Translational Autoimmunity, Volume 4: Autoimmune Diseases in Different Organs 0128244666, 9780128244661

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Translational Immunology TRANSLATIONAL AUTOIMMUNITY, VOL. 4

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Translational Immunology

TRANSLATIONAL AUTOIMMUNITY, VOL. 4 Autoimmune Diseases in Different Organs Edited by

Nima Rezaei

Professor, Department of Immunology, School of Medicine; Head, Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences; Founding President, Universal Scientific Education and Research Network (USERN), Tehran, Iran Editorial Assistant

Niloufar Yazdanpanah

Managing Director, Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN); and School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2022 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-12-824466-1 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisitions Editor: Linda Versteeg-Buschman Editorial Project Manager: Matthew Mapes Production Project Manager: Omer Mukthar Cover Designer: Christian J. Bilbow Typeset by STRAIVE, India

Dedication This book would not have been possible without the continuous encouragement from my family. I dedicate this book to my daughters, Ariana and Arnika, with the hope that we learn enough from today to make a brighter future for the next generation.

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Contents Contributors xi Preface xv Series editor biography  xvii Acknowledgment xix Abbreviations xxi

4 Autoimmune polyendocrine syndrome type 3 (APS-3) 28 5 IPEX syndrome  33 6 Conclusion  34 References 34

3.  Autoimmune thyroid diseases: Peculiarities in pediatric age

1.  Autoimmune diseases in different organs

Giorgia Pepe, Angelo Tropeano, Celeste Casto, Alessandra Li Pomi, and Malgorzata Wasniewska

Nima Rezaei and Niloufar Yazdanpanah

1 2 3 4 5 6 7

Introduction  39 Epidemiology  40 Pathogenesis  41 Thyroid function patterns at presentation  44 Clinical manifestations  45 Diagnosis  48 Thyroid function patterns of evolution over time 50 8 Therapy and management  52 9 Newborn of mother with autoimmune thyroid disease 56 10 Autoimmune thyroid diseases in genetic syndromes 59 11 Conclusion  62 References 62

1 Introduction  1 2 Autoimmune complications of the cardiovascular system 2 3 Autoimmune complications of the respiratory system 4 4 Autoimmune complications of the endocrine system 4 5 Autoimmune complications of the gastrointestinal system  7 6 Autoimmune complications of the hematological system 8 7 Autoimmune complications of the musculoskeletal system  8 8 Autoimmune complications of the nervous system 9 9 Autoimmune complications of the integumentary system 10 10 Conclusion  11 References 11

4.  TSH receptor autoantibodies in Graves’ disease Renato Tozzoli and Nicola Bizzaro

1 2 3 4 5 6

Introduction  69 Basedow-Graves’ disease: Clinical aspects  70 Graves’ orbitopathy and myxedema  71 Immunopathogenesis of Graves’ disease  72 Autoantibodies to the TSH receptor  73 Detection and measurement of autoantibodies to TSHR 74 7 Standardization of TRAb measurement  77 8 Use of TRAb in the management of Graves’ disease 77 9 Therapy of Graves’ disease  78

2.  Autoimmune polyendocrinopathies in pediatric age Domenico Corica, Mariella Valenzise, Carmen Bonanno, Tommaso Aversa, and Malgorzata Wasniewska

1 Introduction  16 2 Autoimmune polyendocrine syndrome type 1 (APS-1)  17 3 Autoimmune polyendocrine syndrome type 2 (APS-2) 26



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viii Contents 10 Conclusion  79 References 79

5.  The heterogeneity of type 1 diabetes: From immunopathology to immune intervention Marco Infante, Rodolfo Alejandro, Andrea Fabbri, and Camillo Ricordi

1 Introduction  84 2 Heterogeneity of type 1 diabetes  85 3 The novel concept of T1D endotypes  87 4 Heterogeneity of autoimmune responses and pancreas histopathology in T1D  90 5 The multifaceted pathophysiology of T1D: Beyond insulin, beta cells, and endocrine pancreas 93 6 The heterogeneous response to immunotherapies in T1D  96 7 Conclusion  97 References 98

6.  Pathophysiology of autoimmune orbital diseases and target therapy for orbital inflammatory and neoplastic diseases

8.  Etiology and pathogenesis of auditory and vestibular dysfunction in patients with autoimmune disorders Arianna Di Stadio, Massimo Ralli, Michael J. Brenner, and Antonio Greco

1 Introduction  139 2 Etiopathogenesis  142 3 Auditory and vestibular symptoms  142 4 Ear symptoms and systemic autoimmune disorders 143 5 Temporal bone aspects (inner and middle ear) 151 6 Conclusion  161 References 161

9.  Autoimmune heart disease Danielle J. Beetler, Katelyn A. Bruno, and DeLisa Fairweather

1 Introduction  167 2 Background  169 3 Organ-specific autoimmunity  171 4 Secondary antibody-mediated autoimmune heart disease 177 5 Conclusion  181 References 181

10.  Autoimmunity and its correlation to inflammatory vascular diseases

Farzad Pakdel, Timothy J. Sullivan, and Niloofar Pirmarzdashti

1 Introduction  106 2 Thyroid eye disease  106 3 Idiopathic orbital inflammatory disease (IOIS) 113 4 Oculofacial malignancies  114 5 Conclusion  117 References 117

7.  Autoimmune uveitis in childhood

Callum Howard, Jonathan Sheridan, Leonardo Picca, Wahaj Munir, Nehman Meharban, Prassana Karthik, Mohammed Idhrees, Emmanuel Keddy Momoh, and Mohammad Bashir

1 Introduction  190 2 Vasculitis  190 3 Conclusion  219 References 220

Ilaria Maccora, Edoardo Marrani, Maria Vincenza Mastrolia, Ilaria Pagnini, and Gabriele Simonini

1 Introduction  121 2 Juvenile idiopathic arthritis-associated uveitis 123 3 Diagnosis  124 4 Complications  126 5 Treatment  126 6 Conclusion  131 References 131

11.  Cryoglobulinemic vasculitis Mohamed A. Hussein, Mohamed Tharwat Hegazy, Ahmed Fayed, Luca Quartuccio, and Gaafar Ragab

1 2 3 4 5 6

Introduction  230 Historical background  230 Etiology and epidemiology  231 Pathogenesis  231 Clinical presentations  234 Risk of malignancy  236



7 VII: The differential diagnosis  237 8 Diagnosis  237 9 Classification criteria  241 10 Treatment  242 11 Conclusion  244 References 245

12.  Immunopathogenesis of acute disseminated encephalomyelitis Nusrat Ahsan and Jonathan D. Santoro

1 Introduction  249 2 Definition and diagnosis  251 3 Origins and etiologies  251 4 Immunopathogenesis  252 5 Clinical features  254 6 Neurodiagnostic features  255 7 Treatment and prognosis  256 8 ADEM as a herald for relapsing neuroinflammatory disorders  256 9 Conclusion  258 References 259

13.  Pulmonary manifestations of autoimmune diseases Tess Moore Calcagno and Mehdi Mirsaeidi

1 Introduction  265 2 Endocrine  269 3 Systemic inflammatory diseases  270 4 Connective tissue/musculoskeletal/ integumentary 275 5 Vascular  278 6 Nervous system  280 7 Gastrointestinal  285 8 Other diseases  287 9 Conclusion  287 References 288

14.  Inflammatory bowel diseases: Sex differences and beyond Alessandra Soriano, Marco Soriano, Marina Beltrami, Francesca Sanguedolce, Andrea Palicelli, Maurizio Zizzo, Stefano Ascani, Magda Zanelli, and Theresa T. Pizarro

1 Introduction  296 2 Sexual dimorphism in IBDs: Not as “nuanced” as it seems  297

Contents   ix

3 Gut microbiome in IBD: Where do we stand?  299 4 Sexual dimorphism in the gut microbiome 301 5 Impact of the gut microbiome on sexual dimorphism in IBDs: Future perspectives and applications, from bench to bedside 303 6 Conclusion  304 References 305

15.  Autoimmunity of the liver Angelo Armandi, Giovanni Clemente Actis, and Davide Giuseppe Ribaldone

1 Introduction  309 2 Pathogenesis  311 3 Pathophysiology  315 4 Diagnosis  317 5 Therapy  322 6 Conclusion  325 References 325

16.  Advances in autoimmune cutaneous diseases Silvia Angélica Carmona-Cruz and María Teresa García-Romero

1 Introduction  333 2 Morphea or localized scleroderma  334 3 Dermatomyositis  344 4 Cutaneous lupus erythematosus  355 5 Conclusion  368 References 368

17.  Pathogenesis-based treatments in bullous pemphigoid Andrés Tirado-Sánchez and Alexandro Bonifaz

1 Introduction  374 2 Epidemiology  374 3 Pathogenesis  375 4 Clinical manifestations  378 5 Diagnosis  378 6 Differential diagnosis  378 7 Treatment  379 8 Conclusion  384 References 384

x Contents 18.  Autoinflammatory disorders Mahnaz Jamee and Nima Rezaei

1 Introduction  390 2 Familial Mediterranean fever (FMF)  390 3 Mevalonate kinase deficiency (hyper IgD syndrome)  392 4 Cryopyrin-associated periodic syndrome (CAPS) 393 5 NLRP1-associated autoinflammatory diseases  394 6 TNF receptor-associated periodic syndrome (TRAPS) 395 7 Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, hyperzincemia, and hypercalprotectinemia 396 8 Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)  397 9 Deficiency of the interleukin 1 receptor antagonist (DIRA)  398 10 Cherubism  398 11 Blau syndrome  400 12 CARD14-mediated psoriasis (CAMPS)  401

13 Deficiency of the IL-36 receptor antagonist (DITRA) 401 14 ADAM17 deficiency  402 15 SLC29A3 mutation  403 16 COPA defect  404 17 Otulipenia/ORAS  405 18 AP1S3 deficiency  406 19 A20 deficiency  406 20 ADA2 deficiency  407 21 Aicardi-Goutières syndrome (AGS)  408 22 Spondyloenchondrodysplasia with immune dysregulation (SPENCD)  409 23 STING-associated vasculopathy with onset in infancy (SAVI)  410 24 X-linked reticulate pigmentary disorder  411 25 USP18 deficiency  411 26 Chronic atypical neutrophilic dermatitis with lipodystrophy (CANDLE)  412 27 Singleton-Merten syndrome  413 28 Conclusion  416 References 416

Index 423

Contributors Giovanni Clemente Actis  The Medical Center Practice Office, Turin, Italy

Michael J. Brenner  Department of Otolaryngology-­ Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI, United States

Nusrat Ahsan  Division of Neurology, Department of Pediatrics, Children’s Hospital Los Angeles; Department of Neurology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, United States

Katelyn A. Bruno  Center for Clinical and Translational Science; Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, United States

Rodolfo Alejandro  Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States

Tess Moore Calcagno  Department of Medicine, University of Miami, Miami, FL, United States Silvia Angélica Carmona-Cruz  Department of Dermatology, National Institute of Pediatrics, Mexico City, Mexico

Angelo Armandi  Department of Medical Sciences, Division of Gastroenterology, University of Turin, Turin, Italy

Celeste Casto  Department of Adult and Childhood Human Pathology “Gaetano Barresi”, University of Messina, Messina, Italy

Stefano Ascani Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, Terni, Italy

Domenico Corica  Department of Adult and Childhood Human Pathology “Gaetano Barresi”, University of Messina, Messina, Italy

Tommaso Aversa  Department of Adult and Childhood Human Pathology “Gaetano Barresi”, University of Messina, Messina, Italy Mohammad Bashir  NHS Wales Health Education and Improvement, Vascular and Endovascular Surgery, United Kingdom Danielle J. Beetler  Center for Clinical and Translational Science, Mayo Clinic, Jacksonville, FL, United States

Arianna Di Stadio  Unit of Otolaryngology, Department of General Surgery and MedicalSurgical Specialties, University of Catania, Catania, Italy; Neuroinflammation Laboratory, University College of London, London, United Kingdom

Marina Beltrami Department of Internal Medicine, Gastroenterology Division and IBD Center, Azienda Unità Sanitaria Locale – IRCCS, Reggio Emilia, Italy

Andrea Fabbri  Department of Systems Medicine, Diabetes Research Institute Federation (DRIF), University of Rome Tor Vergata, Rome, Italy

Nicola Bizzaro  Laboratorio di Patologia Clinica, Ospedale San Antonio, Tolmezzo; Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy

DeLisa Fairweather  Center for Clinical and Translational Science; Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, United States

Carmen Bonanno IRCCS Centro Neurolesi Bonino Pulejo, Messina, Italy

Ahmed Fayed  Nephrology Unit, Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt

Alexandro Bonifaz  Dermatology Department, Hospital General de México, Mexico City, Mexico



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Contributors

María Teresa García-Romero  Department of Dermatology, National Institute of Pediatrics, Mexico City, Mexico

Maria Vincenza Mastrolia  Rheumatology Unit, Anna Meyer Children’s University Hospital, University of Florence, Florence, Italy

Antonio Greco  Department of Sense Organs, Sapienza University of Rome, Italy

Nehman Meharban  Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom

Mohamed Tharwat Hegazy Rheumatology and Clinical Immunology Unit, Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo; Rheumatology and Clinical Immunology Unit, Internal Medicine Department, Faculty of Medicine, Newgiza University (NGU), Giza, Egypt Callum Howard  Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom Mohamed A. Hussein Rheumatology and Clinical Immunology Unit, Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt Mohammed Idhrees  Institute of Cardiac and Aortic Disorders (ICAD), SRM Institutes for Medical Science (SIMS Hospital), Chennai, India Marco Infante  Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States; Department of Systems Medicine, Diabetes Research Institute Federation (DRIF), University of Rome Tor Vergata; UniCamillus, Saint Camillus International University of Health Sciences; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Rome, Italy Mahnaz Jamee  Pediatric Infections Research Center; Pediatric Nephrology Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran Prassana Karthik  Department of General Medicine, Saveetha Medical College Hospital, Chennai, India Ilaria Maccora Rheumatology Unit, Anna Meyer Children’s University Hospital, University of Florence, Florence, Italy Edoardo Marrani  Rheumatology Unit, Anna Meyer Children’s University Hospital, University of Florence, Florence, Italy

Mehdi Mirsaeidi  Division of Pulmonary, Critical Care and Sleep, College of Medicine-­ Jacksonville, University of Florida, Florida, FL, United States Emmanuel Keddy Momoh  Health Education England, West Midlands Deanery, Birmingham, United Kingdom Wahaj Munir  Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom Ilaria Pagnini  Rheumatology Unit, Anna Meyer Children’s University Hospital, University of Florence, Florence, Italy Farzad Pakdel Department of Ophthalmic Plastic & Reconstructive Surgery, Farabi Hospital, Tehran University of Medical Sci­ ences, Tehran, Iran Andrea Palicelli Pathology Unit, Azienda Unità Sanitaria Locale – IRCCS, Reggio Emilia, Italy Giorgia Pepe  Department of Adult and Childhood Human Pathology “Gaetano Barresi”; Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Messina, Italy Leonardo Picca  Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom Niloofar Pirmarzdashti  Pediatric Cell and Gene Therapy Research Center, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran Theresa T. Pizarro  Pathology Department, Case Western Reserve University, Cleveland, OH, United States Alessandra Li Pomi  Department of Adult and Childhood Human Pathology “Gaetano Barresi”, University of Messina, Messina, Italy



Contributors

Luca Quartuccio Clinic of Rheumatology, Department of Medical Area (DAME), University Hospital “Santa Maria della Misericordia”, University of Udine, Udine, Italy Gaafar Ragab Rheumatology and Clinical Immunology Unit, Internal Medicine ­Department, Faculty of Medicine, Cairo University, Cairo; Rheumatology and Clinical Immunology Unit, Internal Medicine Department, Faculty of Medicine, Newgiza University (NGU), Giza, Egypt Massimo Ralli  Department of Sense Organs, Sapienza University of Rome, Italy Nima Rezaei Research Center for Immunodeficiencies, Children’s Medical Center; Department of Immunology, School of Medicine, Tehran University of Medical Sciences; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

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Alessandra Soriano  Department of Internal Medicine, Gastroenterology Division and IBD Center, Azienda Unità Sanitaria Locale – IRCCS, Reggio Emilia, Italy; Pathology Department, Case Western Reserve University, Cleveland, OH, United States Marco Soriano  ‘Luigi Vanvitelli’ University and School of Medicine, Naples, Italy Timothy J. Sullivan  Royal Brisbane Clinical Unit, Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, QLD, Australia Andrés Tirado-Sánchez  Dermatology Department, Hospital General de México; Internal Medicine Department, Hospital General de Zona 30, Instituto Mexicano del Seguro Social, Mexico City, Mexico Renato Tozzoli  Laboratorio di Chimica Clinica ed Ematologia, Ospedale Villa Salus, Venezia, Unità di Endocrinologia, Casa di Cura San Giorgio, Pordenone, Italy

Davide Giuseppe Ribaldone  Department of Medical Sciences, Division of Gastroenterology, University of Turin, Turin, Italy

Angelo Tropeano  Department of Adult and Childhood Human Pathology “Gaetano Barresi”, University of Messina, Messina, Italy

Camillo Ricordi  Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL, United States

Mariella Valenzise  Department of Adult and Childhood Human Pathology “Gaetano Barresi”, University of Messina, Messina, Italy

Francesca Sanguedolce  Pathology Unit Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Foggia, Foggia, Italy Jonathan D. Santoro  Division of Neurology, Department of Pediatrics, Children’s Hospital Los Angeles; Department of Neurology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, United States Jonathan Sheridan  Academic Unit of Medical Education, The University of Sheffield, Sheffield, United Kingdom Gabriele Simonini  Rheumatology Unit, Anna Meyer Children’s University Hospital; NEUROFARBA Department, University of Florence, Florence, Italy

Malgorzata Wasniewska  Department of Adult and Childhood Human Pathology “Gaetano Barresi”, University of Messina, Messina, Italy Niloufar Yazdanpanah  Research Center for Immunodeficiencies, Children’s Medical Center; School of Medicine, Tehran University of Medical Sciences; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran Magda Zanelli  Pathology Unit, Azienda Unità Sanitaria Locale – IRCCS, Reggio Emilia, Italy Maurizio Zizzo  Surgical Oncology Unit, Azienda Unità Sanitaria Locale – IRCCS, Reggio Emilia, Italy

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Preface

The scientific world has witnessed remarkable developments in the field of immunology during recent decades. The novel discovery of genes related to different immune-mediated diseases has enhanced our knowledge about the immune system and its interactions with other systems in the human body and enlightened different aspects of its complexity that lead to promoting diagnostic strategies, designing more efficient therapeutic agents, and reducing potential morbidities and mortality. Due to the broad spectrum of immune-­ mediated diseases, from immunodeficiency to hypersensitivity and autoimmune diseases, the immune system diseases collectively contribute to a considerable prevalence, although every single immune-­mediated disease represents a low prevalence. The responsibility of applying the latest research findings had long been a concern for scientists. Translational research is recognized as a potential tool to utilize scientific findings in ­ ­ clinical settings and patients’ care. Considering the wide spectrum of



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­ iseases related to the immune system bed sides the huge burden for individuals, health care settings, families, and society, identifying promising alternative diagnostic and therapeutic strategies through translational studies is of interest. The Translational Immunology book series is a major new suite of books in immunology, which cover both basic and clinical immunology. The series seeks to discuss and provide foundational content from bench to bedside in immunology. This series intends to discuss recent immunological findings and translate them into clinical practice. The first volumes of this book series are specifically devoted to autoimmune diseases. Translational Autoimmunity: Autoimmune Diseases in Different Organs aims to present a comprehensive guide on autoimmune manifestations in different organs and systems of the body. Keeping in mind the complex pathophysiology of autoimmune diseases, the manifestations of a certain autoimmune disease could vary among different patients. On the other hand, different tissues could be affected by autoimmune conditions that are known to be specific to a particular system or organ of the body. Therefore, a systematic point of view in the physical examination of patients in clinics and in designing research studies is essential to cover all aspects of autoimmune diseases and conduct translational research. This book starts with recapitulating autoimmune manifestations in different tissues, organs, and systems of the body in Chapter 1. Chapters 2 and 3 focus on autoimmune endocrinopathies in pediatric patients

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to ­highlight the impact of autoimmune diseases on an individual’s health from the early years of life. Chapters 4 and 5 dive deep into the pathophysiology of two common autoimmune diseases, Graves’ disease and type 1 diabetes mellitus, respectively. In addition, Chapters  6 and 7 are devoted to autoimmune diseases of the eye and the promising treatment options, while Chapter 8 explores autoimmune diseases of the auditory and vestibular systems. Different autoimmune diseases affect the cardiovascular system in a wide spectrum of ages. To provide a review on these important autoimmune conditions, Chapter  9 delves deep into autoimmune heart diseases and Chapters  10 and 11 discuss different types of vasculitis. Acute disseminated encephalomyelitis is explored in Chapter  12. Although organ-specific autoimmune diseases of the respiratory system are relatively rare, the respiratory system is mainly affected by systemic autoimmune diseases. To address autoimmune complications of this vital system, Chapter 13 adopts a focused view on autoimmune pulmonary

diseases. The gastrointestinal tract and the liver are also affected by different autoimmune mechanisms, which are discussed in Chapters 14 and 15, respectively. Chapters 16 and 17 dissect the immunopathogenesis of cutaneous autoimmune diseases. Finally, Chapter 18 provides an overview of autoinflammatory diseases. The Translational Immunology book series is the outcome of the invaluable contribution of scientists and clinicians from well-known universities/institutes worldwide. I hereby appreciate and acknowledge the expertise of all contributors for generously devoting their time and considerable effort in preparing their respective chapters. I also express my gratitude to Elsevier for providing me the opportunity to publish this book. Finally, I hope this translational book will be comprehensible, cogent, and of special value to researchers and clinicians who wish to extend their knowledge in immunology. Nima Rezaei

Series editor biography

Professor Nima Rezaei earned his MD from Tehran University of Medical Sciences and subsequently obtained an MSc in molecular and genetic medicine and a PhD in clinical immunology and human genetics from the University of Sheffield, UK. He also received a short-term fellowship in



Pediatric Clinical Immunology and Bone Marrow Transplantation in the Newcastle General Hospital. Professor Rezaei is now Full Professor of Immunology and Vice Dean of International Affairs, School of Medicine, Tehran University of Medical Sciences, and the cofounder and head of the Research Center for Immunodeficiencies. He is also the founding president of Universal Scientific Education and Research Network (USERN). Professor Rezaei has already been the director of more than 50 research projects and has designed and participated in several international collaborative projects. He is an editorial assistant and board member for more than 30 international journals. He has edited more than 30 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1000 scientific papers in international journals.

