefore needed to understand causes and pathophysiologic mechanisms involved and to find new therapeutic targets. In this sense, the new Coronavirus, the so-called autoimmune virus, could reveal news on autoimmunity and on PM and DM.

References Adler BL, Christopher-Stine L (2018) Triggers of inflammatory myopathy: insights into pathogenesis. Discov Med 25:75–83 Agyeman P, Duppenthaler A, Heininger U et al (2004) Influenza-associated myositis in children. Infection 32:199–203 Allenbach Y, Solly S, Grégoire S et al (2009) Role of regulatory T cells in a new mouse model of experimental autoimmune myositis. Am J Pathol 174:989–998 Arness MK, Brown DJ, Dubey JP et al (1999) An outbreak of acute eosinophilic myositis attributed to human Sarcocystis parasitism. Am J Trop Med Hyg 61:548–553 Bach M, Lim PP, Azok J et al (2021) Anaphylaxis and rhabdomyolysis: a presentation of a pediatric patient with COVID-19. Clin Pediatr 60:202–204 Bhattacharya SK, Jha TK, Sunda S et al (2004) Efficacy and tolerability of miltefosine for childhood visceral leishmaniasis in India. Clin Infect Dis 38:217–221 Bleau C, Karelis AD, St-Pierre DH et al (2015) Crosstalk between intestinal microbiota, adipose tissue and skeletal muscle as an early event in systemic low-grade inflammation and the development of obesity and diabetes. Diabetes Metab Res Rev 31:545–561 Boehler JF, Horn A, Novak JS et al (2019) Mitochondrial dysfunction and role of harakiri in the pathogenesis of myositis. J Pathol 249:215–226 Bowles NE, Dubowitz V, Sewry CA et al (1987) Dermatomyositis, polymyositis, and Coxsackie-Bvirus infection. Lancet 1:1004–1007 Bruschi F, Marucci G, Pozio E et al (2009) Evaluation of inflammatory responses against muscle larvae of different Trichinella species by an image analysis system. Vet Parasitol 159:258–262 Capo V, Despommier DD (1996) Clinical aspects of infection with Trichinella spp. Clin Microbiol Rev 9:47–54 Chariot P, Ruet E, Authier FJ et al (1994) Acute rhabdomyolysis in patients infected by human immunodeficiency virus. Neurology 44:1692–1696 Chen D-Y, Chen Y-M, Lan J-L et al (2010) Polymyositis/dermatomyositis and nasopharyngeal carcinoma: the Epstein–Barr virus connection? J Clin Virol 49:290–295

634

M. G. Danieli et al.

Chevrel G, Borsotti JP, Miossec P (2003) Lack of evidence for a direct involvement of muscle infection by parvovirus B19 in the pathogenesis of inflammatory myopathies: a follow-up study. Rheumatology (Oxford) 42:349–352 Chinoy H, Adimulam S, Marriage F et al (2012) Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a Europeanwide case study. Ann Rheum Dis 71:961–965 Christensen ML, Pachman LM, Schneiderman R et al (1986) Prevalence of Coxsackie B virus antibodies in patients with juvenile dermatomyositis. Arthritis Rheum 29:1365–1370 Cossermelli W, Friedman H, Pastor EH et al (1978) Polymyositis in Chagas’s disease. Ann Rheum Dis 37:277–280 Coyle CM, Weiss LM, Rhodes LV3rd et al (2004) Fatal myositis due to the microsporidian Brachiola algerae, a mosquito pathogen. New Engl J Med 351:42–47 Crum-Cianflone NF (2008) Bacterial, fungal, parasitic, and viral myositis. Clin Microbiol Rev 21: 473–494 Crum-Cianflone NF (2010) Nonbacterial myositis. Curr Infect Dis Rep 12:374–382 Cuellar ML (1998) HIV infection–associated inflammatory musculoskeletal disorders. Rheum Dis Clin N Am 24:403–421 Cupler EJ, Danon MJ, Jay C et al (1995) Early features of zidovudine-associated myopathy: histopathological findings and clinical correlations. Acta Neuropathol 90:1–6 Cuturic M, Hayat GR, Vogler CA et al (1997) Toxoplasmic polymyositis revisited: case report and review of literature. Neuromuscul Disord 7:390–396 Dalakas MC (2015) Inflammatory muscle diseases N EnglJ Med 372:1734–1747 Dalakas MC (2020) Inflammatory myopathies: update on diagnosis, pathogenesis and therapies, and COVID-19-related implications. Acta Myol 39:289–301 Dalakas MC, Pezeshkpour GH, Gravell M et al (1986) Polymyositis associated with AIDS retrovirus. JAMA 256:2381–2383 Danieli MG, Gambini S, Pettinari L et al (2014) Impact of treatment on survival in polymyositis and dermatomyositis. A single-centre long-term follow-up study. Autoimmun Rev 13:1048–1054 Danieli MG, Gelardi C, Pedini V et al (2020) Subcutaneous immunoglobulin in inflammatory myopathies: efficacy in different organ systems. Autoimmun Rev 19:102426 Daud’en E, Peñas PF, Rios L et al (1996) Leishmaniasis presenting as a dermatomyositis-like eruption in AIDS. J Am Acad Dermatol 35:316–319 Davis LE, Kornfeld M (2001) Experimental influenza B viral myositis. J Neurol Sci 187:61–67 De Paepe B (2019) Sporadic Inclusion Body Myositis: An acquired mitochondrial disease with extras. Biomol Ther 9:15 dos Santos SS, Almeida GM, Monteiro ML et al (1999) Ocular myositis and diffuse meningoencephalitis from Trypanosoma cruzi in an AIDS patient. Trans R Soc Trop Med Hyg 93:535–536 Dourmishev LA, Dourmishev AL (2009) Eosinophilic myositis/perimyositis. In: Dourmishev LA, Dourmishev AL (eds) Dermatomyositis: advances in Recognition. Springer, Understanding and management, pp 195–198 Dwivedi M, Kumar P, Laddha NC et al (2016) Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity. AutoimmunRev 15:379–392 Ehrenfeld M, Tincani A, Andreoli L et al (2020) Covid-19 and autoimmunity. Autoimmun Rev 19: 102597. https://doi.org/10.1016/j.autrev.2020.102597 El-Beshbishi SN, Ahmed NN, Mostafa SH et al (2012) Parasitic infections and myositis. Parasitol Res 110:1–18 Emmer A, Abobarin-Adeagbo A, Posa A et al (2019) Myositis in Lewis rats induced by the superantigen Staphylococcal enterotoxin A. Mol Biol Rep 46:4085–4094 Fabricius E-M, Hoegl I, Pfaeffl W (1991) Ocular myositis as first presenting symptom of human immunodeficiency virus (HIV-1) infection and its response to high-dose cortisone treatment. Brit J Ophthalmol 75:696–697