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Acknowledgment I express my gratitude to the editorial assistant of this book, Dr. Niloufar Yazdanpanah, without whose contribution this book would not have been completed. Nima Rezaei



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Abbreviations anti-SAE

17α-hydroxylase 21-hydroxylase antibodies amyloid A abdominal aortic aneurysm aromatic l-amino acid decarboxylase ANCA-associated vasculitis auditory brainstem responses adrenal cortex autoantibody acetylcholine acetylcholine receptors anticardiolipin ccute CLE anticitrullinated protein antibodies Addison’s disease adalimumab antibody-dependent cell-mediated cytotoxicity ADEM acute disseminated encephalomyelitis ADM adult-onset DM ADM amyopathic DM AECAs antiendothelial cell antibodies AGS Aicardi–Goutières syndrome AHAs antihistone antibodies AIDP acute inflammatory demyelinating polyneuropathy AIED autoimmune inner ear disease AIG autoimmune gastritis AIH autoimmune hepatitis AIHA autoimmune hemolytic anemia AIN autoimmune neutropenia of infancy AIRE autoimmune regulator AITD autoimmune thyroid diseases AITP autoimmune thrombocytopenia ALCAs antilaminaribioside antibodies ANA antinuclear antibodies ANCAs antineutrophil cytoplasmic antibodies ANS autonomic nervous system anti-ARS anti-aminoacyl tRNA synthetase anti-CCP anti-cyclic citrullinated peptide antibodies anti-dsDNA anti-double-stranded DNA anti-GBM anti-glomerular basement membrane anti-IFNω abs anti-IFN-ω antibodies anti-Mi-2 Mi-2 nuclear antigen anti-NXP2 antinuclear matrix protein 2 17α-OH 21OHAbs AA AAA AADC AAV ABR ACA ACh AChRs aCL ACLE ACPAs AD ADA ADCC



anti-ssDNA anti-StCA anti-TG anti-TIF1γ anti-β2GPI AOSD AP APC APECED aPL APRIL APS APS APS AQP4 ASCAs ATD ATG AZA BAFF BBB BCC BCR BD Beff BLyS BM BP BPIFB1 BPPV Breg BVAS C1q CAD CAMPS CANDLE CANOMAD CAPS

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anti-small ubiquitin-like modifier activating enzyme anti-single-stranded DNA anti-steroid-producing cell antibodies antithyroglobulin antibodies anti-transcription intermediary factor 1-gamma anti-beta-2-glycoprotein-I adult-onset Still’s disease autoimmune polyendocrinopathies antigen-presenting cell autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy antiphospholipid a proliferation-inducing ligand antiphospholipid syndrome autoimmune polyendocrine syndrome autoimmune polyglandular syndrome aquaporin-4 water channel anti-Saccharomyces cerevisiae antibodies antithyroid drug antithymocyte globulin azathioprine B-cell activating factor blood–brain barrier basal cell carcinoma B-cell receptor Behcet’s disease effector B lymphocytes B lymphocyte stimulator basement membrane bullous pemphigoid bactericidal/permeability-increasing fold containing B member 1 benign paroxysmal positional vertigo B regulatory lymphocyte Birmingham vasculitis activity score complement component 1q cold agglutinin disease CARD14-mediated psoriasis chronic atypical neutrophilic dermatosis with lipodystrophy chronic ataxic neuropathy with ophthalmoplegia cryopyrin-associated periodic syndrome

xxii CARRA CBZ CCL18 CCL5 CCLE CD CD CD CD CD21 low CFA CG CH CH50 CHL ChLE CHO CIDP CIU CLASI CLD CLE CM CMC CMV CNS COPA COSMC COVID-19 CPE CR CRP CS CS cSCC CSF CTLA4 CTP CV CVB3 CVDs CXC CXCL CXCL10 CyA CYC DAA DC

Abbreviations

childhood arthritis and rheumatology research alliance carbimazole chemokine C–C motif ligand 18 CC chemokine ligand 5 chronic CLE Castleman disease Celiac disease cluster of differentiation (a marker of immune cells) Crohn’s disease low expression of CD21 complete Freund’s adjuvant cryoglobulin chronic hypoparathyroidism total hemolytic complement conductive hearing loss chilblain lupus erythematosus Chinese hamster ovary cell chronic inflammatory demyelinating polyneuropathy chronic idiopathic urticaria Cutaneous Lupus Erythematosus Disease Area and Severity Index chronic lung disease cutaneous lupus erythematosus cerebral microangiopathy chronic mucocutaneous candidiasis cytomegalovirus central nervous system coat complex subunit alpha core 1 β3-GalT-specific molecular chaperone coronavirus disease 2019 carboxypeptidase E complement receptor C-reactive protein Cogan’s syndrome corticosteroids cutaneous squamous cell carcinoma cerebrospinal fluid cytotoxic T-lymphocyte-associated protein 4 consensus treatment plan cryoglobulinemic vasculitis coxsackievirus B3 cardiovascular diseases chemokine chemokine ligand C-X-C motif chemokine ligand 10 cyclosporin A cyclophosphamide direct-acting antiviral drug dendritic cell

DCCT DCM DIET DIF DILE DILI DIRA DI-SCLE DI-SLE DITRA DiViD study DLBCL DM DMARD DNA DNBS DPLD DS DSS dSS DWI EAE EAM EBV EC EEG EGPA ELISA EM EMC EMG EPGA ER ERα ERβ ESKD ESR EU clamp EUGOGO EULAR FcRs F-FDG FMF

diabetes control and complications trial dilated cardiomyopathy depigmentation, induration, erythema, and telangiectasia direct immunofluorescence drug-induced lupus erythematosus drug-induced liver injury deficiency of the interleukin 1 receptor antagonist drug-induced subacute cutaneous lupus erythematosus drug-induced subacute lupus erythematosus deficiency of IL-36 receptor antagonist Diabetes Virus Detection study diffuse large B-cell lymphoma dermatomyositis disease-modifying antirheumatic drug deoxyribonucleic acid dinitrobenzene sulfonic acid diffuse parenchymal lung disease Down syndrome dextran sulfate sodium diffuse systemic sclerosis diffusion-weighted imaging experimental autoimmune encephalomyelitis experimental autoimmune myocarditis Epstein–Barr virus enterochromaffin cell electroencephalogram eosinophilic granulomatosis with polyangiitis enzyme-linked immunosorbent assay electron microscopy essential mixed cryoglobulinemia electromyography eosinophilic granulomatosis with polyangiitis estrogen receptor estrogen receptor alpha estrogen receptor beta end-stage kidney disease erythrocyte sedimentation rate hyperinsulinemic-euglycemic clamp European Group on Graves’ orbitopathy European League Against Rheumatism Fc receptors F-fluorodeoxyglucose familial Mediterranean fever



fecal microbiota transplantation forkhead box P3 GABA type A receptor-associated protein GAD65 glutamic acid decarboxylase-65 GADA glutamic acid decarboxylase antibodies GBS Guillain–Barré syndrome GCA giant cell arteritis GCPR G protein-coupled receptor GD Graves’ disease GI gastrointestinal GID gastrointestinal dysfunction GIP glucose-dependent insulinotropic polypeptide GN glomerulonephritis GO Graves’ orbitopathy GPA granulomatosis with polyangiitis GWAS genome-wide association study HA hyaluronic acid HAI hepatitis activity index HbA1c glycated hemoglobin HBV hepatitis B virus HCC hepatocellular carcinoma HCV hepatitis C virus HDM hypomyopathic DM HHV human herpes virus HIV human immunodeficiency virus HL hearing loss HLA human leukocyte antigen HMGB1 high-mobility group protein B1 HPA hypothalamic-pituitary-adrenal HPG hypothalamic-pituitary-gonadal HPT hypothalamic-pituitary-thyroid HSCT hematopoietic stem cell transplantation HSP Henoch-Schönlein purpura HSV-1 herpes simplex virus 1 HT Hashimoto’s thyroiditis HTLV-1 human T-lymphotropic virus-1 Htx hashitoxicosis HUS hemolytic uremic syndrome HYPO clamp hyperinsulinemic-hypoglycemic clamp IA2 islet antigen 2 IA-2A insulinoma-associated antigen-2 autoantibodies IAA insulin autoantibodies IBD inflammatory bowel disease IC immune complex ICAM1 intercellular adhesion molecule 1 ICLE intermittent CLE IF immunofluorescence IFN interferon FMT FOXP3 GABARAP

Abbreviations

IFR5 IFX Ig IGF-1 IgG4-RD iHMP IK IL IL-1R IL-1RA ILD INF IOIS IP IPEX

IPF IPH IPMSSG IRF5 IRT ITP IV IVIG JAK JDM JDRF JIA JLIS KCNRG KD LAC LATS LC1 LCV LEF LEP LET LFA-1 LKM LN LoSCAT LoSDI Lp(a) LPS LS L-T4

xxiii interferon regulatory factor 5 infliximab immunoglobulin insulin-like growth factor-1 IgG4-related disease integrative human microbiome project interstitial keratitis interleukin IL-1 receptor IL-1R antagonist interstitial lung disease interferon idiopathic orbital inflammatory disease interstitial pneumonia immune dysregulation, polyendocrinopathy, enteropathy, X-linked idiopathic pulmonary fibrosis idiopathic pulmonary hemosiderosis International Pediatric Multiple Sclerosis Study Group IFN-regulatory factor 5 infrared thermography idiopathic thrombocytopenic purpura intravenous intravenous immunoglobulin Janus kinase juvenile-onset DM Juvenile Diabetes Research Foundation juvenile idiopathic arthritis Jessner–Kanof lymphocytic infiltration of the skin potassium channel regulatory protein Kawasaki disease lupus anticoagulant long-acting thyroid stimulator liver cytosol antibodies type 1 leukocytoclastic vasculitis leflunomide lupus erythematosus panniculitis lupus erythematosus tumidus lymphocyte function-associated antigen-1 liver kidney microsomal antibody lupus nephritis Localized Scleroderma Cutaneous Assessment Tool Localized Scleroderma Damage Index lipoprotein (a) lipopolysaccharide localized scleroderma levothyroxine

xxiv MAAs mAChRs MAS MAS MBL MBP MC MCH MCMV MCTD MDA5 MDS mDC MFS MG MGUS

MHA MHC MI miRNA MIWGUC

MKD MMF MMI MMN MMP MMR MMTT MOG MPA MPGN MPO MPZ MRI MS MSAs mTEC MTX MuSK NAFLD NALP5 NASH NETs NF-kB NHL NK

Abbreviations

myositis-associated autoantibodies muscarinic acetylcholine receptors macrophage activation syndrome multiple autoimmune syndrome mannose-binding lectin myelin basic protein mixed cryoglobulinemia mean corpuscular hemoglobin murine cytomegalovirus mixed connective tissue disease melanoma differentiation-associated gene 5 myelodysplastic syndrome myeloid dendritic cell Miller–Fisher syndrome myasthenia gravis monoclonal gammopathy of unknown significance, monoclonal gammopathy of undetermined significance microangiopathic hemolytic anemia major histocompatibility complex myocardial infarct microribonucleic acid Multinational Interdisciplinary Working Group for Uveitis in Childhood mevalonate kinase deficiency mycophenolate mofetil methimazole multifocal motor neuropathy matrix metalloproteinase measles, mumps, rubella mixed-meal tolerance test myelin oligodendrocyte glycoprotein microscopic polyangiitis membranoproliferative GN myeloperoxidase myelin protein zero magnetic resonance imaging multiple sclerosis myositis-specific autoantibodies medullary thymic epithelial cell methotrexate muscle-specific kinase nonalcoholic fatty liver disease NACHT leucine-rich-repeat protein 5 nonalcoholic steatohepatitis neutrophil extracellular traps nuclear factor kappa-light-chainenhancer of activated B cells non-Hodgkin lymphoma natural killer

NMOSD NOD NOD2 nPOD NS NSAID NSIP NTAD NUD OF ON OTOAEs ox-LDL PAH PAMP PAN p-ANCA PAPA PARP1 PBC PCA PCH PCSK1 PCSK2 PCT PD PE PET PGI2 PH p.i. PI:C ratio PLEX PM PN PNH POEMS

POI PR3 PRL/GH PRR PSC PSS

neuromyelitis optica spectrum disorder nonobese diabetic mice nucleotide-binding oligomerization domain 2 Network for Pancreatic Organ Donors with Diabetes neurosarcoidosis nonsteroidal antiinflammatory drug nonspecific interstitial pneumonia nonthyroidal autoimmune disease neutrophilic urticarial dermatosis orbital fibroblast optic neuritis otoacoustic emissions oxidized low-density lipoprotein pulmonary arterial hypertension pathogen-associated molecular pattern polyarteritis nodosa ANCA antibodies of perinuclear pattern pyogenic sterile arthritis, pyoderma gangrenosum, acne poly ADP-ribose polymerase 1 primary biliary cholangitis gastric parietal cell antibody paroxysmal cold hemoglobinuria proprotein convertase subtilisin/kexin type 1 proprotein convertase subtilisin/kexin type 2 procalcitonin Parkinson’s disease pulmonary embolism positron emission tomography prostacyclin pulmonary hypertension post infection proinsulin-to-C-peptide ratio plasma exchange polymyositis peripheral neuritis paroxysmal nocturnal hemoglobinuria polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes premature ovarian insufficiency proteinase-3 prolactin/growth hormone pattern recognition receptor primary sclerosing cholangitis primary Sjögren’s syndrome



PTM PTPN22 PTU PUVA RA RAI RA-ILD RBCs REM RER RF RF rhPTH RNP RORγt ROS RP RP-ILD RPVBMI RTX SAMP SARS-CoV-2 s.c. SCC SCCA sCD14 SCID SCLC SCLE SCT SH SHARE sIL-2R SjS SLA SLE SMAs SNHL SNP SPE SPENCD SPF SPF SPS SS SS

Abbreviations

pretibial myxedema protein tyrosine phosphatase nonreceptor type 22 propylthiouracil psoralen and UVA rheumatoid arthritis radioactive iodine rheumatoid arthritis-related interstitial lung disease red blood cells reticular erythematous mucinosis rough endoplasmic reticulum rheumatic factor rheumatoid factor recombinant human parathyroid hormone ribonucleoprotein retinoid-related orphan receptor gamma t reactive oxygen species relapsing polychondritis rapidly progressive ILD relative pancreas volume adjusted for body mass index rituximab senescence-accelerated mouse prone severe acute respiratory syndrome coronavirus 2 subcutaneous squamous cell carcinoma squamous cell carcinoma antigen soluble CD14 severe combined immunodeficiency small cell lung carcinoma subacute CLE subcutaneous cellular tissue subclinical hypothyroidism Single Hub and Access Point for Pediatric Rheumatology in Europe soluble high-affinity IL-2 receptor Sjögren’s syndrome soluble liver antigen systemic lupus erythematosus smooth muscle antibodies sensorineural hearing loss single nucleotide polymorphism serum protein electrophoresis spondyloenchondrodysplasia with immune dysregulation specific pathogen free sun protection factor stiff person syndrome Sjogren’s syndrome Susac’s syndrome

SSc sST2 STAT4 SUN T1D T1D-GRS T1DM TA TAK TAO TCZ TED Tfh cells TG TgAb TGF Th TH Tim TLR TM TM TNF TNFAIP3 TNFi TnfΔARE

TPH TPHAbs TPMT TPOAb TRAB TRAb TRAPS Treg TREX1 TRIF TRIM tRNP TS TSA TSH TSHR TTP TUS U1 snRNP UC

xxv systemic sclerosis soluble ST2 signal transducer and activator of transcription 4 standardization of uveitis nomenclature type 1 diabetes T1D genetic risk score type 1 diabetes mellitus Takayasu arteritis Takayasu arteritis thromboangiitis obliterans tocilizumab thyroid eye disease follicular helper T cells thyroglobulin thyroglobulin autoantibodies transforming growth factor T helper tyrosine hydroxylase T-cell immunoglobulin mucin Toll-like receptor thrombotic microangiopathy transverse myelitis tumor necrosis factor TNF-alpha-induced protein 3 tumor necrosis factor inhibitor tumor necrosis factor delta (deletion) of AU-rich elements (ARE) gene mouse model tryptophan hydroxylase antibodies against tryptophan hydroxylase thiopurine S-methyltransferase thyroid peroxidase antibodies thyrotropin receptor antibody TSH receptor antibodies TNF receptor-associated periodic syndrome regulatory T cell three prime repair exonuclease-1 TIR-domain-containing adapterinducing interferon-β tripartite motif superfamily transfer-ribonucleoprotein Turner syndrome tissue-specific antigen thyroid-stimulating hormone TSH receptor thrombotic thrombocytopenic purpura thyroid ultrasound U1 small nuclear ribonucleoprotein particle ulcerative colitis

xxvi UCTD UGT UIP UPE UV UVR UVR

Abbreviations

undifferentiated connective tissue disease UDP-glucuronosyltransferase usual interstitial pneumonia urine protein electrophoresis ultraviolet ultraviolet radiation UV irradiation

VCAM vascular cell adhesion molecule VIP vasoactive intestinal peptide VKH disease Vogt-Koyanagi-Harada disease VZV varicella zoster virus WNV West Nile virus Zn2 + zinc ZnT8 zinc transporter 8 ZnT8A zinc transporter 8 autoantibodies

C H A P T E R

1 Autoimmune diseases in different organs Nima Rezaeia,b,d,⁎ and Niloufar Yazdanpanaha,c,d a

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran bDepartment of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran cSchool of Medicine, Tehran University of Medical Sciences, Tehran, Iran dNetwork of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran ⁎ Corresponding author

Abstract Organ-specific autoimmune diseases target specific tissues in the body. The produced autoantibodies, autoreactive immune cells, and immune complexes that mediate the pathophysiology of the disease differ based on the targeted tissue. Nevertheless, systemic autoimmune diseases could affect different tissues of the body by creating an inflammatory state in the body and triggering autoreactive immune components. In this chapter, important autoimmune manifestations in different tissues and physiological systems of the body are overviewed.

Keywords Autoimmunity, Organ-specific, Systemic, Inflammatory, Autoantibody, Autoreactive, Manifestation

1  Introduction Autoimmune diseases are classified into two main groups of organ-specific autoimmune diseases and systemic autoimmune diseases. The first one is indicative of autoimmune conditions targeting specific parts of the body, while the systemic ones are conditions, in which the autoreactive response is not restricted to a particular part of the body. Nevertheless, there are

Translational Autoimmunity, Vol. 4 https://doi.org/10.1016/B978-0-12-824466-1.00021-2

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1.  Autoimmune diseases in different organs

reports concerning the presence of both organ-specific and systemic autoimmune diseases in patients, either concurrently or sequentially [1–3]. Understanding the shared genetic factors and underlying pathogenic mechanisms of organ-specific and systemic autoimmune diseases might help to optimize and develop treatment strategies and pave the way to design a proper screening method to identify the at-risk patients to reduce further complications. In this chapter, the most important autoimmune manifestations of different parts of the body, either in the course of organ-specific or systemic autoimmunity, are recapitulated and briefly overviewed.