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

635

Fayer R (2004) Sarcocystis spp. in human infections. Clin Microbiol Rev 17:894–902 Ferraccioli GF, Mercadanti M, Salaffi F et al (1988) Prospective rheumatological study of muscle and joint symptoms during Trichinella nelsoni infection. Q J M 69:973–984 Ferreira MS, de A Nishioka S, Silvestre MT et al (1997) Reactivation of Chagas’ disease in patients with AIDS: report of three new cases and review of the literature. Clin Infect Dis 25:1397–1400 Fodili F, van Bommel EFH (2003) Severe rhabdomyolysis and acute renal failure following recent Coxsackie B virus infection. Neth J Med 61:177–179 Fourestié V, Bougnoux ME, Ancelle T et al (1988) Randomized trial of albendazole versus tiabendazole plus flubendazole during an outbreak of human trichinellosis. Parasitol Res 75: 36–41 Geng Y, Ma Q, Du YS et al (2021) Rhabdomyolysis is associated with in-hospital mortality in patients with COVID-19. Shock. https://doi.org/10.1097/SHK.0000000000001725 Gergely P Jr, Blazsek A, Dankó K et al (2005) Detection of TT virus in patients with idiopathic inflammatory myopathies. Ann N Y Acad Sci 1050:304–313 Giannini M, Ohana M, Nespola B et al (2020) Similarities between COVID-19 and anti-MDA5 syndrome: what can we learn for better care? Eur Respir J 56:2001618 Giat E, Ehrenfeld M, Shoenfeld Y (2017) Cancer and autoimmune diseases. Autoimmun Rev 16: 1049–1057 Gokhale Y, Patankar A, Holla U et al (2020) Dermatomyositis during COVID-19 Pandemic (a case series): is there a cause effect relationship? J Assoc Physicians India 68:20–24 Gresh JP, Aquilar JL, Espinoza LR (1989) Human immunodeficiency virus (HIV) infectionassociated dermatomyositis. J Rheumatol 16:1397–1398 Guan W, Ni Z, Hu Y et al (2020) Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 382:1708–1720 Guerin PJ, Olliaro P, Sundar S et al (2002) Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis 2:494–501 Hu JJ, Kao CL, Lee PI et al (2004) Clinical features of influenza A and B in children and association with myositis. J Microbiol Immunol Infect 37:95–98 Ichimiya M, Yasui H, Hirota Y et al (1998) Association between elevated serum antibody levels to streptococcal M12 protein and susceptibility to dermatomyositis. Arch Dermatol Res 290:229– 230 Jin RM, Blair SJ, Warunek J et al (2017) Regulatory T cells promote myositis and muscle damage in Toxoplasma gondii infection. J Immunol 198:352–362 Johnson RW, Williams FM, Kazi S et al (2003) Human immunodeficiency virus–associated polymyositis: a longitudinal study of outcome. Arthritis Rheum 15:172–178 Leff RL, Burgess SH, Miller FW et al (1991) Distinct seasonal patterns in the onset of adult idiopathic inflammatory myopathy in patients with anti-Jo-1 and anti-signal recognition particle autoantibodies. Arthritis Rheum 34:1391–1396 Leff RL, Love LA, Miller FW et al (1992) Viruses in idiopathic inflammatory myopathies: absence of candidate viral genomes in muscle. Lancet 339:1192–1195 Lidbury BA, Rulli NE, Suhrbier A et al (2008) Macrophage-derived proinflammatory factors contribute to the development of arthritis and myositis after infection with an arthrogenic alphavirus. J Infect Dis 197:1585–1593 Limaye V, Smith C, Koszyca B et al (2017) Infections and vaccinations as possible triggers of inflammatory myopathies. Muscle Nerve 56:987–989 Lindsay DS, Blagburn BL, Braund KG (1995) Sarcocystis spp. and sarcocystosis. Br Med J 5:249– 254 Lloyd TE, Pinal-Fernandez I, Harlan Michelle E et al (2017) Overlapping features of polymyositis and inclusion body myositis in HIV-infected patients. Neurology 88:1454–1460