2  Autoimmune complications of the cardiovascular system Searching through the recent body of evidence, inflammation has been introduced as a cardinal driver of atherosclerotic cardiovascular diseases (CVD) [4]. Meanwhile, the pivotal role of CD4 + and CD8 + T cells has been emphasized in the pathogenesis of atherosclerotic CVD as well [5]. Putting the data together, the presence of immune cells and chronic inflammation in the cardiovascular system might predispose patients to autoimmunity; however, since this association is counted bidirectional, autoimmune diseases could be a risk factor for developing atherosclerotic CVD. On the other hand, the cardiovascular system is affected in both organ-specific and systemic autoimmune diseases. Rheumatic heart disease and myocarditis are the most well-known autoimmune heart diseases, which both occur after an infection, mainly by molecular mimicry mechanism [6]. Rheumatic heart disease is strongly associated with Streptococcus pyogenes and commonly occurs in susceptible pediatric patients. According to the revised Jones criteria, carditis is one of the important manifestations, which is reported in 30%–45% of patients [7]. Cardiac involvement affects the pericardium, myocardium, and endocardium while causing progressive permanent lesions of cardiac valves [8]. Autoimmune myocarditis is mostly triggered by viral infections, as demonstrated by Neu et al. [9]. They reported the detection of heart-specific autoantibodies in a murine model infected with Coxsackievirus B3. Moreover, Rose et al. observed that 59% of myocarditis patients had detectable levels of hear-specific antibodies [10]. Autoimmune myocarditis could result in dilated cardiomyopathy, which could be counted as an autoimmune complication of the cardiovascular system as well. Nevertheless, cardiovascular complications are also frequently reported in the most prevalent systemic autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). For instance, in RA, cardiovascular manifestations are the e­ xtra­articular manifestations and contribute to a poor prognosis of patients [11]. Vasculitis, inflammation of different vessels, is associated with different autoimmune diseases. Vasculitis presents with different clinical manifestations depending on the affected organ(s). For instance, cutaneous symptoms, hematuria, headache, visual disturbances, paresthesia, weakness, numbness, hemoptysis, epistaxis, abdominal pain, muscle/joint pains [12]. However, fever, weight loss, and fatigue are reported as common constitutional symptoms in different types of vasculitis [12]. According to the International Chapel Hill Consensus Conference Nomenclature of Vasculitides [13], systemic vasculitis is classified into five groups, named as a large vessel, medium vessel, small vessel, variable vessel, and single organ vessel vasculitis. The first three groups are illustrated in Fig. 1. Behçet disease and Cogan syndrome are classified as variable 2

FIG.  1  Classification of vasculitis. The black bands represent the prevalence in different vessels by different shades. (The black parts are more frequently affected by that type of vasculitis than the gray parts.)



1.  Autoimmune diseases in different organs

vessel vasculitis, while cutaneous small vessel vasculitis, testicular arthritis, and central nervous system (CNS) vasculitis are known as single organ vessel vasculitis [13].

3  Autoimmune complications of the respiratory system The respiratory system is mainly affected by systemic autoimmune diseases, while ­ rgan-specific diseases targeting the lungs and airways are not common. Idiopathic pulmoo nary fibrosis (IPF) or fibrosing alveolitis is known as the most common complication of the respiratory system with an autoimmune etiology. It can happen in the context of a systemic autoimmune disease, following pulmonary injury or inhalation of hazardous external substances (e.g., silica dust, cigarette smoke, asbestos), or without any specific etiology [14]. Systemic autoimmune diseases affect different parts of the respiratory system. For instance, RA can involve the lung parenchyma, airways, pleura, and pulmonary vessels. An overview of respiratory system involvement in RA is provided in Fig. 2. Among RA complications affecting the pulmonary interstitial tissue, usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP) are the most common [15]. The development of interstitial lung disease (ILD) is associated with behavioral and environmental risk factors such as smoking. Meanwhile, genetic susceptibility and specific variants of the human leukocyte antigen gene (HLA) contribute to the development of ILD. Higher levels of a rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP) are attributed to the higher risk of ILD as well [16]. Pulmonary complications are frequently reported in SLE (Fig.  3). Nevertheless, the heterogeneity of SLE manifestations challenges the diagnosis and classification of pulmonary symptoms. Similar to other autoimmune diseases, administration of immunomodulatory/ immunosuppressive agents complicates the process of distinguishing whether the pulmonary involvement is the result of drug-induced lung toxicity or is a manifestation of disease pathophysiology [17]. Many types of vasculitis affect the respiratory system [18]. Lung parenchyma is considerably damaged in granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and anti-glomerular basement membrane (anti-GBM). Meanwhile, bronchi are commonly affected in EGPA and nasal sinuses are involved in GPA and EGPA. In addition, Behçet disease and Takayasu arthritis affect the pulmonary arteries rather than other parts of the respiratory system.

4  Autoimmune complications of the endocrine system Although all body organs could be targeted by autoimmune reactions, the endocrine system is remarkably prone to autoimmune insults. The thyroid gland, pancreatic beta cells, and adrenal cortex are three parts of the endocrine system that are frequently affected by autoimmunity. Graves’ disease and Hashimoto’s thyroiditis result from secretion of autoantibodies mimicking TSH function in stimulating TSH receptors and the production of autoantibodies directly attacking the thyroid tissue, respectively. These two conditions compromise the main autoimmune thyroid diseases (AITD). The immune system uncontrolled response

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FIG. 2  Respiratory system involvement in RA. Abbreviations: ILD, interstitial lung disease; UIP, usual interstitial pneumonia; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; LIP, lymphocytic interstitial pneumonia; AIP, acute interstitial pneumonia.

FIG.  3  Respiratory system involvement in SLE. Abbreviations: ILD, interstitial lung disease; UIP, usual interstitial pneumonia; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; LIP, lymphocytic interstitial pneumonia; AIP, acute interstitial pneumonia; DAH, diffuse alveolar hemorrhage.



Nima Rezaei and Niloufar Yazdanpanah

to ­pancreatic beta cells turned into type 1 diabetes mellitus (T1DM), while uncontrolled response against the adrenal cortex causes Addison’s disease [19]. Genetics play an important role in both susceptibility to develop endocrine autoimmunity and the physiopathology of diseases. In line with this, the integration of the three mentioned autoimmune endocrine diseases is reported in autoimmune polyglandular syndrome (APS), which has a known genetic background. APS-1 or APECED (autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy) is strongly attributed to the mutated AIRE gene [20]. Regarding APS-2 or Schmidt’s disease, CTLA4, PTPN22, and certain HLA genes are suggested as contributors to the increased propensity to develop autoimmunity, but not as causative factors [21]. Meanwhile, APS-3 is the presence of AITD in association with other autoimmune conditions, excluding Addison’s disease [22]. Of particular note, an accumulating body of evidence suggests a mutual association between the immune and endocrine systems and the CNS, named as immune neuroendocrine system [23,24]. Five main systems in charge of responding to stressors of the immune neuroendocrine system are the hypothalamic-pituitary-adrenal (HPA) axis, hypothalamic-­ pituitary-thyroid (HPT) axis, hypothalamic-pituitary-gonadal (HPG) axis, prolactin/growth hormone (PRL/GH) system, and the autonomic nervous system (ANS) [23]. Different mediators produced in these systems, including cytokines (mainly from immune cells), neuropeptides (chiefly from nervous system cells), and hormones (from endocrine cells), potentially balance the activation/inhibition of immune responses. Hence, any disturbances in this balanced network could contribute to the initiation/development of autoimmune diseases [24]. Other endocrine glands could be affected by the immune system’s uncontrolled responses as well. For instance, autoimmune parathyroid disease [25], autoimmune hypophysitis [26], autoimmune orchitis [27], and autoimmune oophoritis and ovary disease [28,29].

5  Autoimmune complications of the gastrointestinal system Similar to other physiologic body systems, the gastrointestinal (GI) system is affected by systemic autoimmune diseases. Furthermore, there is a variety of organ-specific autoimmune diseases of different GI parts. RA potentially affects the GI tract function, at all steps of chewing, swallowing, digestions, absorption, and defecation. Temporomandibular joint arthritis, which is associated with severe large joints involvement, impairs the chewing process [30]. RA patients complain of heartburn and dysphagia, which are attributed to amyloidosis (secondary to RA) or GI tract vasculitis [31,32]. Insufficient secretion of hydrochloric acid and hypergastrinemia following chronic atrophic gastritis leads to overgrowth of the intestinal bacteria and its subsequent complications [33,34]. Furthermore, rheumatoid vasculitis, which occurs in about 5% of RA patients, could result in intestinal small-sized and medium-sized vessels damage, which might turn into intestinal ischemic lesions and infarction [35]. In addition, damaged vessels in the colon represent as pancolitis, mimicking ulcerative colitis [36]. In line with these, gastrointestinal and hepatic complications are reported in other systemic autoimmune diseases such as systemic sclerosis (SSc) [37] and SLE [38,39]. On the other hand, the damaged intestinal barrier, also known as the leaky gut, is recognized as one of the contributing factors to the etiology of different autoimmune diseases. The

7



1.  Autoimmune diseases in different organs

intestinal barrier is composed of epithelial cells with tight junctions, which in contribution with gut-associated lymphoid tissue and the neuroendocrine system, maintains the immune tolerance mechanisms and balance of immune responses [40,41]. Leaky gut is known in the pathophysiology of inflammatory bowel disease (Crohn’s disease and ulcerative colitis), SLE, T1DM, multiple sclerosis (MS), and ankylosing spondylitis [41]. Autoimmune diseases affecting the GI system specifically include Crohn’s disease, ulcerative colitis (UC), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis. However, they may occur in the context of systemic autoimmunity as well.

6  Autoimmune complications of the hematological system Autoimmunity against different blood cells, particularly red blood cells (RBCs) and platelets, mainly occurs in the setting of different diseases, including infections, autoimmune disorders, and malignancies. Autoimmune hemolytic anemia (AIHA) is characterized by uncompensated antibody-­ mediated RBC destruction. It is either primary (idiopathic) or secondary, which the latter occurs in the context of autoimmune disorders, primary immunodeficiency diseases, lymphoproliferative diseases, malignancies, infections, and specific drugs usage [42,43]. AIHA is classified based on the underlying pathophysiology to warm AIHA, cold AIHA, paroxysmal cold hemoglobinuria (PCH), mixed-type AIHA, and drug-induced AIHA [42]. Idiopathic thrombocytopenic purpura (ITP) is a common form of hematological autoimmunity, which is defined as the cytotoxic cell-mediated and antibody-mediated destruction of platelets, mainly in the spleen. The antibodies are directed against the platelets’ GPIIb/ IIIa and GPIb/IX [44]. Nevertheless, an ITP diagnosis is made after ruling out other causes of thrombocytopenia. The presence of AIHA and ITP, either concurrently or sequentially, is named Evans’ syndrome [45]. Autoimmune neutropenia is reported in some cases of Evans’ syndrome as well. The diagnosis is made after the exclusion of differential diagnoses. Furthermore, autoimmunity could target immature blood cells. For instance, aplastic anemia (autoimmunity against hematopoietic precursors), paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplastic syndrome (MDS) [46]. Granulocytes are affected by autoimmune reactions as well. The most common example is autoimmune neutropenia of infancy (AIN). AIN, as the most common type of neutropenia in patients lower than 3–4 years of age, represents a benign attitude and is self-limited [47].

7  Autoimmune complications of the musculoskeletal system The skeletal system is affected by systemic autoimmune diseases and chronic inflammation, rather than being specifically targeted by an over-active immune response. For instance, RA, SLE, AS, and IBD result in abnormal bone loss and increased risk of fractures [48]. Muscles could be affected by autoimmune reactions as well. Myositis, a necrotizing autoimmune myopathy, and eosinophilic fasciitis are autoimmune manifestations observed in autoimmune diseases [49]. 8



Nima Rezaei and Niloufar Yazdanpanah

Myasthenia gravis (MG) represents fluctuating fatigue and weakness of specific groups of muscles. Its etiology is attributed to autoimmunity against acetylcholine receptors of muscles at the neuromuscular junction [50].MG affects different muscles; therefore, a variety of manifestations are reported in MG patients. For instance, ptosis, diplopia, impaired mastication, dysphagia, dysarthria, dysphonia, limb weakness (upper limbs rather than lower limbs), problem with neck movements (flexion and extension, in particular), and respiratory muscles’ weakness (exertional dyspnea, orthopnea, tachypnea, respiratory failure) [50,51]. Polymyositis (PM) is a subacute myopathy, mainly affecting the proximal muscles [52]. PM has many common features with dermatomyositis (DM). While the onset of DM is recognized by the presence of the rash, the onset of PM is not easily distinguishable [53]. Diagnosis of PM is made after exclusion of other differential diagnoses. Fibromyalgia is a state of fatigue and generalized pain in association with sleep problems and cognitive disturbances. It remains controversial whether it is an immune-mediated disease or completely irrelevant to the immune system [54,55]. According to the existing literature, fibromyalgia does not induce inflammation and tissue damage in the affected regions of the body, which disqualifies it as an autoimmune condition. However, recent advances in fibromyalgia research are indicative of the contribution of the immune system to the pathophysiology of the disease [54].

8  Autoimmune complications of the nervous system Conditions that are categorized as autoimmune diseases of the nervous system have been recently increased, due to recent advances in the field of neuroimmunology that uncovered the immunologic basis of some neurologic diseases. Neuromyelitis optica spectrum disorder (NMOSD), MS, acute disseminated encephalomyelitis (ADEM), narcolepsy, stiff-person spectrum disorders, and Susac syndrome are examples of autoimmune diseases of the CNS [56,57]. Acute and chronic inflammatory demyelinating polyneuropathy (AIDP and CIDP, respectively), Guillain-Barre syndrome (GBS), Miller-Fisher syndrome (MFS), multifocal motor neuropathy (MMN) or Lewis-Sumner syndrome, monoclonal gammopathy of unknown significance (MGUS), and chronic ataxic neuropathy with ophthalmoplegia (CANOMAD) are of the autoimmune diseases of peripheral nerves [56–58]. In addition, Lambert-Eaton myasthenic syndrome and MG are autoimmune diseases of the neuromuscular junctions [56,57]. The involvement of eyes and optic nerves is documented in different systemic and non-­ systemic autoimmune diseases [59–62]. Table 1 provides an overview of ocular complications of systemic autoimmune diseases. There are eye-specific autoimmune diseases documented through the literature, which are mostly of rare prevalence. For instance, Cogan’s syndrome, pars planitis (primary or secondary to infections and systemic autoimmunity), sympathetic ophthalmia, thyroid eye disease (TED), birdshot chorioretinopathy, Mooren’s ulcer, and Vogt-Koyanagi-Harada syndrome (which is not limited to the eye, but panuveitis is one of its common manifestations) [59,63–67]. Autoimmune inner ear disease (AIED) is defined as a swiftly progressive idiopathic bilateral sensorineural hearing loss (SNHL) [68,69]. Inner ear complications are reported following Cogan’s syndrome and Vogt-Koyanagi-Harada syndrome as well [70]. In addition, 9



1.  Autoimmune diseases in different organs

TABLE 1  Ocular complications of systemic autoimmune diseases. Systemic autoimmune disease

Ocular complications

RA

Episcleritis, scleritis, keratitis, retinal vasculitis

GPA

Episcleritis, scleritis, keratitis, retinal vasculitis

SLE

Retinal vasculitis

Behcet’s disease

Posterior uveitis

seronegative HLAB27 positive spondyloarthritis

Anterior uveitis

Sjogren’s syndrome

Episcleritis, scleritis, corneal scarring and perforation, conjunctivitis, uveitis, keratoconjunctivitis sicca

systemic sclerosis

Eyelid stiffness, eyelid telangiectasia, keratoconjunctivitis sicca

different types of vasculitis such as polyarteritis nodosa (PAN) and GPA could result in progressive hearing loss. Meniere’s disease is defined as fluctuating episodes of SNHL, vertigo, and tinnitus. Although the underlying etiological factors contributing to Meniere’s disease are not fully documented, existing data points to the role of infections and autoimmunity [71]. Meanwhile, the association of Meniere’s disease with autoimmune disease, including RA, fibromyalgia, and AS, strengthens its autoimmune physiopathology [72]. Gustatory and olfactory dysfunctions are evaluated in autoimmune diseases through different studies. There are reports indicative of the impaired olfactory and gustatory sensations in GPA [73,74], MS [75–77], MG [78,79], and SLE [80,81].

9  Autoimmune complications of the integumentary system The skin is affected by a wide spectrum of autoimmune diseases. Different types of vasculitis, particularly small vessels vasculitis, present with dermatological manifestations. Different skin abnormalities and lesions are reported in systemic autoimmune diseases; for example, livedo racemose, panniculitis, pyoderma gangrenosum, granuloma, rheumatoid nodules, and erythema nodosum. Nevertheless, autoimmune bullous disease compromises a variety of autoimmune cutaneous diseases. Pemphigus (vulgaris, foliaceus, erythematosus, vegetans, drug-induced, IgA-mediated, and paraneoplastic), bullous pemphigoid, dermatitis herpetiform, and epidermolysis bullosa acquisita are classified as autoimmune bullous diseases. There are other autoimmune diseases, targeting different components of the integumentary system. Vitiligo is caused by autoimmunity against skin melanocytes, while autoimmune bullous disease usually targets the cutaneous cells’ junctions. Association with infections are observed in autoimmune cutaneous diseases, for instance, hepatitis C virus (HCV) is assumed as a contributor to the etiopathogenesis of lichen planus [82]. Scleroderma, dermatomyositis, subtypes of lupus erythematosus, and psoriasis are autoimmune diseases chiefly targeting the skin while representing manifestations in different body tissues as well. 10



Nima Rezaei and Niloufar Yazdanpanah

10  Conclusion The immune is in close connection with different systems/organs/tissues in the body. Therefore, uncontrolled immune responses and dysregulation of immune activities could lead to autoimmunity targeting different parts of the body. Autoimmunity targeting different parts of the body is reported in the context of both systemic and organ-specific autoimmune diseases. Different organs/tissues involvements potentially challenge the management of the underlying autoimmune disease. Assessment of the benefits and threats of the applied treatment concerning the involved organs is vital since the response to treatment and associated adverse effects are different in each tissue. On the other hand, multiorgan involvement might require a combination of treatments. Hence, the interaction of different therapeutic agents is an important issue to be addressed. In this chapter, we tried to outline autoimmune conditions in different systems of the body. An interdisciplinary approach of different medical specialties could be helpful to achieve better management of patients with autoimmune diseases. Furthermore, translation of preclinical data and results of in vitro and in vivo studies to the clinical application might be facilitated with transdisciplinary approaches.

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C H A P T E R

2 Autoimmune polyendocrinopathies in pediatric age Domenico Coricaa,⁎, Mariella Valenzisea, Carmen Bonannob, Tommaso Aversaa, and Malgorzata Wasniewskaa a

Department of Adult and Childhood Human Pathology “Gaetano Barresi”, University of Messina, Messina, Italy bIRCCS Centro Neurolesi Bonino Pulejo, Messina, Italy ⁎ Coresponding author

Abstract Autoimmune polyendocrinopathies (AP), also called autoimmune polyendocrine syndromes (APS), are rare conditions characterized by the concurrence of at least two endocrine and non-endocrine autoimmune diseases. The prevalence of APS varies widely in relation to ethnicity, sex, age, and genetic predisposition. The onset may occur from childhood to adulthood, and the different components of a given syndrome can appear throughout life, without necessarily following a precise pattern or time interval of appearance. APS-1 is the most common type in pediatric age, moreover, onset in childhood and adolescence is possible in all types of APS. Pathogenesis is attributable to AIRE mutations in APS-1, while is likely multifactorial in other types of APS. Genetic and environmental factors are likely to influence the natural history of APS in any affected individual. In this chapter, we provide an overview of APS in the pediatric age, with regard to epidemiology, genetic, clinical features, immunological patterns, and therapy.

Keywords Autoimmune polyendocrine syndromes, Multiple autoimmune syndromes, APS, AIRE, Autoantibodies, IPEX syndrome, Childhood, Pediatric, Endocrine diseases, Comorbidity

Translational Autoimmunity, Vol. 4 https://doi.org/10.1016/B978-0-12-824466-1.00005-4

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2.  Autoimmune polyendocrinopathies in pediatric age

1  Introduction Autoimmune polyendocrinopathies (AP), also known as autoimmune polyendocrine syndromes (APS), are rare conditions characterized by the concurrence of at least two endocrine and non-endocrine autoimmune diseases belonging to a wide spectrum of disorders. Accordingly, some authors proposed the denomination of multiple autoimmune syndromes (MAS) to refer to these syndromes [1]. In 1980, Neufeld and Blizzard introduced the first APS classification based on clinical peculiarities, including four principal types, as reported in Table 1 [2]. After the first description, the increasing knowledge concerning APS and other autoimmune diseases has led to the outline of new definitions. In particular, it is possible to distinguish between two main lines of thought. The splitters who divide APS into four main types, starting from Neufeld and Blizzard classification [1–4], and the lumpers which distinguish APS in APS-1 (also called “juvenile APS”), caused by mutations in the autoimmune regulator gene (AIRE), characterized by the association of at least two components among Addison’s disease (AD), chronic mucocutaneous candidiasis (CMC) and chronic hypoparathyroidism (CH), and a more common polygenic variety, APS-2 (also called “adult APS”), characterized by the combination of other endocrinopathies, such as autoimmune thyroid diseases (AITD), type 1 diabetes mellitus (T1DM), AD and other non-endocrine autoimmune diseases, as vitiligo and celiac disease (CD) [5–8]. Moreover, in the broad spectrum of APS, two other extremely rare conditions may also be considered, the immune-dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome and the polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome. The prevalence of APS varies widely in relation to ethnicity, sex, age, and genetic predisposition. In all APS, females are more frequently involved than males. The onset of APS may occur from childhood to adulthood, and the different components of a given syndrome can appear throughout life, without necessarily following a precise pattern or time interval of appearance. APS-1 is the most common type in pediatric age; moreover, onset in childhood and adolescence is possible in all types of APS. Genetic and environmental factors are likely to influence the natural history of the disease in any affected individual.