636

M. G. Danieli et al.

Love LA, Weinberg CR, McConnaughey DR et al (2009) Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women. Arthritis Rheum 60:2499–2504 Lundberg A (1957) Myalgiacruris epidemica. Acta Paed 46:18–31 Mack M, Nichols L, Guerrero DM (2021) Rhabdomyolysis secondary to COVID-19 vaccination. Cureus 13:e15004 Magee H, Goldman RD (2017) Viral myositis in children. Can Fam Physician 63:365–368 Maldonado RSC, Ferreira ML, Camargos ERS et al (2004) Skeletal muscle regeneration and Trypanosoma cruzi-induced myositis in rats. Histol Histopathol 19:85–93 Manisty C, Otter AD, Treibel TA et al (2021) Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals. Lancet 397:1057–1058 Manlhiot C, Liang L, Tran D et al (2008) Assessment of an infectious disease history preceding juvenile dermatomyositis symptom onset. Rheumatology (Oxford) 47:526–529 Manta P, Kalfakis N, Vassilopoulos D (1989) Evidence for seasonal variation in polymyositis. Neuroepidemiology 8:262–265 Marie I (2012) Morbidity and mortality in adult polymyositis and dermatomyositis. Curr Rheumatol Rep 14:275–285 Martini A, Ravelli A, Albani S et al (1992) Recurrent juvenile dermatomyositis and cutaneous necrotizing arteritis with molecular mimicry between streptococcal type 5 M protein and human skeletal myosin. J Pediatr 121:739–742 Mecoli CA, Danoff SK (2020) Pneumocystis jirovecii pneumonia and other infections in idiopathic inflammatory myositis. Curr Rheumatol 22:7 Morgan OS, Rodgers-Johnson P, Mora C et al (1989) HTLV-1 and polymyositis in Jamaica. Lancet 2:1184–1187 Morgensen JL (1974) Myoglobinuria and renal failure associated with influenza. Ann Intern Med 80:362–363 Morrison TE, Oko L, Montgomery SA et al (2011) A mouse model of chikungunya virus–induced musculoskeletal inflammatory disease: evidence of arthritis, tenosynovitis, myositis, and persistence. Am J Pathol 178:32–40 Mu Q, Zhang H, Liao X et al (2017) Control of lupus nephritis by changes of gut microbiota. Microbiome 5:73 Murray HW (2004) Progress in the treatment of a neglected infectious disease: visceral leishmaniasis. Exp Rev Anti Infect Ther 2:279–292 Murray SG, Schmajuk G, Trupin L et al (2015) A population-based study of infection-related hospital mortality in patients with dermatomyositis/polymyositis. Arthritis Care Res (Hoboken) 67:673–680 Nagaraju K, Casciola-Rosen L, Rosen A et al (2000) The inhibition of apoptosis in myositis and in normal muscle cells. J Immunol 164:5459–5465 Nassar M, Chung H, Dhayaparan Y et al (2021) COVID-19 vaccine induced rhabdomyolysis: case report with literature review. Diabetes MetabSyndr 15:102170 Nuño-Nuño L, Joven BE, Carreira PE et al (2017) Mortality and prognostic factors in idiopathic inflammatory myositis: a retrospective analysis of a large multicenter cohort of Spain. Rheumatol Int 37:1853–1861 Ozden S, Mouly V, Prevost M-C et al (2005) Muscle wasting induced by HTLV-1 tax-1 protein: an in vitro and in vivo study. Am J Pathol 167:1609–1619 Paciello O, Wojcik S, Gradoni L et al (2010) Syrian hamster infected with Leishmania infantum: a new experimental model for inflammatory myopathies. Muscle Nerve 41:355–361 Peng JM, Du B, Wang Q et al (2016) Dermatomyositis and Polymyositis in the intensive care unit: a single-center retrospective cohort study of 102 patients. PLoS One 26:e0154441 Peravali R, Acharya S, Raza SH et al (2020) Dermatomyositis developed after exposure to EpsteinBarr virus infection and antibiotics use. Am J Med Sci 360:402–405 Plonquet A, Bassez G, Authier F-J et al (2003) Toxoplasmic myositis as a presenting manifestation of idiopathic CD4 lymphocytopenia. Muscle Nerve 27:761–765

23

Microorganisms in Pathogenesis and Management of Dermatomyositis (DM). . .