TABLE 1  APS old classification according to Neufeld and Blizzard definition [2]. APS

Clinical peculiarities

Type 1

At least two of the triad CMC, AD, CH

Type 2

AD (always present) + AITD and/or T1DM

Type 3

AITD + another autoimmune disease (excluding AD)

Type 4

Two or more organ-specific autoimmune diseases (different from association reported into types 1, 2, or 3)

APS, autoimmune poliendocrine syndrome; CMC, chronic mucocutaneos candidiasis; CH, chronic hyphoparathyroidism; AD, Addison’s disease; AITD, autoimmune thyroid diseases; T1DM, type 1 diabetes mellitus.

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TABLE 2  APS new classification according to splitter definition [4]. Types

Clinical manifestations

APS/MAS-1 or APECED

At least two of the triad CMC, CH, AD

aps/mas-2

AD (always present) + AITD and/or T1DM

aps/mas-3

AITD  +  3A) Other autoimmune endocrine diseases (excluding AD) 3B) Other autoimmune gastrointestinal, hepatic, or pancreatic diseases 3C) Other autoimmune diseases of the skin, central nervous system, or hematopoietic system 3D) Other autoimmune rheumatic and cardiovascular diseases or vasculitis

APS/MAS-4

Any other autoimmune disease combination not included in APS 1, 2, or 3

IPEX syndrome

Enteropathy, T1DM, dermatitis (classical triad)

POEMS syndrome

Polyneuropathy and/or monoclonal plasma cell disorder (mandatory) +  Major criteria: Osteosclerotic and/or mixed sclerotic lytic disorders, Castleman’s disease, increased plasma VEGF levels Minor criteria: Organomegaly and/or vascular volume overload and/or endocrinopathies and/or pancreas deficiencies and/or skin changes

APS, autoimmune poliendocrine syndrome; CMC, chronic mucocutaneos candidiasis; CH, chronic hyphoparathyroidism; AD, Addison’s disease; AITD, autoimmune thyroid diseases; T1DM, type 1 diabetes mellitus; IPEX, immune-dysregulation polyendocrinopathy enteropathy X-linked; POEMS, polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes.

Pathogenesis of autoimmune processes is certainly attributable to AIRE mutations in APS1, while is likely multifactorial in other types of APS, involving genetic predisposition (it has been proposed polygenic involvement with autosomal dominant inheritance and incomplete penetrance), epigenetic and environmental factors, although the precise mechanisms remain still unknown [9]. In this chapter, we provide an overview of APS in the pediatric age, with regard to epidemiology, genetic, clinical features, immunological patterns, and therapy, classifying them according to Betterle et al. classification [4], in accordance with splitter categorization (Table 2).

2  Autoimmune polyendocrine syndrome type 1 (APS-1) 2.1  Definition and epidemiology APS-1 (OMIM #240300, ORPHA:3453), also known as autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (APECED), is an inherited rare disease, which affects multiple endocrine and non-endocrine organ systems, caused by AIRE gene dysregulation. APS-1 has an estimated prevalence ranging between 1:90,000 and 1:200,000, although it significantly varies according to ethnic groups. In particular, a higher prevalence was reported in the isolated population such as Iranian Jews (1/9000), Sardinians (1/14,400), Finns (1/25,000), and Slovenian (1/43,000) [10–13]. A female greater prevalence was usually

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2.  Autoimmune polyendocrinopathies in pediatric age

r­eported in ­different studies [14,15]. APS-1 is clinically characterized by the typical triad CMC, CH, and AD, including a wide spectrum of symptoms that are commonly onset in childhood with a variable and progressive appearance of other manifestations throughout life. The variability of APS-1 phenotypic expression is documented even within the same family, supporting the hypothesis of an interaction between genetic and environmental factors influencing the course of the disease [15,16]. Diagnosis is generally made between 5 and 15 years of age, according to clinical manifestations [16]. Pediatric onset is likely related to the timing of AIRE expression during thymus progressive involution. Impaired AIRE ­expression seems to compromise processes promoting self-tolerance during the perinatal period [17].

2.2  Genetics APS-1 has an autosomal recessive inheritance related to AIRE mutations and dysregulation. The human AIRE gene is located on chromosome 21q22.3 and consists of 14 exons (Fig. 1). The principal AIRE domains are the caspase recruitment domain/homogeneously staining (CARD/HSR) region, the SAND domain (SP100, AIRE, Nuc p41/75, DEAF), two plant homeodomain (PHD) zinc fingers at the C-terminal region of the protein, four LXXLL motifs (where L stay for leucine and X for any amino acid) and a proline-rich region (PRR) (Fig. 1) [13]. AIRE encodes a 545-amino-acids transcription regulator (AIRE) of 58 kDa, which plays a crucial role in immune tolerance by inducing the ectopic thymic expression of many ­tissue-specific antigens (TSAs) [18]. AIRE promotes the expression of a broad spectrum of different TSA genes in both ordered and stochastic manners. Therefore, a single medullary thymic epithelial cell (mTEC) will either express TSAs clustered on a single chromosome or clustered between chromosomes [13,19]. This process physiologically influences the apoptosis of autoreactive T cells, an essential mechanism to prevent autoreactive T cells with specificity for autoantigens from being able to determine an autoimmune process. Moreover, AIRE is involved in promoting the activity of forkhead box P3 (FoxP3 +) regulatory T cells (Tregs), capable of suppressing self-reactive T cells [4,17]. In particular, in mTECs, TSAs are presented to potentially self-reactive thymocytes, during T cells development, in order to induce T cells negative selection or to induce the production of FoxP3 + Tregs in the thymus able to suppress self-reactive T cells [7]. In the case of AIRE altered function, self-reactive T cells may escape negative selection, reaching the general circulation and peripheral lymphoid organs where they can trigger autoimmune processes [17]. The detection of autoantibodies, even in a preclinical phase of the disease, represents a precocious marker of the loss of immune tolerance in APS-1 patients. AIRE is not only expressed in the antigen-presenting cell (APCs) in the thymus, but also in other tissue including spleen, lymph nodes, pancreas, adrenal cortex, gonads, fibroblasts, and keratinocytes, suggesting a possible role of these tissues in immune regulation processes. Although the mechanism of action is not yet entirely clear, AIRE would seems to act differently from conventional transcription regulators, promoting transcription indirectly by interacting with chromatin and several other molecules, and regulating post-transcriptional processes [17].

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FIG. 1  Schematic representation of the human AIRE gene and Aire protein. At the top of the image, colored numbered boxes represent the 14 exons of AIRE gene. On the exons boxes, the main encountered mutations are reported in black and in red, respectively, according to recessive or dominant inheritance patterns. At the bottom of the picture the AIRE gene product and its main functional domains are represented; caspase recruitment domain/ homogeneously staining (CARD/HSR) region, the SAND domain (SP100, AIRE, Nuc p41/75, DEAF), two plant homeodomain (PHD) zinc fingers at the C-terminal region of the protein, four LXXLL motifs (where L stay for leucine and X for any amino acid).



2.  Autoimmune polyendocrinopathies in pediatric age

Studies carried out on murine models, in which AIRE has been identified on chromosome 10, have made it possible to study the characteristics of AIRE and to understand mechanisms of action of its product. In fact, knockout animal models, AIRE −/−, develop a clinical condition similar to APS-1, characterized by multiple autoimmune diseases, with lymphocytic infiltration in the target organs and circulating autoantibodies against several tissues [4,20,21]. AIRE is involved in other actions aimed to negatively select self-reactive thymocytes by a TSAs-independent mechanism. Specifically, AIRE promotes the expression of XCL1 chemokine involved in the recruitment of thymic dendritic cells, which in turn play a key role in the apoptosis of self-reactive thymocytes and in the development of Tregs [22]. Furthermore, on the other hand, an increased expression of AIRE seems to be also related to autoimmune processes triggering. Recently, Nishijima et  al. documented that murine models, expressing augmented AIRE, developed muscle-specific autoimmunity associated with incomplete maturation of mTECs and impaired expression of AIRE-dependent ­tissue-specific antigen, resulting in failure of self-reactive thymocytes negative selection and Treg formation [23]. Over 130 different mutations of the human AIRE gene have been described so far [24] including nonsense, frameshift, and missense mutations located both on AIRE domains as on intronic and promoter regions (Fig. 1) [25]. APS-1 is typically caused by biallelic mutations. However, it has been recently documented that some APS-1 patients carry a unique negative dominant pathogenic mutation of AIRE [26,27]. Usually, AIRE dominant mutations have incomplete penetrance; therefore, in these cases, the disease phenotype can be milder or incomplete with the late presentation, so that these cases have been called “non-classical” APS-1 [26,27]. A correlation between certain pathogenic mutations and specific areas and populations has been documented. The most frequently documented mutation is R257X, a nonsense mutation in exon 6 within the SAND domain, resulting in a truncated and non-functional protein, reported in about 90% of Finnish patients, but it has also been documented in patients from Russia, Central, and Eastern Europe [25,28]. A deletion localized in the exon 8 within the PHD1 domain, p.C322del13 (del-13 bp), responsible for the production of a truncated protein, has been reported in patients from Britain, Ireland, North America, Norway, France, and northern Italy [13,29]. Y85C on exon 2, within CARD/HSR domain, is a typical mutation among Iranian-Jewish APS-1 patients [13]. The R139X mutation on exon 3 is a nonsense mutation, peculiar to the Sardinian cluster, which causes a total absence of AIRE resulting in a severe phenotype [29]. Other different mutations, more frequently reported in specific Italian clusters, are the W78R on exon 2 and Q358X on exon 9 identified in the Apulia cluster, the R203X on exon 5, the S107C, and the Q108fs on exone 3 in Sicilian patients [29] (Fig. 1). Moreover, a dominant mutation on exon 6, G228W, has been identified in an Italian family in which some individuals had only autoimmune thyroid disease, while others had a clinical picture of a mild APS-1 [30]. Although APS-1 is certainly determined by mutations of the AIRE gene, a clear ­genotype-phenotype correlation is missing. In fact, APS-1 phenotypes are very heterogeneous in both the number and severity of clinical manifestations even between subjects sharing the same genotype. This variability is likely to be influenced by the different types of mutations in AIRE domains, such as biallelic and monoallelic mutations, by the interaction between AIRE and

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s­ everal functional regulators, such as microRNA, which may be able to condition AIRE function through post-translational modifications [31], and by the close interaction between genetic and environmental factors influencing the clinical expression of APS-1.

2.3  Diagnostic criteria and main clinical manifestations APS-1 is characterized by a classic triad including CMC, CH, and AD [1,2] (Table  1). Besides the classical triad, many other endocrines and non-endocrine autoimmune manifestations may occur in this condition and significantly vary even inside the same families and in patients with the same AIRE mutations. APS-1 clinical spectrum has significantly enlarged in the last years and other non-classic components have been recently described. Chronic lung disease (CLD), chronic inflammatory demyelinating polyneuropathy (CIDP), and gastrointestinal dysfunction (GID) represent novel components of APECED that may alert pediatricians when they are associated with one element of the triad [32]. Considering the severity of these diseases, early diagnosis is crucial for patient safety. Therefore, it is important to be aware of the great variability of the early clinical picture. The classical clinical triad allows early recognition of only a minority of new cases since its presence is diagnostic, but its absence has no diagnostic value. The triad occurred with a frequency in the range of 80%–90% in the various cohorts of European patients examined, while the other minor autoimmune and non-autoimmune manifestations were reported in a small minority (5%–20%) [13,18,33]. The wide spectrum of the phenotype and the gradual appearance of symptoms over time strongly suggest that although APECED is the first well-documented example of an autoimmune disorder inherited as a monogenic disease, several functional, environmental, or molecular factors may contribute to the clinical expression of the disease. 2.3.1  Clinical diagnosis The clinical diagnosis is classically based on the presence of at least two of the three main components, CMC, CH, and AD. The presence of only one component is sufficient for the diagnosis if a sibling is already affected. Since the early clinical picture can be dominated by one of the minor components, there is a considerable delay, of about 10 years, between first symptoms appearance and diagnosis of APS-1 [34]. Identifying causal genetic mutations in AIRE confirm the diagnosis and may be helpful in those cases with atypical presentation. Neutralizing autoantibodies against type 1 interferons (IFN-ω and IFN-α) have been highly correlated with AIRE deficiency, regardless of AIRE mutations, features, and duration of APECED. Anti-IFN-ω antibodies (anti-IFNω Abs) seem to appear early in life and their presence virtually confirms the diagnosis [35]. Therefore, these autoantibodies have been recently included in the new diagnostic criteria for the diagnosis of APECED as reported by Husebye et al. [7,36] (Table 3). A probable diagnosis of APECED might be performed in presence of (1) one element of the triad (developed before 30 years) along with one of the following minor components including periodic rash with fever, severe constipation, autoimmune hepatitis, chronic diarrhea, keratitis, vitiligo, alopecia, and enamel hypoplasia; (2) any of the triad or minor component associated with the presence of anti-IFN Abs; and (3) any of the triad or minor component and positivity of antibodies against NACHT leucine-rich-repeat protein 5 (NALP5), aromatic

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2.  Autoimmune polyendocrinopathies in pediatric age

TABLE 3  Diagnostic criteria for the diagnosis of APECED [36]. Definitive diagnosis 1. At least two components of the classical triad (CMC, CH, AD) 2. One component of the triad if a sibling has been diagnosed with APS-1 3. Disease-causing mutations in AIRE gene Probable diagnosis 1. One component of the classical triad (diagnosed before 30 years of age) associated with at least one of the following minor components: periodic rash with fever, severe constipation, autoimmune hepatitis, chronic diarrhea, keratitis, vitiligo, alopecia, and enamel hypoplasia 2. One triad or minor component associated with anti-IFNAbs 3. One triad or minor component associated with antibodies against NALP5, AADC, TPH, or TH APECED, autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy; CMC, chronic mucocutaneous candidiasis; CH, chronic hypoparathyroidism; AD, Addison’s disease; AIRE, autoimmune regulator gene; anti-IFNAbs, antibodies against interferon; NALP5, NACHT leucine-rich-repeat protein 5; AADC, aromatic L-amino acid decarboxylase; TPH, tryptophan hydroxylase; TH, tyrosine hydroxylase.

L-amino acid decarboxylase (AADC), tryptophan hydroxylase (TPH), or tyrosine hydroxylase (TH) [36] (Table 3). In conclusion, patients with a clinical phenotype suggestive of APS-1 should be screened for anti-IFN Abs before AIRE sequencing. Since anti-IFN Abs screening is not currently used in routine laboratories, the patients should be directly tested for AIRE gene mutations [7]. 2.3.2  Main clinical manifestations Chronic mucocutaneous candidiasis (CMC)

Candidiasis is generally the first manifestation of the disease, usually appearing in the first years of life. It is often followed by CH, before the age of 10 years, and later by AD. However, the clinical phenotype is often only partially expressed in infancy. In fact, most of the patients with the classic triad of symptoms belong to the second or third decade of life. Clinical complications gradually appear over time, culminating in a complete clinical portrait of the disorder between the second and third decade of life. CMC is the most common infection occurring in APECED patients (77%–100%) [7,15,33], except in Iranian Jews (17%) [37]. It represents the most common first clinical manifestation of APECED syndrome (40%–93%) [15,38]. The clinical course of CMC varies from periodic to chronic, and its severity differs between individuals. The oral cavity was involved in 100% of patients in the Finnish cohort [33]. CMC can affect the oral mucosa, causing intermittent angular cheilitis. More severe cases include inflammation of the oral mucosa with leukoplastic areas and potential for evolving into squamous cell carcinoma (SCC). In more severe cases, the entire mouth is involved making it impossible to consume acidic or spicy foods. CMC can also cause esophageal mucositis, complicated by retrosternal pain, dysphagia, and stenosis that requires endoscopic dilation. Intestinal candidiasis can cause abdominal pain, flatulence, and diarrhea, which may be severe. Symptomatic intestinal candidiasis may also be present in absence of oral disease [7,36,39].

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Females may suffer from vulvovaginitis. Systemic candidiasis is very rare, even in APECED patients, and is frequently associated with immunosuppressive therapy that reduces T lymphocytes and T helper-17, which are involved in protecting against Candida albicans [33,38]. There is a normal B cell response to Candida, which prevents the onset of systemic candidiasis. The diagnosis of CMC is clinical and confirmed by cultures [40]. CMC has been reported to be involved in carcinogenesis. The role of chronic Candida infection in the etiopathogenesis of oral SCC is unclear. Possible mechanisms by which oral Candida infection might contribute to cancer development include (a) induction of chronic inflammation mediated by the production of cytokines that enhance cell proliferation and inhibit apoptosis; (b) metabolism of procarcinogens (such as the conversion of ethanol to acetaldehyde by Candida); and (c) production of carcinogens (such as the production of nitrosamine by Candida species) [41,42]. Endocrine diseases

Endocrine autoimmune disease is the hallmark of APECED syndrome, as the acronym indicates. Chronic hypoparathyroidism (CH), which typically develops earlier than any other endocrinopathy, and adrenal insufficiency are the most common endocrine manifestations. CH is more prevalent in females. The prevalence of CH in the national cohorts of APECED ranged from 50% to 100% [13,37,40]. CH is usually the second disease to develop, and the first endocrine occurring dysfunction [33,37]. The disease developed at a mean age of 11 years (range 0.5–74), with latent or manifest hypocalcemia. Chvostek and Trousseau signs are hallmarks of neuromuscular irritability and can be positive. Hypocalcemia, however, may lead to tetany, laryngospasm, seizures, and potential brain injury, and thus conventional management involves a delicate balance between hypercalciuria and hypocalcemia. The diagnosis of CH has been based on decreased plasma calcium, elevated plasma phosphate, and decreased or absent plasma intact parathyroid hormone [13]. Autoantibodies against NALP5Abs have been found in patients with APECED and long-standing CH, but not in patients with isolated CH or with other autoimmune diseases [43] and have been included in the latest criteria for diagnosing APECED syndrome [36]. AD represents the last element of the triad and it often manifests between 5 and 15 years. AD is a life-threatening condition that needs to be recognized and promptly treated in order to prevent the risk of severe morbidity or mortality. Clinical presentation is characterized by fatigue, weight loss, salt craving, hypotension, abdominal pain, and increased skin pigmentation. The physical examination may show hyperpigmentation of knuckles, joints, oral mucosa, and scars. In addition, the absence of axillary and pubic hair in girls due to the lack of production of adrenal androgens is reported as well. Classic biochemical signs include hyponatremia, hyperkalemia, hypoglycemia, and ketonemia or ketonuria. The clinician needs a high index of suspicion when facing a patient with fatigue, weight loss, upper gastrointestinal distress, and hypotension, especially when of subacute or chronic presentation, regardless of the absence of hyperkalemia and hyperpigmentation. At diagnosis, AD shows a high frequency (> 90%) of adrenal cortex autoantibodies (ACA) or 21-hydroxylase antibodies (21OHAbs). In fact, ACA or 21OHAbs are markers of high future clinical manifestations of AD. Therefore, it is important to test for these autoantibodies in all the patients with APECED without clinical AD in order to make the diagnosis promptly [44].