637

Pozio E, Gomez Morales MA, Dupouy-Camet J (2003) Clinical aspects, diagnosis and treatment of trichinellosis. Expert Rev Anti-Infect Ther 1:471–482 Pozio E, Sacchini D, Sacchi L et al (2001) Failure of mebendazole in the treatment of humans with Trichinella spiralis infection at the stage of encapsulating larvae. Clin Infect Dis 32:638–642 Prisco F, De Biase D, Piegari G et al (2021) Leishmania spp.-infected dogs have circulating antiskeletal muscle autoantibodies recognizing SERCA1. Pathogens 10(463) Punda-Polic V, Bradarić N, Grgić D (1997) A 9-yearold with fever and severe muscle pains. Lancet 349:1666 Ray CG, Minnich LL, Johnson PC (1979) Selective polymyositis inducted by coxsackievirus B1 in mice. J Infect Dis 140:239–243 Rayavarapu S, Coley W, Kinder TB et al (2013) Idiopathic inflammatory myopathies: pathogenic mechanisms of muscle weakness. Skelet Muscle 3:13 Redondo-Benito A, Curran A, Villar-Gomez A et al (2018) Opportunistic infections in patients with idiopathic inflammatory myopathies. Int J Rheum Dis 21:487–496 Rivas-García S, Bernal J, Bachiller-Corral J (2020) Rhabdomyolysis as the main manifestation of coronavirus disease 2019. Rheumatology 59:2174–2176 Rothwell S, Chinoy H, Lamb JA et al (2019) Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups. Ann Rheum Dis 78:996–1002 Rothwell S, Cooper RG, Lundberg IE et al (2017) Immune-array analysis in sporadic inclusion body myositis reveals HLA-DRB1 amino acid heterogeneity across the myositis spectrum. Arthritis Rheumatol 69:1090–1099 Saberin A, Lutgen C, Humbel RL et al (2004) Dermatomyositis-like syndrome following acute toxoplasmosis. Bull Soc Sci Med Grand Duche Luxemb:109–119 Sakata H, Taketazu G, Nagaya K et al (1998) Outbreak of severe infection due to adenovirus type 7 in a paediatric ward in Japan. J Hosp Infect 39:207–211 Santos Durán-Ortiz J, García-de la Torre I, Orozco-Barocio G et al (1992) Trichinosis with severe myopathic involvement mimicking polymyositis. Report of a family outbreak. J Rheumatol 19: 310–312 Sarkar K, Weinberg CR, Oddis CV et al (2005) Seasonal influence on the onset of idiopathic inflammatory myopathies in serologically defined groups. Arthritis Rheum 52:2433–2438 Saud A, Naveeb R, Aggarwal R et al (2021) COVID-19 and myositis: what we know so far. Curr Rheum Rep 23:63–76 Schulze C, Munoz LE, Franz S et al (2008) Clearance deficiency—a potential link between infections and autoimmunity. Autoimmun Rev 8:5–8 Shoenfeld Y (2004) The idiotypic network in autoimmunity: antibodies that bind antibodies that bind antibodies. Nat Med 10:17–18 Shoenfeld Y, Agmon-Levin N (2011) 'ASIA'—autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun 36:4–8 Singh U, Scheld WM (1996) Infectious etiologies of rhabdomyolysis: three case reports and review. Clin Infect Dis 22:642–649 Sofronic-Milosavljevic L, Ilic N, Pinelli E et al (2015) Secretory products of Trichinella spiralis muscle larvae and immunomodulation: implication for autoimmune diseases, allergies, and malignancies. J Immunol Res 2015:523875 Stanford MR, Gilbert RE (2009) Treating ocular toxoplasmosis: current evidence. Mem Inst Oswaldo Cruz 104:312–315 Svensson J, Holmqvist M, Lundberg IE et al (2017) Infections and respiratory tract disease as risk factors for idiopathic inflammatory myopathies: a population-based case-control study. Ann Rheum Dis 76:1803–1808 Takács AC, Swierzy IJ, Lüder CG (2012) Interferon-γ restricts Toxoplasma gondii development in murine skeletal muscle cells via nitric oxide production and immunity-related GTPases. PLoS One. https://doi.org/10.1371/journal.pone.0045440 Talotta R, Atzeni F, Ditto MC et al (2017) The microbiome in connective tissue diseases and vasculitides: an updated narrative review. J Immunol Res 2017:6836498

638

M. G. Danieli et al.

Tan A, Stepien KM, Narayana ST (2021) Carnitine palmitoyltransferase II deficiency and postCOVID vaccination rhabdomyolysis. QJM Int J Med. https://doi.org/10.1093/qjmed/hcab077 Tappe D, Slesak G, Pérez-Girón JV et al (2015) Human invasive muscular sarcocystosis induces Th2 cytokine polarization and biphasic cytokine changes, based on an investigation among travelers returning from Tioman Island, Malaysia. Clin Vaccine Immunol 22:674–677 Teixeira AR, Nascimento RJ, Sturm NR (2006) Evolution and pathology in chagas disease--a review. Mem Inst Oswaldo Cruz 101:463–491 Theodorou DJ, Theodorou SJ, Axiotis A et al (2021) COVID-19 vaccine-related myositis. QJM Int J Med. https://doi.org/10.1093/qjmed/hcab043 Urayoshi S, Matsumoto S, Miyatani H et al (2015) A case of myositis of the deltoid muscle of the upper arm developing 1 week after influenza vaccination: case report. Clin Case Rep 3:135–138 Van den Enden E, Praet M, Joos R et al (1995) Eosinophilic myositis resulting from sarcocystosis. J Trop Med Hyg 98:273–276 Veyseh M, Koyoda S, Ayesha B (2021) COVID-19 IgG-related autoimmune inflammatory necrotizing myositis. BMJ Case Rep 14:e239457. https://doi.org/10.1136/bcr-2020-239457 Wang DX, Shu XM, Tian XL, Chen F, Zu N, Ma L, Wang GC (2012) Intravenous immunoglobulin therapy in adult patients with polymyositis/dermatomyositis: a systematic literature review. Clin Rheumatol 31(5):801–806. https://doi.org/10.1007/s10067-012-1940-5 Warin JF, Davies JB, Sanders FK et al (1953) Oxford epidemic of Bornholm disease, 1951. Br Med J 1:1345–1351 Watad A, Sharif K, Shoenfeld Y (2017) The ASIA syndrome: basic concepts. Mediterr J Rheumatol 28:64–69 Watt G, Saisorn S, Jongsakul K et al (2000) Blinded, placebo-controlled trial of antiparasitic drugs for trichinosis myositis. J Infect Dis 182:371–374 Wohlfert EA, Blader IJ, Wilson EH (2017) Brains and Brawn: toxoplasma infections of the central nervous system and skeletal muscle. Trends Parasitol 33:519–531 Xiao Y, Zuo X, You Y et al (2016) Investigation into the cause of mortality in 49 cases of idiopathic inflammatory myopathy: a single center study. Exp Ther Med 11:885–889 Zandman-Goddard G, Shoenfeld Y (2002) HIV and autoimmunity. Autoimmun Rev 1:329–337

Microorganisms in Pathogenesis and Management of Necrotising Autoimmune Myopathy (NAM) and Inclusion Body Myositis (IBM)

24

Maria Giovanna Danieli, Eleonora Antonelli, Cristina Mezzanotte, Mario Andrea Piga, and Eleonora Longhi

Abstract

This chapter aims to describe two clinical-pathological alterations of the muscles, named, respectively, necrotizing autoimmune myopathy (NAM) and inclusion body myositis (IBM). Both conditions have an inflammatory-immunological background, and they result from specific interactions between genetic and environmental risk factors. Histologically, NAM is characterized by muscle fibre necrosis in the absence of prominent inflammatory infiltrate, whereas IBM present in vacuoles within which there are clumps of protein. We paid specific attention to the role of microbes in taking part in the pathogenetic process. Due to current pandemic, we focused on SARS-CoV-2 infection. Considering that