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Additional endocrinopathies that develop with lower frequencies include (1) AITD, as Hashimoto’s thyroiditis (HT), characterized by the presence of anti-thyroid peroxidase (­anti-TPO) and/or anti-thyroglobulin antibodies (anti-TG); (2) primary ovarian failure, testicular failure, and isolated azoospermia that may also accompany the hypogonadism; (3) growth hormone deficiency; and (4) T1DM, an uncommon complication of patients with APECED, which typically occurs later in adolescence or adulthood in ~ 5%–10% of patients and is accompanied by the positivity of islet antigen 2 (IA2) antibodies. 2.3.3  Other clinical manifestations Other manifestations of APS-1 include alopecia (the most common dermatological manifestation that typically appears around 40 years of age and correlates with the levels of anti-­ tyrosine hydroxylase antibodies), vitiligo (that may be the initial manifestation of the disease and correlates with the positivity of antibodies against SOX9 and SOX10), keratitis (in about a quarter of the patients), enamel dysplasia, gastritis, and pernicious anemia. Asplenia, related to splenic atrophy due to autoimmunity or vasculitis, is reported in about 20% of adults and 10% of children with APECED. Asplenia makes the patient susceptible to infections by encapsulated organisms; therefore, vaccinations against pneumococcus, meningococcus, and Haemophilus influenzae are necessary. Autoimmune hepatitis is described in about 20% of patients with APS-1. Furthermore, recent reports highlight the possibility of unusual and peculiar components such as CLD, CIDP, and GID. Chronic lung disease (CLD)

Despite sporadic reports of respiratory illnesses in APS-1 patients, CLD had not been initially considered as a typical manifestation of the disease. The discovery of APECED patients with bilateral and diffuse bronchiectasis, frequent respiratory infections, with subsequent progressive corpulmonale and terminal respiratory failure [45] induced to hypothesize that CLD might be included among the autoimmune manifestations of APECED. This hypothesis has been supported by the detection of serum-specific autoantibodies directed against the potassium channel regulatory protein (KCNRG), an antigen preferentially expressed in the epithelial cells of terminal bronchioles in the lungs, in some patients with APECED-related lung disease [46]. Later, autoantibodies against bactericidal/permeability-increasing fold containing B member 1 (BPIFB1), considered as a lung-specific autoantigen, have been demonstrated [47] and were proposed to contribute to the pathogenesis of interstitial lung disease (ILD), both in patients with APECED and in those without APECED. Autoantibodies against BPIFB1 and KCNRG appear highly specific for lung autoimmunity in APECED patients, but their sensitivity is ~ 65% and ~ 30%, respectively, suggesting that yet-­ unknown lung autoantigens may be involved in some cases of pneumonitis in APS-1. Therefore, the best available screening modality for pneumonitis in these patients has computed tomography of the chest, which reveals ground-glass opacities and/or bronchiectasis; moreover, captures the ~ 5%–10% of patients with early lung disease that are as-yet asymptomatic. Chronic inflammatory demyelinating polyneuropathy (CIDP)

CIDP had not been included among the possible components of APECED until the first description of two unrelated APECED adolescents [48], who developed progressive ­muscular

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weakness involving both arms and legs, associated with sensory loss and absent tendon reflexes. In both patients’ electrophysiological studies disclosed a reduction of nerve conduction velocity, which was consistent with the diagnosis of CIDP. Based on these findings, it is suggested that the association of CIDP and APECED may not be coincidental and the peripheral nerve demyelination could be considered as a novel manifestation of APECED resulting from an autoimmune process. This view was subsequently substantiated by another study [49] in which the identification of antibodies against myelin protein zero (MPZ) confirmed that MPO is a target of autoimmunity in APECED individuals and that AIRE-mediated autoimmune peripheral neuropathy should be included among the clinical components of this syndrome [49,50]. Gastrointestinal dysfunction (GID)

APS-1 patients often present with gastrointestinal symptoms. CD was found in 2% of the patients, detectable by transglutaminase autoantibodies of IgA or IgG classes. Another GID, characterized by chronic or periodic constipation or recurrent diarrhea and malabsorption, occurring in 15% of patients, might interfere with replacement therapies in the cases with endocrine deficiencies. It had been found that antibodies against tryptophan hydroxylase (TPHAbs) may be associated with this idiopathic form of GID in patients with APECED. GID is characterized by reduced serotonin serum levels and positive TPHAbs, with lymphocytic infiltration and absence of enterochromaffin cells (EC) in gastric and duodenal biopsies. Although TPHAbs do not have a directly pathogenic role in APECED-related GID, they are important hallmarks of this disease and may also have some predictive value for its evolution over time [51].

2.4  Treatment Management of APECED is multi-faceted and needs a multi-disciplinary approach at a tertiary center [13]. Because of the complexity of the disease, patients with APECED should have a minimum of two follow-up visits per year, while asymptomatic mutations carriers should be followed at least annually. Treatment of APECED includes hormonal replacement therapy and treatment of complications. Oral CMC is generally managed with oral preparations of nystatin and amphotericin B. It is important to avoid drug resistance often encountered with continuous use of azole preparations because azole drugs inhibit steroidogenesis with the risk of precipitation of AD, especially in cases of unrecognized adrenal failure. CH is managed with oral vitamin D derivatives combined with calcium supplementation in non-acute cases. Acute hypocalcemia warrants intravenous supplementation of calcium gluconate or calcium chloride. The objective of treatment is to maintain calcium in the low normal range. Recombinant human parathyroid hormone (rhPTH) may be an option when conventional treatment fails to normalize calcium levels, especially in the presence of malabsorption and in order to avoid an increased renal excretion of calcium and the risk of nephrocalcinosis [52]. AD is managed with glucocorticoid supplementation with hydrocortisone in two or three divided oral doses a day. In cases of malabsorption, higher doses of hydrocortisone may be necessary. A once-daily, dual-release hydrocortisone tablet has recently become available and it seems to reflect the normal daily cortisol rhythm better than the conventional treatment.

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Fludrocortisone may be used to replace mineralocorticoids. All patients with adrenal insufficiency should wear an alert bracelet. They increase their glucocorticoid doses in the event of stress, using parenteral glucocorticoids in emergency conditions, such as fever, vomiting, and diarrhea, or surgical interventions in order to prevent adrenal crises. Other symptoms, such as keratitis, pneumonitis, hepatitis, or enteritis, may need immunosuppressive treatment. Rituximab, a monoclonal antibody against CD20, has been reported to have beneficial effects on pneumonitis and malabsorption [53]. Autoimmune hepatitis in APECED can be aggressive and lead to hepatic failure and death if not promptly treated with high-dose steroids and azathioprine. More studies are needed to optimize immunosuppressive treatment.

3  Autoimmune polyendocrine syndrome type 2 (APS-2) 3.1  Definition and epidemiology APS-2 (OMIM #269200, ORPHA:3143) is defined by the coexistence of an always present autoimmune AD together with both/either AITD and/or T1DM (Table 1). It was firstly described by Schmidt, who in 1926 reported the association of hypothyroidism and adrenal insufficiency with lymphocytic infiltration of both the thyroid and adrenal glands [4]. In 1932, the first case with the clinical triad of AD, hypothyroidism, and diabetes mellitus was published [54]. Compared with APS-1, APS-2 is a more common syndrome with an estimated prevalence ranging between 14 and 45 cases per million [55] and 100–200 cases per million inhabitants in the general population [6]. The increased prevalence reported over time could be due to the fact that incomplete forms of APS-2 are currently more easily detectable by autoantibody screening tests. APS-2 can occur at all ages, but it is more frequent in young adulthood, with a female to male ratio of 3 to 1, and very rare in childhood [56]. However, it has been recently reported that 40% of children and adolescents with AD develop this autoimmune condition in the context of APS-2 [57].

3.2  Genetics The inheritance pattern of APS-2 is complex and seems to be autosomal dominant with incomplete penetrance in some patients. In fact, several genetic loci may interplay with environmental factors. However, the exact underlying pathogenic mechanisms are not yet completely characterized [9]. Nevertheless, it is reported that either isolated AD or APS-2 are present in more than one patient of the same family in less than 2% of cases [40]. The influence of genetic factors on multiple autoimmune disorders has been demonstrated by the significant clustering of AITD within families and twin studies for both HT and Graves’ disease (GD), but mostly through recent genome-wide association studies (GWASs), which suggest a common genetic susceptibility [58,59]. APS-2 is strongly associated with certain alleles of HLA genes within the major histocompatibility complex (MHC). A genetic correlation has been found between APS-2 and HLA DR3 and DR4 haplotypes. In fact, AD is associated with HLA class II antigens, particularly with the HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3/DQ2) and DRB1*0404-DQA1*0301-DQB1*0302

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(DR4/DQ8) haplotypes. The presence of DR3-DQ2 and/or DR4-DQ8 determines, in addition to the risk of developing AD, an increased risk of T1DM, AITD, and CD. This could partially explain why these four autoimmune diseases may develop in the same patient. However, while the DRB1*04:04-DQA1*03:01-DQB1*03:02 haplotype is associated with AD and therefore APS-2, the DRB1*04:01-DQA1*03:01-DQB1*03:02 haplotype is susceptible for APS-3, including T1DM [60–62]. Other genes that lead to an increased risk of developing APS-2 are those that encode cytotoxic T lymphocyte antigen 4 (CTLA4), protein tyrosine phosphatase nonreceptor type 22 (PTPN22), the transcriptional regulator protein BACH2, and the CD25– interleukin-2 receptor [7,8]. While genetic factors determine disease susceptibility, environmental factors may have an important influence on the development of autoimmune diseases. However, exposure to environmental pathogens does not always lead to disease. Therefore, only the synergic action of both genetic and environmental factors may contribute to the loss of immune self-tolerance. To sum up, in individuals with a genetic predisposition, epigenetic external factors, such as viral or bacterial infections, and psychosocial factors might contribute to determine an autoimmune cascade [6,63].

3.3  Diagnostic criteria and main clinical manifestations To frame a multiple autoimmune disorder as APS-2, AD needs to be always present in association with at least one other condition between AITD andT1DM. Other autoimmune disorders such as premature ovarian insufficiency (POI), autoimmune gastritis (AIG) with or without pernicious anemia, vitiligo, alopecia, celiac disease, thrombocytopenia, may be present [40]. Among the endocrine autoimmune conditions, AD is found in 100% of APS-2 patients since it is a “conditio sine qua non” for the diagnosis, can develop at different ages, and precede or follow other autoimmune disorders. In the largest Italian cohort published by Betterle et al., AD developed mainly in adulthood, but it is reported in12.2% of the case, which AD was developed in the first two decades of life [4,40]. In patients with AD, ACA and/or 21-OHAbs were detected in almost all patients within 2 years from the diagnosis and can still be found in more than 80% of patients after 10 years [64]. In literature, a prevalence ranging between 61% and 93% of AITD is reported in the different cohorts of APS-2 patients [6,55,65,66]. HT is present in around 80% of patients with APS-2, and generally causes clinical or subclinical hypothyroidism, even if some patients can maintain a normal thyroid function. In 50% of patients, HT develops before AD, while in the remained patients develops simultaneously or afterward. GD leads to hyperthyroidism and it can be found in around 10% of patients with APS-2 [40]. In three out of four patients with APS-2, GD precedes AD. Anti-TPO and/ or ­anti-TG antibodies are detected in about 90% of patients with HT and 80% of GD patients, while TSH-receptor antibodies (TRAbs) are positive in almost all patients with GD. Children and adolescents with HT and normal thyroid function are at risk of developing thyroid dysfunction and should check their thyroid function tests every 6–12 months [40,67,68]. In the national cohorts of APS-2 patients, T1DM is present in 23%–52% of cases [6,55,65,66] and diagnosed at a mean age of 25 years, often (75%) before AD. Positivity of islet cell antibodies (ICA), and/or against glutamic acid decarboxylase-65 (GAD) and zinc transporter 8 (ZnT8) occurs in almost all patients with T1DM. An 8% of patients with APS-2 and islet cell antibodies (ICA, GAD, IA2, or ZnT8) with a normal glucose tolerance test are described.

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Thus, patients need to be carefully monitored with periodical controls of both glycemia and HbA1c for the high risk of developing a classical onset of T1DM [40]. A combination of these three major endocrinopathies is possible. Often AD is associated only with either AITD or T1DM, but around 10% of APS-2 patients are present all these three endocrinopathies [40]. An incomplete or subclinical form of APS-2 can also occur. Around 8% of patients with isolated AD may have positivity for one or more autoantibodies for AITD or T1DM without any clinical manifestation of the relative diseases. Among patients with T1DM and/or AITD, 0.5%–2% are positive for ACA/21-OHAbs but with normal cortisol levels both basal and after the ACTH stimulation test. These patients should be carefully followed up with a periodical reevaluation of cortisol secretion because at risk of clinical AD [40,44]. Other autoimmune disorders such as primary hypogonadism, AIG, vitiligo, alopecia, and CD can be present in patients with APS-2 and can develop during childhood and adolescence as well. Among them, primary hypogonadism affects mainly the female sex and it can be found in 3.6%– 10% of APS-2 patients. A positivity for anti-steroid-producing cell antibodies (StCA), and/or 17α-hydroxylase (17α-OH), and/or squamous cell carcinoma antigen (SCCA) is detected in these patients, who may develop lymphocytic oophoritis [40]. POI can occur both before and after the onset of AD [40]. AIG can be associated with pernicious anemia. It is reported in 5%–12% of patients with APS-2, and more frequently occurs in patients with already diagnosed AD. Vitiligo is diagnosed in 4.5%–20% of APS-2 patients. Unlike APS-1 patients, those with APS-2 are negative for circulating autoantibodies to SOX9 and SOX10 or to melanocytes [40]. Alopecia is reported in 0%–4%–5%, while celiac disease occurs in 2% of patients with APS-2 [4].

3.4  Treatment Treatment must be focused on the singular components of the APS-2. In particular, for endocrine diseases, it is specifically directed at replacing with appropriate hormonal replacement therapy for hormones that are deficient. An accurate and regular follow-up of patients with monoglandular autoimmune syndrome, most especially those with AD and T1DM, must be performed, because a second autoimmune glandular disease may become evident even after 20 years since the diagnosis of the first endocrinopathy [69].

4  Autoimmune polyendocrine syndrome type 3 (APS-3) 4.1  Definition and epidemiology APS-3 (ORPHA:227982) is more common compared to other APSs and may occur even in pediatric age, especially during adolescence and early adulthood. Nevertheless, there are only a few studies, aiming to specifically ascertain the clinical spectrum of this syndrome in the pediatric age, although it is worthy to be recognized as a separate entity [6,70,71]. According to the original and historical classification of Neufeld and Blizzard [2], APS-3 is a separate clinical entity that differs from the remaining APSs for both the mandatory presence of AITD and the mandatory absence of AD and hypoparathyroidism [70]. Moreover, the absence of immunodeficiency differs it also from IPEX syndrome [70,71]. According to the most

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FIG. 2  AITD associated with other organ-specific and non-organ-specific autoimmune diseases in APS-3. AITD, autoimmune thyroid diseases; APS-3, autoimmune polyendocrine syndrome 3; AA, alopecia areata; AIG, autoimmune gastritis; CD, celiac disease; CIU, chronic idiopathic urticaria; AITP, autoimmune thrombocytopenia; MG, myasthenia gravis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; T1DM, type 1 diabetes mellitus.

recent classification [4], APS-3 was categorized into four types in relation to endocrine and/ or non-endocrine-associated autoimmune diseases (Table 2) (Fig. 2). APS-3 is a complex, heterogeneous disorder in which various autoimmune diseases can occur, affecting both endocrine and non-endocrine organs. AITD is a group of frequent organ-specific autoimmune diseases, increasing with age and presenting a female predominance. From one in four to one in three patients with AITD have another associated autoimmune disease, making APS-3 the most frequent APS [4]. In recent decades, many published cohorts of patients have revealed high rates of other autoimmune diseases, both in adults and children with AITD [72–74]. A recent pediatric study highlighted that about 30% of young patients with HT may exhibit a clinical picture consistent with APS-3. In the context of pediatric APS-3, T1DM and CD were the most frequent autoimmune diseases that cluster with HT [71]. Moreover, APS-3 occurs in 14.5% of children with T1DM, and the incidence is positively correlated with patients’ age and female gender [75]. In a recent metaanalysis, the prevalence of associated autoimmune disease in APS-3 was investigated in a series of 665 cases. The prevalence of HT was significantly higher than that of GD. In APS-3, two other autoimmune endocrinopathies, six non-endocrine organ-specific, and four systemic autoimmune disorders were found in combination with AITD [76].

4.2  Genetics It is not clear why a patient develops a single autoimmune disease or an APS. This event is not casual and still requires an explanation. A hypothesis could be that tissues deriving from the same germ layer might share similar germ-layer-specific antigens, which would serve as 29



2.  Autoimmune polyendocrinopathies in pediatric age

targets for autoimmune responses. This hypothesis could in part explain APS-3 since for example the thyroid and the stomach derive from the same endodermal germ layer. The lack of animal models capable to develop spontaneously these syndromes did not make the process easier to understand [4]. APS-3 may be seen in more than one family member, suggesting that its inheritance could be as an autosomal dominant trait with incomplete penetrance, but the underlying genetic factors have yet to be clearly established. This syndrome is correlated with different HLA class II alleles, depending on the associated types of autoimmune disease. The genetic risk of the diseases overlaps and includes genes of HLA class II DR and DQ or HLA class I (MIC-A) [9,77]. Moreover, it was confirmed that the sharing of the immunogenetic background could be responsible for the development of multiple autoimmune diseases, with a different risk depending on the number and type of susceptible HLA-DQ heterodimers. It was suggested that combinations of DQA1 and DQB1 alleles are the real culprits of the progression towards multiple autoimmune diseases and that HLA-DQ genomic typing would improve the capability to predict associated autoimmune diseases in infancy. The possibility of this phenomenon had been studied in the pediatric population with T1DM, CD, and AITD [78]. Furthermore, other genes have been associated with these APS, including the genes encoding CTLA4 and PTPN22 [77]. To summarize, more autoimmune diseases tend to aggregate in the same patient (polyautoimmunity) and affected individuals tend to cluster in the same nuclear family (familial autoimmunity). Such shared characteristics suggest that the development of autoimmune diseases is affected by similar genetic, epigenetic, and environmental factors [79].

4.3  Diagnostic criteria and main clinical manifestations APS-3 has been categorized into four types in relation to endocrine and/or non-­endocrineassociated autoimmune diseases (Table 2). Although APS-3 is the most common polyglandular syndrome in the pediatric age, there are only a few studies aiming to specifically ascertain the clinical spectrum of this syndrome in childhood and adolescence [6]. Recent reports highlighted that the clustering of different non-thyroidal autoimmune diseases (NTADs) in patients with AITD may be conditioned also by other intrinsic factors, such as age [74], comorbidity with specific chromosomopathies like Down syndrome (DS) and Turner syndrome (TS) [80–82], and genetic predisposition [79]. 4.3.1  APS-3A—Association between AITD and other autoimmune endocrine diseases The prevalence of T1DM in pediatric HT populations was reported as 3.4%–6.9% and might go up to 25% in children and adolescents with chromosomopathies such as DS and TS [79]. In the case of pediatric GD, the prevalence of T1DM was reported as 3.7%–4.5% and might go up to 7.1% and 14.3% in children and adolescents with DS and TS, respectively [79]. Moreover, the higher prevalence of AITD in children and adolescents with T1DM (14.5%) compared to the general population and the availability of effective treatment, should favor the introduction of a screening program in that population [75]. Therefore, early diagnosis of AITDs can improve thyroid diseases and T1DM management. No literature data on the association between AITD and other autoimmune endocrine diseases as hypergonadotropic hypogonadism, lymphocytic adenohypophysitis, lymphocytic neurohypophysitis, and lymphocytic mastopathy are currently available for pediatric age. 30



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4.3.2  APS-3B—Association between AITD and autoimmune diseases of the digestive system The association between AITD and AIG, first known as “thyro-gastric syndrome,” is poorly characterized in the pediatric age. Recently, Calcaterra et al. confirmed the positivity of gastric parietal cell antibodies (PCA) in 10 (4.5%) of 220 children and adolescents with AITD. The prevalence of PCA positivity resulted in similar in GD and HT patients. Autoantibody positivity was more prevalent in female patients, in both HT and GD groups. PCA screening proved useful to detect subjects at risk for AIG. Due to the longer life expectancy of the pediatric population and considering the relatively high risk of malignant transformation, the authors suggested early surveillance monitoring of PCA as mandatory for children and adolescents with AITD [83]. The prevalence of CD in pediatric HT populations was reported as 1.9%–7.2% and might go up to 11%–14.3% in children and adolescents with DS [79]. In the case of pediatric GD, the prevalence of CD was reported as 2.7% and might go up to 14.3%– 32.1% in children and adolescents with TS and DS, respectively [79]. In view of this significant prevalence, the screening for CD seems to be very useful in pediatric population with AITD [84,85]. No literature data on the association between AITD and other autoimmune diseases of the digestive system as pernicious anemia, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune pancreatitis, and inflammatory bowel diseases are currently available for pediatric age. 4.3.3  APS-3C—Association between AITD and autoimmune skin, nervous system, or hematological diseases Skin autoimmune diseases were detected with similar prevalence in both adults and children, with vitiligo being the commonest one [74,79]. The prevalence of vitiligo in pediatric HT populations was reported as 2.7%–3.4% and might go up to 13.2% in children and adolescents with DS [79]. In the case of pediatric GD, the prevalence of vitiligo was reported as 4.5%–4.6% [79]. Moreover, the higher prevalence of AITD in children and adolescents with vitiligo (6.2%) compared to the general population and the availability of effective treatment, suggest the opportunity to introduce a screening program in that population [86]. The prevalence of alopecia areata in pediatric HT populations was reported as 0.9%–3.4% and might go up to 11.4%–27% in children and adolescents with DS [79]. In the case of pediatric GD, the prevalence of alopecia areata was reported as 0.9%–1.1% [79]. Chronic idiopathic urticaria (CIU) is not common in children (prevalence close to 1.8%) but is associated with autoimmunity in 30%–45% of cases and in 4.3%–57.4% of cases with AITD [87]. In some cases, CIU was associated with GD and treatment with anti-thyroid drugs resolved the CIU. There are conflicting reports of the complete or partial remission of CIU after L-thyroxine treatment in patients with HT. Nevertheless, in the large pediatric and adult HT series published by Ruggeri et al., only one pediatric case of CIU and two of psoriasis were observed [74]. Data on the association between myasthenia gravis (MG) and AITD in pediatric populations are lacking. Only a recent paper contained pediatric cases in a large study population from 4 to 89 years, unfortunately without separate evaluation of the pediatric patients [88]. AITD was diagnosed in 26.8% of MG patients including 4.4% with GD, 9% with HT, and 13.4% with only anti-thyroid antibodies positivity.MG coexisting with AITD followed a milder course than MG alone [88]. 31