M. G. Danieli (*) Clinica Medica, Dipartimento di Medicina Interna, Ospedali Riuniti di Ancona e DISCLIMO, Università Politecnica delle Marche, Ancona, Italy School of Specialisation in Allergology and Clinical Immunology, Dipartimento di Medicina Interna, Ospedali Riuniti di Ancona e DISCLIMO, Università Politecnica delle Marche, Ancona, Italy e-mail: [email protected] E. Antonelli · C. Mezzanotte School of Specialisation in Internal Medicine, Dipartimento di Medicina Interna, Ospedali Riuniti di Ancona e DISCLIMO, Università Politecnica delle Marche, Ancona, Italy M. A. Piga School of Specialisation in Allergology and Clinical Immunology, Dipartimento di Medicina Interna, Ospedali Riuniti di Ancona e DISCLIMO, Università Politecnica delle Marche, Ancona, Italy E. Longhi Scuola di Medicina e Chirurgia, Alma Mater Studiorum, Università degli Studi di Bologna, Bologna, Italy # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 M. K. Dwivedi et al. (eds.), Role of Microorganisms in Pathogenesis and Management of Autoimmune Diseases, https://doi.org/10.1007/978-981-19-1946-6_24

639

640

M. G. Danieli et al.

myalgia, muscle weakness and increased serum Ck levels are common during COVID-19 infection, it is difficult to distinguish simple muscle damage secondary to infection or an autoimmune SARS-CoV-2-triggered myositis with consequent diagnostic and therapeutic delay. In view of the growing importance of microbiome’s involvement in autoimmune disorders, we tried to find any possible link between its alterations and the development of NAM or IBM, but, so far, literature is very scant. To better understand the pathogenesis and to offer new therapeutic options, further research on this subject is needed. Keywords

Necrotizing autoimmune myopathy · Inclusion body myositis · Microbes · Microorganisms · Virus · SARS-CoV-2 · Microbiome

24.1

Introduction: Necrotising Autoimmune Myopathy

Among the idiopathic inflammatory myopathies (IIM), it is possible to distinguish the necrotising autoimmune myopathy (NAM), also known as immune-mediated necrotising myopathy (IMNM), characterized by muscle fibre necrosis in the absence of prominent inflammatory infiltrate (Watanabe et al. 2016). Muscle biopsy allowed to categorized patients as having NAM, but nowadays autoantibodies play a crucial role as disease subtype markers, defining homogeneous subsets of patients (Pinal-Fernandez et al. 2018). The most recent European Neuromuscular Centre criteria for IMNM divide this syndrome into three subgroups: myopathy characterized by the presence of antibodies targeting the signal recognition particle (SRP), myopathy with antibodies directed against hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and autoantibody-negative IMNM (Allenbach et al. 2018b). Clinically, patients report myalgia, muscle weakness that predominantly involves proximal lower limbs, and concomitant dysphagia is occasionally observed. Extramuscular involvement is rare when present myocarditis or lung disease can be detected. The clinical features associated with both elevated serum creatine kinase levels (CK, a marker of muscle damage) and the finding of anti-HMGCR or antiSRP autoantibodies consent to diagnose IMNM without muscle biopsy, which remains necessary when one of the latter is doubtful or unclear (Allenbach et al. 2020). Specifically, compared with anti-HMGCR+, anti-SRP+ patients display more severe weakness, a higher number of necrotic myofibres and more frequent dysphagia, respiratory insufficiency and muscle atrophy (Allenbach et al. 2018a; Watanabe et al. 2016).

24.1.1 Causes, Associations and Pathogenesis Like many other chronic immunological conditions, IMNM is a consequence of specific interactions between genetic and environmental risk factors.

24

Microorganisms in Pathogenesis and Management of Necrotising. . .

641

24.1.1.1 The Role of Genetics Genetic risk factors regulating immune responses against environmental agents have been suggested. It has been observed that certain HLA gene polymorphism represents predisposing conditions for IIM (Rothwell et al. 2019). Regarding IMNM, the HLA allele DRB1*11:01 has been associated with anti-HMGCR+ IIM in adults, whereas DRB1*07:01 is linked with the same antibodies in children. It has been described an association between SRP positivity and HLA-C*07:01, HLA-B*08:01 and HLA-DRB1*08:03 (Day and Limaye 2019).

24.1.1.2 Autoantibodies If on one hand the pathogenesis of seronegative IMNM is still unclear, on the other, anti-HMGCR and anti-SRP autoantibodies seem to play a role. First, in seropositive IMNM, the antibody titre correlates with disease activity. Second, the presence of sarcolemmal complement deposits and the signs of classical pathway activation suggest that muscle fibre necrosis is antibody- and complement-dependent. Third, in vitro experiment has showed a pathogenic role of anti-SRP and anti-HMGCR antibodies (Allenbach et al. 2020). Both, SRP and HMGCR antibodies, are against ubiquitous and non-musclespecific antigens localized in the endoplasmic reticulum of every cell, so an obvious question comes to mind about their specific pathogenic role in muscle autoimmune disease (Dalakas 2020). Therefore, to become pathogenic, these antibodies need to penetrate the cell membrane and reach their targets, but growing evidence suggests that SRP and HMGCR are ectopically present at the surface of muscle fibres where they can be easily targeted. As a result of this binding (Fig. 24.1), the classical complement pathway is activated, the membrane attack complex is formed, and necrosis occurs. Recruitment of macrophages leads to myophagocytosis (antibody-dependent-cellmediated cytotoxicity) and to the release of pro-inflammatory cytokines such as IL-1, IL-6 and TNF which contributes to the damage. Normal muscle regeneration occurs by activation of resident satellite cells (myoblasts) that are programmed to fuse into mature myofibres. Autoantibody-mediated impairment of myoblast differentiation influences muscle regeneration, and in addition, their binding with autoantigens triggers non-immune mechanisms that lead to muscle damage and atrophy(Allenbach et al. 2020).

Histopathological Feature IMNM is characterized by different stages of scattered myonecrosis, myophagocytosis and muscle fibre regeneration, indicating temporal evolution. There is a relative paucity of lymphocytic infiltration, where macrophages are the predominant mononuclear cell type, whereas T and B cells are very scant. Non-specific elements, such as focal tissue sclerosis, muscle fibre size variation and nuclear centralization, can be observed (Andalib et al. 2021).

642

M. G. Danieli et al.

Fig. 24.1 Proposed pathogenesis of seropositive IMNM (from Allenbach et al. 2020, modified)

24.1.1.3 Microorganisms and Microbiome in NAM Infectious agents have been described as possible protagonists in the pathogenesis of IMNM/NAM; however, literature is very scant about that. Among microbes, viruses are likely to play the main role. In this regard, a seasonal pattern for the development of anti-SRP myopathy has been observed, with a peak during the month of November, suggesting that the production of antiSRP autoantibodies may be triggered by upper respiratory viral infections, notoriously more frequent during winter cold periods; furthermore, patients often report an acute “viral” illness before muscle weakness (Leff et al. 1991). Both, the 54-kDa subunits of SRP and the HMGCR protein, share regions of homology with proteins of the varicella zoster virus and the human papillomavirus type 58, respectively; this similarity may lead to molecular mimicry, a probable mechanism for the generation of an immune response (Pinal-Fernandez et al. 2018). An ample study described possible NAM in 5 out of 33 HIV positive patients; no myotoxic factor was identified, and nobody received zidovudine (AZT) treatment, known to have a toxic effect on the muscle fibres (Lane et al. 1993). Another case of AIDS-associated necrotizing myopathy was histologically documented in a patient with a several-month history of brief muscle cramps and tenderness in the calves: the symptoms and high CK levels resolved without treatment (Snider et al. 1983). In literature there have been described 13 cases of HCV-associated myopathy. HCV-RNA was not detected by PCR analysis of the muscle tissue, suggesting that

24

Microorganisms in Pathogenesis and Management of Necrotising. . .

643

myopathy was more probably due to an immune process, rather than direct infection and active replication of HCV in the muscle. This necrotizing myopathy successful responded to interferon therapy (Satoh et al. 2000). Currently, the human microbiome is worth considering. Microbiome is the whole of microorganisms which live in human body, establishing with it a mutualistic relationship which benefits both sides. These microbes are in different sites of our body: the vast majority is in the gut, but they can be also found in the skin, lungs, urinary tract, female reproductive system and sperm. A growing number of evidence have supported the tight link between altered microbiota composition and the onset of several different autoimmune disorders. In fact, gut microbiota exerts a modulating effect on immune system maturation. On one hand it stimulates the immune system, strengthening its protective action, and on the other hand, it induces tolerance, essential for the enormous number of exogenous antigens entering the gastrointestinal tract every day. An altered microbiota composition influences the gut immune system, including defective tolerance to food antigens, intestinal inflammation and enhanced gut permeability (Gianchecchi and Fierabracci 2019). Microbiota may provide cross-reactive antigenic material that activates autoreactive lymphocytes within the gut environment. Then, dysbiosis may result in an uncontrolled immune response against resident gut microbes. This leads to chronic and relapsing inflammation in the GI tract known as inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis (Zárate-Bladés et al. 2016). In view of the huge diversity of commensals, it is conceivable that they may provide surrogate antigens triggering autoreactive lymphocytes of other tissues resulting in inflammatory/autoimmune diseases in those districts (Zárate-Bladés et al. 2016). Beside inflammatory bowel diseases, other examples of autoimmune disease relating to an altered microbiota composition are rheumatoid arthritis, systemic lupus erythematosus, Behcet’s disease, vitiligo, psoriasis, atopic dermatitis, multiple sclerosis and type 1 diabetes (Talotta et al. 2017; Gianchecchi and Fierabracci 2019). Aware of this evidence, new therapeutic options for autoimmune diseases seem to be available in the next future. Faecal transplantation or special dietary approaches represent two alternatives able to remodulate the altered microbiome and to rebalance the immune dysregulation. To our knowledge, there is no evidence about a possible link between microbiome alterations and development of idiopathic inflammatory myopathies or IMNM/NAM.

24.1.1.4 Statins Muscular toxicity is a common side effect of statin therapy, whose severity can range considerably. Even if in most cases myotoxicity is self-limiting, a form of statin-associated necrotic myopathy that persisted, and often progressed, after stopping the drug was described in 2007 (Needham et al. 2007). From these observations it was possible to assume that statins might initiate an immune-mediated myopathy which persisted

644

M. G. Danieli et al.

after the withdrawal of the medicament. At a later time, the discovery of antiHMGCR autoantibodies confirmed this hypothesis (Christopher-Stine et al. 2010). The possible explanation is that the increased level of HMGCR due to statins results in aberrant processing by antigen-presenting cells (APC) and in the subsequent production of cryptic epitopes which may induce an autoimmune response. In addition, not only the absolute HMGCR quantity but also other factors (e.g. conformational changes, genomic sequence variants, etc.) can increase HMGCR-derived peptides’ immunogenicity. Finally, it is possible that certain peptides derived from HMGCR protein are significantly more immunogenic when presented in the context of risk factor HLA alleles (i.e. HLA-DRB1*11:01 and 07: 01) (Mohassel and Mammen 2018). The evidence that most patients develop IMNM after years on these drugs suggests that other factors are required to trigger the immune attack on muscle: intercurrent illness, switching statins, increasing the prescribed dose, an inadvertent increase in plasma concentration of statins through co-prescription of CYP3A4 inhibitors or renal failure or some other physical or environmental factors (Day and Limaye 2019).