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The association between AITD and autoimmune hemolytic anemia or autoimmune neutropenia is very rare and has only been described in some case reports of adult patients. By contrast, the association between AITD and autoimmune thrombocytopenia (AITP) is much more common also in the pediatric age. The results of a retrospective multicenter Italian study demonstrated a significantly higher (11.6%) prevalence of anti-thyroid antibodies (anti-TPO and anti-TG) positivity in children with chronic ITP compared to the general pediatric population. Moreover, no correlation had been found between platelets count and the prevalence of positive anti-thyroid antibodies at any time of the follow-up in that study population [89]. In a recent review, four papers including studies only on pediatric ITP population were discussed. Pediatric ITP patients had been shown to have a statistically significant prevalence of anti-thyroid antibodies compared to healthy controls (11.6%–36% vs 1.2%–1.3%) [90]. There are no clear data about the role of autoimmune thyroiditis as prognostic factor for chronic course of ITP in pediatric age. Data on the association between AITD and other autoimmune skin (e.g., autoimmune bullous diseases), nervous system (e.g., stiff-man syndrome, Guillain-Barré syndrome, neuromyelitisoptica, multiple sclerosis, and Lambert–Eaton syndrome), or hematological diseases are not currently available for the pediatric age. 4.3.4  APS-3D—Association between AITD and autoimmune rheumatic and cardiac diseases or vasculitis Thyroid function abnormalities and thyroid antibodies positivity have frequently been described in patients with autoimmune rheumatic diseases. However, limited data are available on the AITD prevalence in rheumatic disorders in childhood. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that affects any organ of the body, including the thyroid gland. Both hypothyroidism and hyperthyroidism have been found in SLE patients more frequently than in the general population. In a cohort of Egyptian children and adolescents with SLE, 35% presented thyroid dysfunctions (euthyroid sick syndrome in 15%, hypothyroidism in 10%, hyperthyroidism in 5%, and subclinical hyperthyroidism in 5%) that is related to the severity of SLE [91]. Another more dated study looked for autoimmune lesions of the thyroid gland in children suffering from rheumatoid arthritis (RA) and SLE. HT was found in 44.4% of children with RA (85.2% of them were euthyroid, 11.1% had a compensated hypothyroidism, and 3.7% had Hashitoxicosis); instead thyroglobulin antibodies were positive in 58% of SLE patients. Moreover, the serum levels of T3, T4, and TSH were in the reference limits in all children with SLE [92]. Nevertheless, in a large pediatric and adult HT series by Ruggeri et al., only one pediatric case of RA and one of vasculitis were observed [74]. However, according to that report, the clustering of autoimmune diseases might be significantly conditioned by patients’ age at the time of HT presentation. In fact, in HT adults the most frequently associated illnesses were found to be arthropathies and connective tissue diseases. On the contrary, in HT children and adolescents, these disorders were absent or very rare, while the most frequent ones were T1DM and CD [74]. Data on the association between AITD and other autoimmune rheumatic and cardiac diseases or vasculitis (e.g., systemic scleroderma, mixed connective tissue disease, Sjögren’s syndrome, dermatomyositis/polymyositis, anti-phospholipid syndrome, rheumatic fever, autoimmune myocardial diseases) are not currently available for pediatric age.

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In conclusion, APS-3 might have peculiar epidemiology and phenotypical expression in the pediatric age. Age at AITD presentation might itself influence the aggregation of NTADs by conditioning a different clustering of diseases in pediatric/adolescent and adult age. Children with APS-3 should be carefully monitored as a risk group of other autoimmune diseases development, also in subclinical or latent form. DS might be able to modify the aggregation of extra-thyroidal autoimmune diseases that are generally observed in children with AITD but without DS. The association with TS seems to be not able to modify the clustering of NTADs in the girls with AITD.

5  IPEX syndrome 5.1  Definition, epidemiology, and genetics IPEX syndrome (OMIM #304790, ORPHA:37042) is a very rare inherited disease, with a prevalence of about 1 case per 1.000.000 population, caused by mutation of the FOXP3 gene [4]. Human FOXP3, located on chromosome Xp11.2, encodes for a transcription factor playing a pivotal role in the development and regulation of Treg CD4+ CD25+ lymphocytes, which are involved in the regulation of immune response by blocking self-reactive T cells through interaction with APCs. FOXP3 mutations cause the loss of the inhibition of self-reactive T cells, which will trigger autoimmune processes [7]. This condition was studied on murine models in which an X-linked condition called scurfy, similar to IPEX, is related to mutations on FOXP3 gene [7]. Autoimmune conditions called IPEX-like syndromes have been described and related to mutations in other genes coding for proteins essential to Treg function, such as CTLA4 and CD25 and CD4 [7]. Circulating autoantibodies can be identified in IPEX patients. Autoantibodies against ­enteropathy-related 75 kDa antigen (AIE-75), harmonin and villin, proteins involved in anchoring intestinal villi and expressed in the renal proximal tubule, are considered markers of enteropathy and nephritis in these patients, while autoantibodies against GAD, IA2, and ICA, identified even a few weeks after birth, are related to the early onset of T1DM [7].

5.2  Diagnostic criteria and main clinical manifestations IPEX syndrome is typically characterized by very early onset T1DM, autoimmune enteropathy, and dermatitis. T1DM was diagnosed in about 70% of IPEX patients, and usually onset in the first weeks of life [4]. Enteropathy, reported in about 97% of patients, is characterized by intractable mucoid or bloody diarrhea and malabsorption, due to partial or total villous atrophy with infiltration of lymphocytes (CD3 +), plasma cells, and eosinophils, with consequent growth impairment and higher risk of infections [7]. Skin involvement, characterized by eczema, erythematous dermatitis, urticarial, and/or alopecia areata is documented in about 65% of cases. Other rarer manifestations may be diagnosed, including membranous glomerulonephritis, interstitial nephritis, autoimmune thyroiditis, exocrine pancreatitis, cholestatic hepatitis, hepatosplenomegaly, hemolytic anemia, thrombocytopenia, neutropenia. Infections, commonly due to Staphylococchi, C. albicans, cytomegalovirus, Enterococchi, can occur up to 50% of cases and have a severe course [4].

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2.  Autoimmune polyendocrinopathies in pediatric age

5.3  Therapy IPEX syndrome is often fatal within the first few years of life as a result of malabsorption or infections. Hematopoietic stem cell transplantation resulted in disease resolution in selected patients with a low organ involvement score [93]. Other therapeutic approaches such as immunosuppressants (e.g., cyclosporine A, tacrolimus, sirolimus, steroids), only partially reduce disease recurrence or complications, influencing long-term disease-free survival [93]. T1DM usually required insulin. Enteropathy sometimes responds to a gluten-free diet or, alternatively, needs parenteral nutrition [4].

6  Conclusion In the last decade, knowledge concerning APS has increased considerably, although many aspects remain unknown. APS-1is the most common type in pediatric age, but, as reported in recent studies, other types of APS can also occur and be diagnosed in childhood and adolescence. Clinical diagnosis, which may be delayed by the gradual appearance of the various components of the syndrome, should be supported by autoantibody detection. Autoimmune screening could allow an early diagnosis of APS improving clinical management. Further studies are needed to better clarify the pathogenesis of these rare conditions with the aim of promoting early diagnosis and implementing the clinical and therapeutic approach.

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C H A P T E R

3 Autoimmune thyroid diseases: Peculiarities in pediatric age Giorgia Pepea,b,⁎, Angelo Tropeanoa, Celeste Castoa, Alessandra Li Pomia, and Malgorzata Wasniewskaa a

Department of Adult and Childhood Human Pathology “Gaetano Barresi”, University of Messina, Messina, Italy bDepartment of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Messina, Italy ⁎ Corresponding author

Abstract Autoimmune thyroid diseases (AITD) include Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). HT is the most common autoimmune condition in the general population and the most frequent pediatric thyroid disease. GD is a relatively rare disease, but it is considered by far the most important cause of hyperthyroidism in the pediatric age. AITD are both characterized by lymphocytic infiltration of the thyroid parenchyma and by the production of different antibodies against thyroid antigens. The development of AITD is complex and involves a combination of genetic susceptibility as well as environmental triggering factors. Clinical and biochemical features are related to hyperthyroidism in GD, while HT may exhibit a huge variability of thyroid function patterns. The aim of this chapter is to report the most updated views on epidemiology, pathophysiology, diagnosis, long-term prognosis, treatment, and management of AITD in childhood and adolescence.

Keywords Hashimoto’s thyroiditis, Graves’ disease, Pediatric age, Hashitoxicosis, Thyroid autoimmunity, Neonatal autoimmunity, Turner syndrome, Down syndrome

1  Introduction Autoimmune thyroid diseases (AITD) are the most common organ-specific autoimmune disorders. AITD includes two main clinical presentations, Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). HT is the most frequent pediatric thyroid disease, and the first

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3.  Autoimmune thyroid diseases: Peculiarities in pediatric age

cause of goiter and acquired hypothyroidism in children and adolescents from iodine-­replete areas in the world [1]. GD is a relatively rare disease, but it represents by far the most important etiology of hyperthyroidism in the pediatric age [2]. AITD are characterized by lymphocytic infiltration of the thyroid parenchyma, and the release of different antibodies against thyroid antigens. Thyroid cells produce many immunological factors, such as cytokines, inflammatory mediators, and adhesion molecules, which can actively interact with the immune system, and that may explain why the thyroid gland is more prone to autoimmunity than many other organs. The development of AITD is complex and involves a combination of genetic susceptibility, environmental and endogenous factors that finally lead to the breakdown of tolerance [3–6]. Clinical and biochemical features are related to hyperthyroidism in GD, while HT may exhibit a huge variability of thyroid function patterns (ranging from hypothyroidism to euthyroidism, or even to hyperthyroidism) [7]. Although HT and GD show different phenotypes, they share a variety of common etiological and pathophysiological factors. In recent years, the evidence of fluctuations of thyroid functions, which may occur from HT to GD and vice versa, shed new light on AITD and suggested the existence of a continuum in the process of thyroid autoimmunity [8,9]. The aim of this chapter is to report the most updated views on epidemiology, pathophysiology, diagnosis, long-term prognosis, treatment, and management of AITD in childhood and adolescence.

2  Epidemiology The prevalence of AITD is estimated to be around 5%; however, the percentage of increased serum levels of antithyroid antibodies may be even higher. Furthermore, there is a growing trend in the incidence of these diseases, above all for HT. Diagnosis of AITD is made 5–10 times more often in women than in men, and the frequency increases with age (with a peak at around 45–65 years) [5,10,11]. There is also substantial geographic variability in the prevalence and incidence of AITD, and antithyroid antibodies levels differ with race. Indeed, people from iodine-sufficient areas have a higher incidence of HT than those from iodine-­ deficient ones [12–14]. TABLE 1  Prevalence rates of autoimmune thyroid diseases: Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) in the general pediatric population and in young patients with either Turner syndrome (TS) or Down syndrome (DS). HT

GD

Pediatric general population

1.2%–1.3%

1.07%

TS

10%–21%

1.7–3%

DS

13%–34%

6.5%

Adapted from T. Aversa, et al., Peculiarities of autoimmune thyroid diseases in children with Turner or Down syndrome: an overview. Ital. J. Pediatr., 2015;41:39.

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In the pediatric age, the prevalence of AITD is lower (1.2%–1.3% for HT and 1‰ for GD), but it increases in the case of chromosomopathies such as Down syndrome (DS) and Turner syndrome (TS) (Table 1) [15]. The most common age at presentation of AITD is adolescence, but they may develop at any time, rarely even in infants. Sexual dimorphism is similar to the adult population [2,5,15]. Therefore, the epidemiological evidence of genetic susceptibility to AITD emerged by the familial clustering of the disease (20%–30% of cases with family history for AITD) [12,16].

3  Pathogenesis The pathogenic mechanism of AITD is still under investigation. These conditions result from a complex interplay of genetic, environmental, and endogenous factors that lead to the breakdown of tolerance and the development of the disease (Fig. 1). In particular, AITD development occurs due to the loss of immune tolerance against thyroid autoantigens, including thyroid peroxidase (TPO), thyroglobulin (TG), and thyroid-stimulating hormone receptors (TSHR). This leads to the infiltration of the gland by T and B cells that produce antibodies

FIG. 1  Complex interplay of environmental, genetic, and endogenous factors in the pathogenesis of autoimmune thyroid diseases.

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3.  Autoimmune thyroid diseases: Peculiarities in pediatric age

responsible for the clinical manifestations of GD and HT. In addition, T cells in HT induce apoptosis in thyroid follicular cells, inducing the destruction of the gland. The different phenotypic picture of AITD probably depends on the type of immunological response [3]. Literature data confirmed the importance of cytokines and chemokines in the pathogenesis of HT and GD, and their involvement in the induction and effector phases of the immune response and inflammation [12]. Cytokines are produced by both lymphocytes and thyroid follicular cells and can modulate the growth and the function of thyroid follicular cells themselves, playing an important role in the extrathyroid AITD complications, particularly ophthalmopathy. Cytokines derived from T cells can directly damage thyroid cells, leading to functional disorders, and may also stimulate the production of nitric oxide (NO) and prostaglandins (PGs), thus increasing the inflammatory response [3]. The presence of several cytokines has been confirmed within the inflammatory and thyroid follicular cells; for instance, interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-14, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) [17]. Cytokine secretion profile can be considered as pro- or antiinflammatory, and pro- or antiapoptotic. Under the influence of chronic antigen challenge, macrophages and CD4 + T cells can be divided into T helper (Th)1 subset, producing cytokines involved in the cellular response (IL-2, IFN-γ, TNF-α, IL-1β), Th2 subset, which secrete cytokines associated with humoral response (IL-4, IL-5, IL-6, IL-10, IL13), and Th17 producing IL-17, IL-21, IL-22. Th3 immune cells produce mainly transforming growth factor-beta (TGF-β) and play a protective role against the occurrence of autoimmune diseases [3,18–20]. Cytokines enhance the inflammatory response by stimulation of both T and B lymphocytes, resulting in the production of antibodies and the damage of thyroid tissue by apoptosis, especially in HT [18]. HT is predominantly characterized by Th1 immune response, favoring the development of cell-mediated immunity, and thyroid follicular cell death by apoptosis [3,19]. GD promotes predominantly Th2 humoral response, with increased production by B cell of antibodies (of immunoglobulin G subtype) and cytokines. Such cytokine network inhibits the expression of Fas/FasL and activates the antiapoptotic molecule Bcl-2. This process protects thyrocytes from apoptosis, but instead increases the apoptosis of cytotoxic lymphocytes infiltrating thyroid tissue [3,19,20]. Schematic pathogenesis of AITD is illustrated in Fig. 2. A newer subtype of Th17 response may also be involved in the pathogenesis of GD, characterized by the secretion of proinflammatory cytokines (IL-17, IL-17F, IL-21, and IL-22). It is known that Th17 can also play an important role in chronic inflammatory diseases such as asthma and systemic lupus erythematosus (SLE) [21]. More recently, it has been considered that Th1, Th17, and effector B lymphocytes (Beff) are responsible for the upregulation of the immune response. Conversely, T regulatory lymphocytes (Tregs) and B regulatory lymphocytes (Bregs) cooperate against the spread of inflammation. B cells are considered to have both positive and negative regulatory roles in immune processes [4,22–24]. Thyroid peroxidase antibodies (TPOAb) as a marker of AITD are detectable in nearly all HT patients, and in 75% of patients with GD. Thyroid peroxidase is a key enzyme involved in thyroid hormonogenesis. Antibodies are produced mainly by lymphocytes infiltrating the thyroid gland and only to a small extent by the local lymph nodes or by the bone marrow. TPOAb, in contrast to anti-thyroglobulin antibodies (TGAb), are able to induce the complement system, cellular cytotoxicity, and thyroid failure [12,25].

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Stimulation of immune system

Presentation of autoantigen to APC cells

Reduction of immune tolerance, Changes in thyroid microenvironment

INF-γ IL-12

IL-4

↑ Th1 cytokines

↑ Th2 cytokines

TNF-α, IL-1β, INF-γ, IL-2 IL-2, IL-12, CD40L

IL-4, IL-5, IL-6, IL-10, IL-13, CD40L

Apoptosis of thyrocytes, but not infiltration lymphocytes

Apoptosis of infiltrating lymphocytes, but not thyrocytes

Destruction of thyrocytes

Proliferation of thyrocytes

HT

GD

FIG. 2  Pathogenesis of autoimmune thyroid diseases: Hashimoto’s thyroiditis (HT) involves predominantly Th1 immune response, whereas Graves’ disease (GD) is mainly characterized by TH2 lymphocyte subset activation. Adapted from H. Mikos, et al., The role of the immune system and cytokines involved in the pathogenesis of autoimmune thyroid disease (AITD). Endokrynol. Pol. 2014;65(2):150–155.

The prevalence of TGAb in patients with HT is 60–80%. In young patients with thyroiditis, however, TGAb may be present in the absence of TPOAb [26]. TSH receptor antibodies (TRAb) mimic the function of TSH and cause disease by binding to the TSH receptor, thus stimulating or inhibiting thyroid cells in terms of T3 and T4 production. Patients with AITD may present both stimulating and blocking antibodies [3]. In fact, the stimulating TRAbs are responsible for the hyperthyroidism of GD, and are detectable in more than 90% of GD patients, whereas blocking TRAbs are mostly detected in a fraction of patients with HT [12]. Several genes have been identified as significantly associated with AITD and/or with the presence of thyroid antibodies; for instance, PTPN22, CTLA4, Histocompatibility antigen (HLA) classes I and II molecules, IL2RA, FCRL3, RNASET2, BACH2, RNASET2, FOXE1, FOXP3, and RORC [3,4,27,28]. Their role and function are detailed in Table 2. Environmental factors which may contribute to the activation of innate immune response and, in susceptible individuals, to the development of AITD are above all radiation, iodine, smoking, infection, stress, and drugs [29]. They can contribute to the occurrence of AITD for about 20%. It has been confirmed that children exposed to radiation from Chernobyl showed a greater prevalence of thyroid autoantibody [12,30]. Moreover, iodine supplementation of populations that were previously iodine-deficient is associated with a transient increase of both autoimmune subclinical hypo- and hyperthyroidism [12,31]. Stress has been considered

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3.  Autoimmune thyroid diseases: Peculiarities in pediatric age

TABLE 2  Genes implicated in the pathogenesis of autoimmune thyroid diseases. Gene

Role (Immune recognition/response)

HLA class II

Antigenic recognition by CD4 + T-helper cells

CTLA-4

Costimulatory molecule; downregulates T-cell activation

PTPN-22

Inhibits T-cell signaling

IL2RA

Encodes CD25, which downregulates T-cells activity

FCRL3

Expressed during B-cell maturation, positively and negatively regulates B-cell signaling

HLA class I

Endogenous antigens presentation, such as virally derived antigens, for recognition by CD8 + T cells

GDCC4p14 and RNASET2

Expressed in CD4 + T helper and CD8 + T cells

BACH2

Controls B-cell development and antibody production

RORC2

Subpopulation differentiation of Th17 phenotype and increased number of these cells in peripheral blood and thyroid tissue

FOXP3

Development and functioning of T- regulatory cells

Thyroid-specific Thyroglobulin

Storage form, precursor of thyroxine

TSH-receptor

Autoantigenic target in GD

FOXE1

Involved in thyroid gland morphogenesis and binds response elements in thyroglobulin and thyroid peroxidase promoters

as a trigger factor for GD [32]. Some studies evaluated the contribution of viruses to the occurrence of AITD, mainly with no fully conclusive or negative results [33]. However, recently, some authors reported an association between hepatitis C virus (HCV) infection and AITD both in adults [34,35] and in children [36]. Finally, several studies enhanced the association of AITD with thyroid nodules and cancer, above all papillary thyroid carcinoma (PTC) [37,38], even though an increased risk of thyroid cancer in children and adolescents with nodular HT is still controversial and not constantly reported (cf., Section 7.3). The above mentioned data suggest that AITD patients should be accurately monitored for thyroid dysfunctions, the appearance of thyroid nodules, and other organ-specific or systemic autoimmune disorders during the course of the disease [12].