24.1.1.5 Association with Cancer The association between malignancy and IIM, in particular DM, has been widely studied for many years (Di Rollo et al. 2014). Although cancer-associated myositis is typically defined as malignancy arising within 3 years of IIM diagnosis, most neoplasms in IMNM patients are detected within 1 year of myopathy, and the risk of cancer may also depend on autoantibody status (Day and Limaye 2019). Concomitant cancer has been mainly documented in seronegative patients. In antiHMGCR+ IMNM the risk has been described as mildly increased, whereas the risk appeared not augmented in anti-SRP+ patients (Allensbach et al. 2016; Kadoya et al. 2016). This suggest that routine cancer screening should be recommended in seronegative IMNM and in anti-HMGCR+ patients (Allenbach et al. 2018b).

Immune Checkpoint Inhibitors (ICPIs) An increasing number of patients treated with ICPIs can develop immune-related complications. Usually, tumour cells express on their surface inhibitory ligands (PD-L1/PD-L2 and B7-1/B7-2), which bind PD-1 and CTLA-4 on T cells, downregulating T-cell responses. The ICPIs prevent the CTLA-4 or PD-1 from binding to their respective receptors and, by doing so, inhibit the inhibitory stimulation between T cells and tumour cells resulting in positive signal. In conclusion, T cells can kill the malignant cells, but at the same time, there is an uncontrolled activation of immune cells that disrupts immune tolerance and facilitates the onset of immune-related events against muscle (especially DM and NAM) (Dalakas 2020).

24

Microorganisms in Pathogenesis and Management of Necrotising. . .

24.2

645

SARS-CoV-2 Infection and NAM

The ongoing coronavirus disease 2019 (COVID-19) is characterized by the occurrence of respiratory and/or gastrointestinal manifestations. In addition, neurological manifestation, with both peripheral and central nervous system symptoms, is being increasingly registered (Reggio et al. 2021). Musculoskeletal involvement is common, ranging from mild muscle weakness to rhabdomyolysis. Myalgia is experienced by 30–60% of patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Myalgia and increased levels of creatine kinase (CK) were found to be more pronounced in patients with critical illness needing intensive care support than individuals with mild form (Aschman et al. 2021). In general, the pathophysiology of viral-associated myositis seems to rely on different protagonists. Virus-antibody complexes can activate the classical complement pathway with subsequent muscle damage, viral toxins can be responsible of a direct harm, but also T-cell- or macrophage-mediated injury can be found on muscle biopsy (Veyseh et al. 2021). It has been hypothesized that the interaction between SARS-CoV-2 and its receptor angiotensin-converting enzyme 2 (ACE-2) may be implicated, supported by the apparent expression of the receptor on skeletal muscle (Pitscheider et al. 2020). Nevertheless, a recent study did not find ACE-2 and accessory proteases (TMPRSS2 and CTSL) expressed in skeletal muscle tissue (Muus et al. 2021). Currently, there is only limited literature regarding NAM triggered by COVID19. Veyseh et al. (2021) presented a case report of a 57-year-old woman with SARSCoV-2 IgG who presented, a month later the initial infection, rhabdomyolysis and a gradual progression to myositis. The muscle biopsy revealed scattered necrotic myofibres with minimal inflammatory cell infiltrate, suggestive of NAM. ANA serology was positive, but antibodies against Jo-1, HMGCR and SRP were not found, weakening the hypothesis of an entirely idiopathic autoimmune phenomenon. This case calls attention to musculoskeletal autoimmune processes triggered by COVID-19, which requires clinical suspicion and early initiation of treatment. Dalakas (2020) published other two cases of COVID-19-triggered NAM. The first was an 88-year-old man, COVID-19 positive, who moaned bilateral thigh weakness and raised CK levels (13,581 U/l). The other was a 60-year-old man who developed, 7 days later the onset of COVID-19 respiratory symptoms, painful muscle weakness and high CK levels, even though he systemically improved. Through intravenous immunoglobulin (IVIg) therapy, his strength got better while becoming COVID-19 negative. HyperCKemia and painful muscle involvement have been seen in almost 10% of patients with SARS-CoV-2 infection, and, therefore, it is possible that autoimmune myopathy has been disregarded. However the diagnosis of COVID-19 NAM requires muscle biopsy and antibody screening because myopathic symptoms in a severe systemic viral disease are multifactorial. Another remarkable point regards the outcome of patients with IIMs who contract COVID-19 while receiving immunosuppressive medicaments. Bolig et al. (2020) described the case of a 54-year-old man with a history of NAM (successfully

646

M. G. Danieli et al.

controlled through mycophenolate mofetil and IVIg) and obesity who developed classical symptoms of SARS-CoV-2 infection (fever, cough, chills and myalgia). At the onset of these symptoms, he was instructed to stop his immunosuppressive therapy. He resumed mycophenolate mofetil (MMF) and monthly infusions of IVIg respectively 6 and 8 weeks since first symptoms, and as expected from this withdrawal, his IMNM flared. A COVID-19-triggered myositis could have explained this flare, but it would have been a delayed manifestation of an otherwise unremarkable COVID-19 course. That is the reason why the suspension of MMF and IVIg seemed the most likely cause supporting the current discussion that immunosuppression could be continued during selected COVID-19 infection. The American College of Rheumatology COVID-19 guidelines suggest restarting disease-modifying antirheumatic drugs (DMARDs) within 7–14 days from resolution of symptoms or 10 17 days from a positive SARS-CoV2 RT-PCR test (Mikuls et al. 2020). However, this case is a reminder that there is much to be studied and learnt regarding prognosis and management of patients with connective tissue disease who develop SARS-CoV-2 infection.

24.3

Introduction: Inclusion Body Myositis (IBM)

24.3.1 General Clinical Features and Pathogenesis Inclusion body myositis (IBM) is the most common idiopathic inflammatory myopathy (IIM) in patients older than 50. In this chapter we refer to sporadic IBM, not to be confused with hereditary inclusion body myopathies characterized by distinct clinical and pathological features. The main clinical manifestations that distinguish IBM from other myopathies are distal and asymmetric muscle weakness (wrist or finger flexors and foot extensors in addition to quadriceps), slow and insidious clinical course with a high prevalence of dysphagia and possible progression to muscle atrophy already from the onset of the disease (Panginikkod and Musa 2021). As with most autoimmune diseases, the aetiopathogenesis of IBM is not yet completely understood; however the disease is sustained by both inflammation and muscle degeneration. Inflammatory pathway is well characterized by histological findings: non-necrotic muscle fibres are invaded by cytotoxic CD8+ T cells with macrophages and are surrounded by CD4+ T cells and macrophages (Greenberg 2020). Moreover, the presence of large amounts of antigen-presenting cells (APCs) near T cells confirms that it is an antigen-driven response. Also, humoral response seems to play a fundamental role after the identification of cN1A antibodies, as described below. Other significant features are major histocompatibility complex (MHC)-I upregulation and 15–18-nm tubulofilaments identified by electron microscopy. Degeneration is supported by the presence of rimmed vacuoles in muscle fibres, abnormal protein processes, deposition of congophilic polymers (such as amyloid-β

24

Microorganisms in Pathogenesis and Management of Necrotising. . .

647

peptides, ubiquitin, phosphorylated tau, TDP-43 and prion protein) and mitochondrial disorders (Naddaf et al. 2018). It is still debated whether IBM is primarily an immune-inflammatory disease leading to muscle degeneration or a degenerative disease resulting in muscle inflammation. From recent evidence, it seems that the inflammation is the main driver as suggested by T-cell response and the association with HLA genes, cN1A antibodies and other autoimmune diseases, like Sjögren’s syndrome and systemic lupus erythematous (SLE).

24.3.2 Role of Genetics In IBM the main relevant predisposing genetic factors seem to be related with HLA-DRB1 molecule: HLA-DRB1*03:01, DRB1*01:01 and DRB1*13:01 alleles were found to be most implicated (Rothwell et al. 2013). In contrast to previous studies, Rothwell et al. (2013) demonstrated that there was not a significant correlation between these alleles and age of onset or disease severity. CCR5 is a protein on leukocyte membrane that acts as a receptor for chemokines, attracting T lymphocytes to specific tissues and organs; in IBM it was demonstrated an upregulation of CCR5 expressed on monocytes, macrophages and T cells in muscle tissue (Rothwell et al. 2017).

24.3.3 Autoantibodies The only antibody that appears to correlate with IBM is directed against 5'-cytosolic nucleotidase1A (cN1A), an enzyme that is found in large quantities in muscles where it catalyses the dephosphorylation of adenosine monophosphate (AMP), which is thus converted into adenosine and phosphate. Anti-cN1A antibodies have high specificity (87–100%) but low sensitivity (33–76%), and they can be detected also in other inflammatory myopathies or autoimmune diseases (specially in systemic lupus erythematosus and Sjögren’s syndrome) (Mavroudis et al. 2021). In their cohort of 62 IBM patients, Lucchini et al. (2021) recently demonstrated that the presence of anti-cN1A antibodies did not influence the age of onset of the disease or its duration. Rather, anti-cN1A positivity seems to correlate with the presence of swallowing disorders, and more severe dysphagia may be related to significant bulbar involvement in these patients. Other studies found out higher mortality due to pneumological complications or development of IBM in older age in patients with anti-cN1A antibodies, but these data have not been further confirmed. The high specificity of anti-cN1A antibodies supports IBM diagnosis in certain cases, for instance, when a muscle biopsy cannot be performed or when there are some IBM clinical features but histological findings on biopsy are not specific. On the contrary, when IBM diagnosis is well defined, anti-cN1A positivity does not add significant clinical or pathological information.

648

M. G. Danieli et al.

24.3.4 Environmental Factors Since IBM is most common after the age of 50, cellular ageing may contribute to disease development by supporting aggregation of abnormal proteins, reducing degradation rate of these proteins and developing mitochondrial abnormalities and oxidative stress (Askanas and Engel 2003). IBM pathogenesis results from the interaction between genetic susceptibility and environmental exposure, as we already know for other similar immune diseases (Prieto and Grau 2010). The prevalence (4.5–9.5 cases/million population, males vs females 3:1) varies depending on geographic area, ethnicity and age, even if some of these variations may be caused by diagnostic and reporting bias. The main environmental factors are infections, exposure to UV rays, toxins and drugs, and all of them can trigger IBM or its exacerbations. A significant environmental agent is exposure to UV rays: Parks et al. (2020) demonstrated that sunburn was more common in younger white patients regardless of IIM phenotype, even if history of sunburn in the year prior to diagnosis was more frequent in DM compared with PM/IBM (42% vs 28%). Cigarette smoking and prior exposure to environmental toxins (such as asbestos, silica, fibreglass, solvents or coal dust) were observed frequently in IBM patients (Lilleker et al. 2018).

24.3.5 Association Between IBM and Autoimmune Diseases IBM is rarely reported in association with autoimmune diseases, above all with primary Sjögren’s syndrome (pSS). Chung et al. (2021) described eight patients affected by both IBM and pSS in their cohort, while two IBM patients had SSA antibody without fully satisfying diagnostic criteria for pSS (