4  Thyroid function patterns at presentation The presenting features of GD are related to hyperthyroidism, whereas HT clinical and biochemical onset may be highly diversified. At the time of HT diagnosis, thyroid function is usually preserved, with normal or only slight TSH serum levels increase. However, it is well

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TABLE 3  Thyroid function patterns at diagnosis of autoimmune thyroid diseases: biochemical definition. Thyroid function pattern

Biochemical definition

Euthyroidism

TSH and FT4 within the normal reference range

Subclinical hypothyroidism

Normal FT4, elevated TSH (up to 10 IU/mL)

Overt hypothyroidism

Low FT4, elevated TSH

Subclinical hyperthyroidism

Normal FT4, suppressed TSH

Overt hyperthyroidism

Elevated FT4, suppressed TSH

known that there could be a great variability of thyroid function at presentation, ranging from euthyroidism to hypothyroidism or, more rarely, to hyperthyroidism. The spectrum of the biochemical mode of HT presentation is elucidated in Table 3 [39]. The prevalence rate of thyroid function patterns at diagnosis may significantly vary according to different epidemiological studies [40–44]. Euthyroidism is by far the most common initial pattern (about 52% of patients), followed by overt hypothyroidism (22.2%) and subclinical hypothyroidism (SH, 19.2%). Furthermore, at least 6.5% of HT patients may present with hyperthyroidism, either subclinical or overt hyperthyroidism [16]. The overt hyperthyroid phase of HT is known as Hashitoxicosis (Htx), and it is usually a transient process due to the unregulated release of stored thyroid hormones during inflammatory injury of the gland. Htx is the second commonest cause of thyrotoxicosis in childhood after GD. Clinical and biochemical features of HTx are similar to those observed in GD, therefore the differential diagnosis could be particularly challenging and should be based mainly on the absence of TRABS in Htx [45,46] (cf., Section 6). Overall, thyroid function patterns at HT onset seem to be mainly influenced by children’s age, with an increased risk of severe thyroid dysfunctions in case of early HT presentation. Association with chromosomopathies (especially DS and TS), other autoimmune diseases, and environmental factors may also significantly influence HT presentation [16].

5  Clinical manifestations Signs and symptoms of AIDT may be subtle even with marked biochemical derangement, therefore it is not surprising to diagnose a thyroid dysfunction incidentally during a medical examination for unrelated purposes. Regardless of the specific thyroid autoimmune process, the initial history should investigate energy level, school performance, sleep cycle, heat and cold tolerance, frequency of bowel movements, and menstrual cycle regularity in postpubertal girls. On the other hand, the palpation of the thyroid gland and the assessment of the ocular movements, orbital inflammation, and auxological status are important elements at physical examination. Signs and symptoms of AITD are detailed in Table 4.

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3.  Autoimmune thyroid diseases: Peculiarities in pediatric age

TABLE 4  Signs and symptoms of overt hypothyroidism and hyperthyroidism. Hypothyroidism

Hyperthyroidism

Goiter

Goiter with or without bruit

Fatigue/lethargy and/or impaired school performance

Irritability/ nervousness/fatigue and/or Impaired concentration and school performance

Bradycardia

Palpitations/tachycardia and/or systolic hypertension

Myxedema

Exophthalmos

Dry, pale, or yellowish skin

Warm skin

Dry, brittle, coarse hair/Increased body hair and/or alopecia

Fine hair

Increased weight

Weight loss

Delayed pubertal development/pseudoprecocious puberty

Tremor

Poor growth and bone maturation

Acceleration of linear growth and bone maturation

Cold intolerance

Heat intolerance

Constipation

Increased bowel movements

Abnormal menses

Abnormal menses

5.1  Hashimoto’s thyroiditis Due to the huge variability of biochemical pictures observed (cf., Section 4), also HT clinical presentation could be heterogeneous, elusive, and influenced by the severity and duration of the disease. Goiter, which may be a presenting feature, is typically diffuse, non-tender, and sometimes firm [47]. It may rarely cause the compression of the cervical structures originating symptoms like hoarseness, cough, dysphonia, dysphagia, or dyspnea [39]. Its prevalence varies from 28% to 100% in several studies [43,48], with higher frequency in hypothyroid children according to some authors [43], or in euthyroid patients according to other ones [49]. Furthermore, in recent research including only children with severe hypothyroidism (TSH value above 100 μIU/mL), the presence of goiter was demonstrated only in 42% of the study population [48]. Although such heterogeneity in the prevalence rate could be dependent on the modality of detection (thyroid ultrasound or physical examination), it is possible that non-TSH-­ dependent determinants (such as lymphocytic infiltration, apoptosis, inflammation-mediated thyroid destruction) can influence the thyroid size. Several lines of evidence seem to show a less important role played by TSH receptor-blocking antibodies in the incidence of goiter in childhood [50]. Thyroid hormones perform a pivotal function in linear growth during prepubertal life. Normal height, growth velocity, and bone maturation are usually observed in children with autoimmune euthyroidism and SH, even of many years duration [7,51]. Conversely, decreased growth velocity and weight gain are common clinical manifestations of severe hypothyroidism. Growth delay could be insidious at onset and, if undiagnosed, may result in

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incomplete catch-up growth [48,52,53]. Additionally, primary hypothyroidism can arouse the prolactin secretion, which, in turn, may cause puberty arrest, oligomenorrhea, or secondary amenorrhea [48]. However, some authors also reported clinical cases of precocious menarche, breast development, testicular enlargement, and metrorrhagia [48,54]. Skin involvement is the hallmark of hypothyroidism, because of the direct action of thyroid hormones on skin tissues. Generalized myxedema, a classic cutaneous sign, is caused by the deposition of dermal acid mucopolysaccharides (especially hyaluronic acid). The hygroscopic propriety of mucin as well as the increased transcapillary escape of albumin and the inadequate lymphatic drainage are the major components of non-pitting edema (myxedema). The skin of hypothyroid patients tends to be pale (because of the dermal mucopolysaccharides and water content) or yellowish on the palms, soles, and nasolabial folds (due to the increased dermal carotene), coarsened, thin, scaly, and dry (for the decreased eccrine gland secretion). The cutaneous appendages are also involved; hair can be dry, coarse, brittle, and slow-growing, as well as the nails, which may be thickened, brittle and slow-growing. In addition, diffuse or partial alopecia may be observed along with hypertrichosis on other skin areas [55]. Other frequent symptoms of hypothyroidism are constipation, bradycardia, cold intolerance, weakness, tiredness, sleepiness, and school failure. Instead, myopathy, rhabdomyolysis (with increased serum level of creatinine), liver injury (associated with increased serum level of transaminases), and anemia are less frequent presenting manifestations [48,56]. Unusual manifestations of severe hypothyroidism are muscle pseudohypertrophy (Kocher-DebreSemelaigne-syndrome), pericardial effusion, ventricular myocardial hypertrophy, and pituitary hyperplasia (due to TSH-hypersecretion) [48,53,57,58]. Finally, the presenting clinical picture of Hashitoxicosis is not very different from that observed in GD [39,45].

5.2  Graves’ disease The presentation of GD in childhood may be insidious, and nearly one-fourth of patients are referred to another subspecialist before being evaluated by a pediatric endocrinologist [59]. The symptoms at diagnosis seem to vary with age; in prepubertal patients, the main complaints are weight loss and frequent bowel movements, while irritability, palpitations, and heat intolerance occur more often in pubertal and postpubertal adolescents [60]. The most common clinical feature at diagnosis is tachycardia, with or without other cardiac signs such as elevated blood pressure, precordial thrill, ejection murmur, and arrhythmia [39,61,62]. Physical examination should also investigate for restlessness, fine hand tremor (at arm extension), warm thin skin, and thyroid enlargement [61]. Goiter is found in the majority of cases and is characterized by diffuse, firm, and non-tender enlargement of the gland with often a detectable bruit. Behavioral disturbances, such as hyperactivity, nervousness, fatigue, decreased attention span, and deteriorated school performance as well as neuropsychiatric problems, including anxiety, depression, agitation, aggressiveness, or confusion, are very common and often misinterpreted. From an auxological point of view, accelerated growth rate and advanced bone maturation are signs of prolonged hyperthyroidism, and then of late diagnosis. Thyroid-associated ophthalmopathy (TAO) occurs in up to one-third of pediatric patients, and its appearance is less severe if compared with adults [47,63]. TAO usually accompanies

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3.  Autoimmune thyroid diseases: Peculiarities in pediatric age

GD, even if it may also occur in association with HT (both in hypothyroidism and euthyroidism). It is more frequent in girls than in boys, with predominance for adolescents. The most common signs of TAO are lid retraction, lag of the lids behind the globes on downward rotation, failure to wrinkle the forehead in looking upward, and mild proptosis [64]. Conversely, signs or symptoms such as burning, photophobia, tearing, foreign body sensation, diplopia, restrictive strabismus, and exposure keratopathy are expressions of severe inflammation of orbit tissues and extraocular muscles [39,64]. Finally, uncommon signs of GD in childhood are pretibial edema, involuntary movement disorders (chorea, athetosis, and ataxia), osteoporosis, shortness of breath, dysphagia, polydipsia, and irregular menses [39,61].

6  Diagnosis Diagnosis of AITDs is based on clinical features, biochemical findings (positivity of thyroid autoantibodies, laboratory alteration of thyroid function), and evidence of specific patterns at the imaging (such as ultrasound evaluation or scintigraphy). The most remarkable tools for the diagnosis of HT and GD are synthetized in Table 5.

6.1  Hashimoto’s thyroiditis Signs and symptoms of HT are non-specific, and goiter can be absent at clinical evaluation, so the diagnosis is often made during screening evaluations in children with risk factors. TPOAb are the best serological markers for diagnosis, since they are positive in about 95% of HT patients and correlate with the rate of autoreactive lymphocytes infiltrating the thyroid and the degree of ultrasonographic hypoechogenicity. TGAb are detectable in only 60%–80% of HT patients. In addition, the prevalence of TGAb in healthy individuals is higher if compared to TPOAb [47,65]. The biochemical evaluation of thyroid function involves the measurement of serum levels of TSH and FT4. Serum FT3 is less useful than FT4, and in mild hypothyroidism FT3 concentration can be normal, as a result of an increased peripheral conversion from TABLE 5  Differential diagnosis between Graves’ disease and Hashimoto’s thyroiditis. Graves’ disease

Hashimoto’s thyroiditis

TSH

Low/suppressed

Normal/high

FT4/FT3

Normal/high

Normal/low

TRABs

++

–

TPOAb

−/+

++

Ultrasonography

− enlarged and hypoechoic gland − enlarged and hypoechoic gland − vascular flow increment at color- − heterogeneous echotexture flow doppler analysis − pseudo-nodules

Radioactive iodine or technetium-99 uptake

Diffuse increased uptake

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FT4 [66]. However, at the time of diagnosis, in the majority of cases, TSH and FT4 serum levels could be in the normal range, even if thyroid function may significantly vary from SH to overt hypothyroidism, or rarely to hyperthyroidism (cf., Section  4). Such a huge variability in the biochemical mode of HT presentation, make thyroid function assessment less relevant criteria for diagnosis, but an excellent tool to monitor HT evolution over time [16,47,67]. As far as thyroid ultrasound (TUS) is concerned, it is by far the most commonly used imaging technique to support the diagnosis of HT, in spite of scintigraphy and fine-needle aspiration (FNA) cytology, which are less frequently performed nowadays [65]. Classical sonographic findings are present in 20%–95% of cases, and the sonographic picture reflects the degree of structural and functional thyroid involvement [68,69]. In the early stage of the autoimmune process, the thyroid can be normal or slightly enlarged with normal or mild heterogeneous echotexture. About 50% of HT children with initially normal TUS will exhibit changes within 7 months [70]. Due to inflammatory cell infiltration, the gland classically appears diffusely enlarged (goiterous form) and hypoechoic, or it could show a pseudo-nodular pattern with multiple hypoechoic areas. Later, as a consequence of the fibroblastic proliferation, inhomogeneous parenchyma and pseudonodules could be found at TUS. The volume of the gland may also be reduced (atrophic form) [71,72]. Micronodular patterns and focal nodules can also be detected by TUS. Finally, ­ultrasound-guided FNA biopsy can be helpful to exclude malignancy in case of large nodules (> 1 cm of diameter) or small nodules ( 5 IU/L) and free thyroid hormones levels high (FT4 > 40 pmol/L) in the serum in the first 2–4 days after delivery, should lead to the initiation of ATDs treatment in the infant shortly after birth [124,128] (Fig. 3). MMI should be started at a dose of 0.2–0.5 mg/kg/day. Propranolol should be added at a dose of 2 mg/kg/day for signs of sympathetic hyperactivity, including tachycardia and hypertension. PTU is not recommended in neonates, as well as in children, because of the increased risk for hepatotoxicity [123]. The disease is transient and may last from 1 to 3 months

TRAb positive or unknown at II-III trimester in pregrant women with Graves Disease Newborn at high risk

TRAb negative at II-III trimester in pregrant women

Newborn at low risk: no specific follow-up is required

Dose TRAb in cord blood TRAb positive or sample not available First day of life: - Medical history and physical examination - Dose TRAb in sample available and if not dosed on cord blood 3°-5° day of life: - Medical history and physical examination - Dose FT4 and TSH: if pathological, start therapy

If TRAb negative at cord blood and serum: newbord at low risk no specific follow-up is required

10°-14° day of life: - Medical history and physical examination - Dose FT4 and TSH: if pathological, start therapy - Dose TRAb if sample available and if not dosed before

If TRAb unknown or positive in asymptomatic newborn and normal thyroid function tests clinical follow-up after 4 weeks and then after 2-3 months FIG. 3  Management of newborn to mother with Graves’ disease. Adapted from D.C. van der Kaay, J.D. Wasserman, and M.R. Palmert, Management of neonates born to mothers with Graves' Dis. Pediatr. 2016;137(4).

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until maternal TRAb are eliminated from the infant’s bloodstream. Mothers can breastfeed while taking ATDs, with no adverse effects on the thyroid status of their infants [124].

9.2  Neonatal hypothyroidism Neonatal Hypothyroidism caused by transplacental passage of maternal inhibiting TRAb represents only 1%–2% of cases of congenital hypothyroidism [129] and differently from ­hypothyroidism caused by thyroid dysgenesis, it appears in the last weeks of gestation. In contrast, the presence of TPOAb and TGAb in the serum of pregnant women (and their eventual transplacental passage) does not influence fetal and/or neonatal thyroid function. In the case of TRAb positivity in neonatal blood associated with pathological FT4 and TSH, it is required urgent substitutive therapy with L-T4 at the dosage of 10 μg/kg/day, continued until the age of 3. TRAb can block the thyroid uptake of radioiodine and technetium stimulated by TSH; for this reason, thyroid scintigraphy can be falsified, suggesting a misdiagnosis of thyroid agenesis or hypoplasia [130]. Apart from the transplacental passage of maternal inhibiting TRAb, neonatal hypothyroidism can also occur when the dose of the replacement therapy with L-T4 is not adequate in the mother with autoimmune hypothyroidism, in a condition -such as the pregnancy-­ characterized by increased requirement of thyroid hormones.

10  Autoimmune thyroid diseases in genetic syndromes Turner syndrome (TS) and Down syndrome (DS) are two chromosomopathies strictly associated with autoimmune diseases. Both in TS and DS, the thyroid is one of the organs most frequently involved in the autoimmune process, and the prevalence of AITDs is higher in presence of chromosomopathies. HT and GD are characterized by some peculiarities in terms of epidemiology, pathophysiology, and clinical course when they occur in association with TS or DS (Table 12). Moreover, patients with chromosomopathies may display the well-known metamorphosis of clinical phenotype from HT to GD, with a higher rate of conversion than that reported in the general population. Given the increased frequency of HT and GD and the higher risk of thyroid function deterioration over time, a periodic follow-up of thyroid function is highly recommended in these patients.

10.1  Turner syndrome TS is one of the most common chromosomal abnormalities, affecting 1 in 2000–2500 liveborn females. It is caused by partial or total monosomy of one X chromosome, with or without cell line mosaicism [131]. The clinical spectrum of TS includes short stature, gonadal dysgenesis, peculiar facial and skeletal dysmorphisms, renal and cardiovascular anomalies, and lymphedema. TS girls are at high risk of developing autoimmune diseases. Several mechanisms have been proposed to explain the increased susceptibility to autoimmune diseases in TS; haploinsufficiency of genes localized in the pseudoautosomal region of the X chromosome, hypogonadism, increased production of proinflammatory cytokines, and decreased production of antiinflammatory cytokines [86,94,132–134].

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3.  Autoimmune thyroid diseases: Peculiarities in pediatric age

TABLE 12  Main peculiarities of autoimmune thyroid diseases in children and adolescents with Turner syndrome or Down syndrome, compared to the general pediatric population.

HT

Turner syndrome

Down syndrome

Pediatric general population

Prevalence

10–20%a

13–34%a

1.2%a

Gender predominance

NA

No gender predominance

Female

AITD antecedents

Not common

Not common

Common

Euthyroidism: 73.3%

Euthyroidism: 13.7%

Euthyroidism: 54.3%a

Subclinical hypothyroidism: 23.4%a

Subclinical hypothyroidism: 63.0%a

Subclinical hypothyroidism: 17.2%a

Overt hypothyroidism: 3.3%a

Overt hypothyroidism: 19.2%a

Overt hypothyroidism: 22.1%a

Hyperthyroidism: 0%a

Hyperthyroidism: 4.1%a

Hyperthyroidism: 6.4%a

Prevalence

1.7–3%a

6.5%a

1.07%a

Gender predominance

NA

No gender predominance

Female

AITDs antecedents

Not common

Not common

Common

Presentation patterns

GD

Evolution from HT to GD

a

4.3%

a

c

c

21.4%

3.7%b

HT, Hashimoto thyroiditis; GD, Graves’ disease; NA, not applicable; AITDs, autoimmune thyroiditis. a Aversa et al. [15]. b Wasniewska et al. [93]. c Aversa et al. [94].

AITD are the most frequent organ-specific autoimmune disease in patients with TS. A possible explanation of this process includes the association between AITD and the female gender [135]. Specifically, it has been hypothesized that the haploinsufficiency of the FOXP3 gene, located on the X chromosome, may contribute to the increased susceptibility of TS girls to AITD [136,137]. The association between a specific TS karyotype and AITDs is still controversial. According to some authors, patients with X isochromosome are more prone to develop thyroid autoimmunity [135,138,139], whereas others found no evidence of a correlation with TS karyotypes [137,140]. In TS girls, HT is overall the most common autoimmune disease, and the prevalence increases with age. Compared to the general population, TS subjects have a lower frequency of family history for HT antecedents, suggesting an inherent predisposition to develop HT in these girls [141,142]. Detection of thyroid autoantibodies increases mainly after the age of 13, but hypothyroidism can appear even under 2 years old [142]. Therefore, a careful assessment of thyroid function should be performed at the time of diagnosis and closely monitored annually, regardless of age [131]. At diagnosis, thyroid function impairment is milder in girls with TS than in those without, as shown by a higher prevalence of initial euthyroidism and lower median serum TSH levels of TSH and TPOAb. These findings are probably related to earlier detection of thyroid dysfunction due to a greater awareness of pediatricians, in addition to a milder autoimmune

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pattern [15,141,142]. Despite a less severe presentation pattern and irrespective of karyotype, in TS, there is a progressive spontaneous deterioration of thyroid function over time, especially in the case of SH at diagnosis [15,86,141,143]. As well as for HT, also the prevalence rate of GD in TS girls is higher (about 1.7%–3%) than in the general population and increases with age [133,144]. GD biochemical picture at diagnosis and clinical course are similar in TS and non-TS girls. Indeed, methimazole dose required to maintain euthyroidism during the first cycle of therapy, remission, and relapse rates does not significantly differ from those observed in non-TS girls [133]. Finally, GD in TS patients may be often preceded by HT (about 25.7% of cases), regardless of thyroid function and autoimmunity tests at HT diagnosis [94,133].

10.2  Down syndrome DS is the commonest chromosomal aneuploidy, affecting 1 in 1000 live births. In 95% of cases, DS is caused by chromosome 21 trisomy (non-disjunction), while the remaining ones are due to mosaicism or Robertsonian translocation. DS is associated with facial dysmorphisms, mental retardation, hypotonia, short stature, congenital heart defects, gastrointestinal anomalies, increased risk of hematologic malignancies, immunological disorders, and thyroid disorders [145]. Autoimmune diseases exhibit higher incidence among individuals with DS, in particular AITD, alopecia, vitiligo, type 1 diabetes mellitus, celiac disease, and juvenile idiopathic arthritis [146,147]. Several mechanisms have been proposed to explain the increased susceptibility to autoimmunity in DS subjects, and in particular: • partial central tolerance failure due to altered thymic expression of AIRE gene, which is located on chromosome 21 and involved in immune regulation [148]. • thymic atrophy and T and B lymphocytes reduction [149,150]. • increased proinflammatory cytokine levels and decreased antiinflammatory cytokine levels due to alterations in the extracellular adenine nucleotides and nucleosides levels [151]. HT is the most common autoimmune disease in DS children and adolescents, ranging in prevalence from 13% to 34% [15,152]. If compared to the general population, HT in DS shows no gender predominance, lower frequency of family history of thyroid diseases, and higher prevalence of extra-thyroidal autoimmune disorders, indicating that DS subjects are per se more prone to develop AITD [15,146,152]. Moreover, HT in DS occurs earlier (often under the age of 10), with a more severe biochemical presentation and clinical course, and with a higher rate of conversion to GD over time(about 25% of cases) than the general population. Indeed, the most common pattern at HT diagnosis is SH, followed by overt hypothyroidism [86,94,153,154]. Overall, DS patients are exposed to a higher risk of thyroid function deterioration, which seems to be related to higher baseline TSH levels at diagnosis and autoimmunity. Nevertheless, it is worth noting that thyroid dysfunction—especially in very young DS infants—may be also of non-autoimmune etiology, suggesting a congenital thyroid alteration, which is directly related to the trisomy condition of chromosome 21. This phenomenon could be explained by a non-pathological shift in the normal range of TSH as a characteristic of DS, which results in

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3.  Autoimmune thyroid diseases: Peculiarities in pediatric age

a generally mild and transient form of SH at group level [154]. As well as HT, GD in DS has a higher prevalence and occurs at a younger age than in the general population (about 6.5%), without gender preference, and frequently in association with other autoimmune disorders [155,156]. GD presentation is not different in children with or without DS, but the clinical course of the disease seems to be less severe in DS subjects. Indeed, according to some authors, GD in DS children shows lower relapse rates during the first methimazole therapy cycle, lower methimazole dosages requested to maintain biochemical euthyroidism, higher remission rates after methimazole withdrawal, and less need for non-pharmacological treatments [15,142,156]. However, this is not a constant finding, since other authors observed a shorter duration of remission and higher relapse rates with medical treatment in DS patients, suggesting that radioactive iodine treatment may be the best option [155,157].

11  Conclusion GD and HT are the two major AITD. In pediatric age, AITD show a peak of incidence during puberty and a gender predominance for female sex (as well as in adulthood). They result from a yet poorly clarified defect in immunoregulation, which causes T and B lymphocytes infiltration of the gland, together with the production of thyroid autoantibodies. The autoimmune process develops when a combination of genetic susceptibility and environmental triggering factors leads to the breakdown of tolerance. Diagnosis of AITD is based on clinical features, thyroid autoantibodies positivity, thyroid function tests, and specific ultrasound alterations. Clinical and biochemical patterns are related to hyperthyroidism in GD, thus requiring therapy with antithyroid drugs, and sometimes also radical non-­ pharmacological treatments. HT presentation and long-term prognosis could be highly heterogeneous, ranging from euthyroidism to subclinical or overt hypothyroidism, and occasionally even to subclinical or overt hyperthyroidism (Hashitoxicosis). For this reason, thyroid function assessment is a less relevant criteria for HT diagnosis but remains an excellent tool to monitor the evolution of the disease over time. In case of overt hypothyroidism, replacement therapy with L-T4 is mandatory, especially in very young infants, to optimize growth and neurodevelopment. The association with chromosomopathies, such as TS and DS, may significantly influence AITD natural course, by increasing the risk of future thyroid function deterioration and promoting the conversion from HT to GD. All AITD patients should be accurately followed-up for thyroid dysfunctions, the occurrence of thyroid nodules, and other associated autoimmune diseases.

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[147] J. Carnicer, et  al., Prevalence of coeliac disease in Down's syndrome, Eur. J. Gastroenterol. Hepatol. 13 (3) (2001) 263–267. [148] M. Gimenez-Barcons, et al., Autoimmune predisposition in down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens, J. Immunol. 193 (8) (2014) 3872–3879. [149] Y.C. de Hingh, et al., Intrinsic abnormalities of lymphocyte counts in children with down syndrome, J. Pediatr. 147 (6) (2005) 744–747. [150] L. Nespoli, et al., Immunological features of Down's syndrome: a review, J. Intellect. Disabil. Res. 37 (Pt 6) (1993) 543–551. [151] R. Rodrigues, et  al., Alterations of ectonucleotidases and acetylcholinesterase activities in lymphocytes of down syndrome subjects: relation with inflammatory parameters, Clin. Chim. Acta 433 (2014) 105–110. [152] G. Popova, et al., Hashimoto's thyroiditis in Down's syndrome: clinical presentation and evolution, Horm. Res. 70 (5) (2008) 278–284. [153] T. Aversa, et  al., Metamorphic thyroid autoimmunity in down syndrome: from Hashimoto's thyroiditis to Graves' disease and beyond, Ital. J. Pediatr. 41 (2015) 87. [154] G. Pepe, et al., Prospective evaluation of autoimmune and non-autoimmune subclinical hypothyroidism in down syndrome children, Eur. J. Endocrinol. 182 (4) (2020) 385–392. [155] A. Goday-Arno, et al., Hyperthyroidism in a population with Down syndrome (DS), Clin. Endocrinol. (Oxf) 71 (1) (2009) 110–114. [156] F. De Luca, et al., Peculiarities of Graves' disease in children and adolescents with Down's syndrome, Eur. J. Endocrinol. 162 (3) (2010) 591–595. [157] N. Damle, K. Das, C. Bal, Graves' disease in a Down's syndrome patient responds well to radioiodine rather than antithyroid drugs, J. Pediatr. Endocrinol. Metab. 24 (7–8) (2011) 611.

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C H A P T E R

4 TSH receptor autoantibodies in Graves’ disease Renato Tozzolia,⁎ and Nicola Bizzarob,c a

Laboratorio di Chimica Clinica ed Ematologia, Ospedale Villa Salus, Venezia, Unità di Endocrinologia, Casa di Cura San Giorgio, Pordenone, Italy bLaboratorio di Patologia Clinica, Ospedale San Antonio, Tolmezzo, Italy cAzienda Sanitaria Universitaria Integrata di Udine, Udine, Italy ⁎ Corresponding author

Abstract Graves’ disease (GD) is an autoimmune disease characterized by the excessive production of thyroid hormones, often accompanied by an inflammatory ocular disorder (Graves’ orbitopathy). The pathogenesis is strongly related to the presence of autoantibodies against the TSH receptor (TRAb), functionally distinguished in three types: stimulating, blocking, or neutral (apoptotic). These autoantibodies can be simultaneously present in GD patients and the relative amount of each one of these distinct subtypes influences the clinical expression of the disease. TRAb can be detected and measured by immunoassays or by bioassays. While immunoassays measure the total concentration of autoantibodies, bioassays permit the study of the functional activity of TRAb. As they are present in percentages close to 100% in untreated GD patients, measurement of TRAb is recommended by international guidelines for GD diagnosis and for the differential diagnosis of autoimmune thyroid diseases.

Keywords Graves’ disease, Basedow disease, Graves’ orbitopathy, TSH receptor autoantibodies, Immunoassays, Bioassays

1  Introduction Autoimmune thyroid diseases (AITD) are the most frequent autoimmune diseases, affecting 5% of the population, with a female/male ratio of about 10:1 [1,2]. AITD constitutes a continuous spectrum of pathologies, mainly represented by Hashimoto’s thyroiditis (HT)

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4.  TSH receptor autoantibodies in Graves’ disease

and Graves’ disease (GD), which are characterized by lymphocytic infiltration of the thyroid gland and by autoimmune phenomena that eventually lead to clinical hypothyroidism or hyperthyroidism, respectively. HT and GD often occur in patients with other autoimmune diseases, setting up the most common example of poly-autoimmunity that defines multiple autoimmune syndromes [3]. AITD are characterized by the presence of autoantibodies directed against thyroid ­autoantigens such as anti-thyroglobulin (TgAb), anti-thyroperoxidase (TPOAb), and anti-­ thyroid stimulating hormone (TSH) receptor (TRAb) antibodies, which represent markers of ­intra-thyroid autoimmune reactions. While TgAb and TPOAb are detected by consolidated tests carried out for many years, only recently the determination of TRAbs has been made available to clinical laboratories for the differential diagnosis of AITD.

2  Basedow-Graves’ disease: Clinical aspects Graves’ disease (also called Basedow disease) is an autoimmune disease characterized by the widespread enlargement of the gland (toxic diffuse goiter), associated with excessive production of thyroid hormones (hyperthyroidism). An inflammatory ocular disorder (Graves’ orbitopathy—GO) is also often present. More rarely, localized infiltrative dermopathy (myxedema) and acropachia may be present (Table 1). Therefore, the classical clinical picture of GD is synthetized in the “GD triad,” consisting of hyperthyroidism, thyroid eye disease, and myxedema [4]. The clinical forms of GD are now considered explicable by the type of TSHR involved in immune activation (monomeric or dimeric), the heterogeneous sites of TSHR expression (thyrocytes, fibroblasts, adipocytes, bone cells, and other cell types), and the multiplicity of biochemical pathways involving TSHR (G-protein dependent or G-protein independent) [5]. The first description of the disease dates back to 1835 when the Irish physician Robert James Graves described three cases of women with prolonged palpitations and goiter. In 1805, however, the Italian Giovanni Flajani had already described two cases of goiter associated with prolonged palpitations, but had not recognized the thyroid origin of the disease, calling it “bronchocele.” In 1840, the German Carl A. von Basedow described exophthalmos caused by the hypertrophy of the cells of the retroorbital tissue. His first complete description of the triad exophthalmos, diffuse goiter, and palpitations spread widely, so much so that in many non-English speaking European countries the disease is known by his name [6]. GD is the major cause of hyperthyroidism in humans [7], with an annual incidence of 2% in females and 0.2% in males, and a prevalence of 1% in the general population [7–9]. The TABLE 1  Clinical classification of GD. Hyperthyroidism with/without goiter Hyperthyroidism with/without orbitopathy Hyperthyroidism with/without pretibial myxedema Isolated Graves’ orbitopathy Thyroid acropachy

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lifetime risk is 3% for women and 0.5% for men [10]. GD can appear within two extremes, as an asymptomatic form usually identified only by decreased TSH concentrations, or as a life-threatening thyroid storm with high mortality [8]. The peak incidence is in the third to fourth decade of age; however, the disease can occur at any age, including childhood. Most scholars believe that GD is a multifactorial pathology, determined by the intersection of genetic, hormonal, and environmental factors [9,11]. When genetically susceptible individuals are exposed to certain environmental triggers, autoreactive thyroid-specific T cells are formed that infiltrate the thyroid gland and activate B cells to produce TSHR stimulating antibodies. TSHR stimulating antibodies stimulate thyroid cells to proliferate and secrete excess thyroid hormones causing goiter and hyperthyroidism. The excess of circulating hormones is directly responsible for the specific manifestations in various organs and systems. The overproduction of thyroid hormones may induce goiter, weight loss, fatigue, heat intolerance, tremor, palpitations, decreased appetite, cardiac manifestations, orbitopathy, and dermopathy (Table  1). In general, the clinical manifestations of GD depend on the age of affected patients; elderly patients tend to present with cardiovascular symptoms, that range from tachycardia and atrial fibrillation to heart failure; in patients  38°C, no cause) Fibromyalgia

• Articular involvement

Arthralgia Arthritis

• Vascular involvement

Purpura Skin ulcers Necrotizing vasculitis Hyperviscosity syndrome Raynaud’s phenomenon

• Neurologic involvement

Peripheral neuropathy Cranial nerve involvement Vasculitic CNS involvement

ITEM 3—Laboratory item: at least two of the following three (present) • Reduced serum C4 • Positive serum RF • Positive serum M component Legend: CNS, central nervous system; RF, rheumatoid factor. Criteria fulfillment is satisfied if at least two of the following three items (questionnaire, clinical, laboratory) are positive. The patient must be positive for serum Cryoglobulins in at least two determinations at ≥ 12-week intervals [78].

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Positive serum CGs should be measured at two occasions at least 12 weeks apart. Cases with typical clinical features of CV but with negative CGs should be followed carefully with repeated measurements for serum CGs. Finally, patients with previous positive CGs should be considered positive even if CGs are negative at the time of evaluation [87].

10  Treatment Treatment depends on the type of the CGs, etiology, and the severity of the disease (according to the type and the extent of organ involvement [8].

10.1  Treatment according to disease severity Asymptomatic CV patients are not candidates for therapy. Mild cases like those with arthralgias, myalgias, purpura, and fatigue need only symptomatic treatment together with treatment of the underlying cause (e.g., DAAs for HCV-CV). Despite the absence of precise and agreed criteria for severe disease, suggested manifestations associated with moderate to severe CV that can be life-threatening include [88]: • Biopsy-proven GN associated with or without a rapidly progressive course • Severe limb ischemia threatening amputation • Severe gastrointestinal vasculitis associated with abdominal pain and/or gastrointestinal bleeding • Progressive neuropathy • Central nervous system vasculitis manifesting as a stroke or acute cognitive impairment • Pulmonary vasculitis associated with diffuse alveolar hemorrhage or respiratory failure Cases presenting by one or more of these manifestations should be treated as early and aggressively as possible with immunosuppressive therapy in addition to treating the underlying cause “whenever detected.” This strategy guarantees rapid clearance of circulating ICs and suppresses de novo ICs formation to improve or resolve target-organ damage [88,89]. Immunosuppressive treatment includes high-dose corticosteroids (CS) with rituximab (RTX) rather than cyclophosphamide (CYC). RTX induces longer periods of remission, decreases the Birmingham vasculitis activity score (BVAS), and depletes CD19 +  B cells reported to be HCV reservoirs [90]. CYC may be only recommended when RTX is unavailable, not tolerated, or shows a poor response. Plasma exchange (PLEX) should be added to the management plan in life-threatening cases like CG-associated hyperviscosity syndrome; extreme refractory skin ulcers, rapidly progressive GN, severe gastrointestinal vasculitis, severe mono neuritis multiplex, or a high cryocrit level (≥ 10%). Management should be started at first by immunosuppressive therapy followed by treating the underlying condition (e.g., DAAs for chronic HCV infection) after disease stabilization. In MC induced by HIV or HBV, antiviral therapy should always be initiated before or concomitant to immunosuppressive therapy [88,89,91]. High CS regimens include intravenous methylprednisolone (0.5–1.0 g/day for 3–5 days). The best RTX dosing regimen is 375 mg/m2 per week for four consecutive weeks [84]. Patients who advance to end-stage kidney disease (ESKD) may be treated with dialysis or kidney

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transplantation. Survival on either hemodialysis or peritoneal dialysis is broadly similar to that of patients with other kidney diseases [92].

10.2  Treatment according to the type of CGs and underlying disease 10.2.1 Type I CGs In patients with symptomatic type I CG, the treatment strategy focuses on the underlying lymphoproliferative disease. Lymphomas require combination chemotherapy while myelomas are treated with bortezomib, thalidomide, lenalidomide, or alkylating agents. Autologous bone marrow transplantation may also be an option in myeloma-related cryoglobulinemia [3]. IgG MGUS, which is mostly due to plasma cell proliferation, is treated with drugs that target the plasma cells, while in IgM MGUS, which is due to lymphoplasmacytic proliferation, RTX is preferred [16,93]. However, it was reported that RTX may be associated with IgM hyperviscosity syndrome flare in patients with WM, so PLEX should precede RTX in cases where IgM exceeds 4 g/dL [94]. 10.2.2 Treatment of HCV-CV Interferon-free DAAs combinations proved to be effective for the treatment of HCV-CV and have radically transformed its management. The clearance of HCV and maintaining SVR are associated with a higher rate of complete clinical remission in patients with HCV-CV [9]. Despite the marked efficacy of antivirals on the symptoms of HCV-CV, immunosuppressive drugs such as CS, CYC, or RTX are recommended in selected patients according to the disease severity [95,96]. During treatment, patients with CV should be closely monitored according to the underlying disease manifestation(s) and the chosen immunosuppressive(s). In those with renal involvement, blood pressure, urine analysis, serum creatinine, complement and RF levels should be monitored. Cases with rapidly progressive GN may be assessed weekly or even biweekly versus monthly monitoring of those without rapidly progressive disease. Repeated neurological and cutaneous examinations including careful monitoring of peripheral pulsations and color changes are warranted for cases with neurological and skin involvement, respectively. During RTX therapy, some experts prefer to measure CD19 + and CD20 + B-cell numbers in peripheral blood to ensure adequate B-cell depletion [89]. HCV-CV treatment outcomes

Despite marvelous viral clearance and persistent SVR in HCV-CV patients after the introduction of DAAs, many studies reported significant resistant and relapsing cases [10,13,97] or even development of de novo CV manifestations including GN and progression to CKD [11]. Marcella and her colleagues reported five HCV-CV patients who had either persistence (one patient) or late relapse (four patients) of vasculitis despite SVR with negative HCV RNA in both their serum and cryoprecipitate. All five patients were closely associated with either infection or with the diagnosis of a solid tumor, but none of them had evidence of lymphoma [98]. Many authors believe that the delay of anti-viral therapy will allow B-cell stimulation/proliferation to proceed irreversibly. Patients were still positive for serum CGs in up to 42%–61%

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of cases after clearance of HCV by DAAs. Reported relapse rates were 3%–10% [10,13,97] and even higher “12.07%” according to a recent multicenter prospective study conducted on 1019 consecutive cases [99]. Another study showed continuous B-lymphocyte clonal expansion in a cohort of HCV-CV patients despite SVR [100]. The clonal B‐cells, responsible for the production of CGs, may persist in the bone marrow, lymphoid tissue, or the liver [97]. B-cell clones’ survival after HCV clearance may be related to the polyreactive nature of B-cell receptors, the low specificity of HCV antibodies, the RF activity with ICs formation which could reactivate the B cells and cause its autonomous proliferation [12], and high expression of BAFF and a proliferation-inducing ligand (APRIL), the two well-known peripheral B-cell survival, maturation, and differentiation factors [13]. There was also evidence of high chromosomal breaks and increased genomic instability markers during DAAs therapy which persisted over 12 months from treatment onset. These data suggest that not only B-cell activation but also DNA damage are important determinants of HCV-CV treatment outcomes [18]. Del padre et al., reported that B-cells with low expression of CD21 (CD21 low), and unusual homing and inhibitory receptors were increased in Essential mixed cryoglobulinemia (EMC), and in HCV-CV but to a lower extent in the former. The CD21 low B-cells in both shared functional features of exhaustion and energy namely reduced proliferation upon ligation of Toll-like receptor 9, high constitutive expression of phosphorylated ERK, and proneness to spontaneous apoptosis [101]. Based on their results they proposed that EMC and HCV-CV had common pathogenic mechanisms based on autoantigen-driven clonal expansion and exhaustion of RF producing B cells, whereas, in HCV CV, the virus can provide a costimulatory signal resulting in a massive clonal expansion, Chronic HCV impairs T-cell responses. A recent study reported a persistence in T-cell function impairment in spite of SVR by DAAs [102]. Treatment of refractory CV

CV patients with no clinical response to therapy “within 4–6  weeks after induction” or those who show partial response defined as  70% of cases [7–9]. The median age at presentation is 5.3 years (± 3.9 years) with a slight male predominance [7,8]. Studies in adults also report an early age of onset, with a mean of 33.5 years of age [9]. Studies have shown that approximately quarter of all children admitted to the hospital with ADEM experience severe clinical symptomatology resulting in intensive care unit admission [10]. The mortality rate is approximately 1%–3% of the affected children that have been reported [8,11]. Initially, ADEM was diagnosed by loose and heterogeneous criteria based on the clinical symptoms and neurodiagnostic findings. The first consensus-based diagnostic criteria for ADEM was proposed in 2007 by International Pediatric Multiple Sclerosis Study Group (IPMSSG) [12]. The IPMSSG was composed of adult and pediatric neurologists, immunologists, epidemiologists, and genetics specialists organized by National Multiple Sclerosis Society. This criterion was further modified in 2013 (Table 1) [4]. TABLE 1  Comparison of definitions of ADEM by 2007 and 2013 IPMSSG criteria. IPMSSG criteria 2007 [12]

IPMSSG criteria 2013 [4]

Monophasic ADEM

– A first polysymptomatic clinical event, – A first polyfocal clinical CNS event with presumed inflammatory cause with presumed inflammatory cause that affects multifocal areas of the CNS – Encephalopathy cannot be explained by fever or other causes and the presence of encephalopathy – New or fluctuating symptoms, signs, – No new symptoms, signs, or MRI or MRI findings within 3 months of findings after 3 months of the incident the incident ADEM are part of the ADEM acute event

Recurrent ADEM

– New event of ADEM with a – Now subsumed under multiphasic recurrence of the initial symptoms and ADEM signs, three or more months after the first ADEM event

Multiphasic ADEM

– New event of ADEM, but involves – New event of ADEM 3 months or new anatomic areas of the CNS and more after the initial event that can be must occur at least 3 months after the associated with new or reemergence onset of the initial ADEM event and at of prior clinical and MRI findings. least 1 month after completing steroid Timing in relation to steroids is no therapy longer pertinent

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2  Definition and diagnosis As noted in the IPMSSG criteria, there are multiple forms of ADEM, which necessitates a nuanced way of evaluating a singular disease entity with heterogeneous etiologies and pathology. Clinically, the definition of ADEM is described as diffuse, poly-focal CNS event, which is manifested for the first time in a previously healthy individual under the presumption of immune-mediated inflammation and demyelinating background [4]. Encephalopathy, defined as any alteration in mental status, is considered a sentinel feature and is regarded as a differentiating symptom from the other relapsing inflammatory conditions such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Of particular note, encephalopathy does not necessarily indicate somnolence as irritability and agitation are often observed in younger patients. Neuroimaging with MRI characteristically demonstrates demyelinating lesions within the first 3 months of the illness [3,4,12]. These lesions are often large, confluent, and bilateral in appearance, indicating diffuse CNS pathology [13–17]. ADEM has traditionally been considered a monophasic illness although longitudinal studies have revealed that approximately 35% of patients will develop other relapsing inflammatory disorders of the central nervous system (CNS) over time, which include MS, myelin oligodendrocyte glycoprotein (MOG) antibody spectrum disorders, and NMOSD [8,18–21]. In rare cases, episodes similar to initial ADEM episodes are being observed but at a much lower frequency [20,22]. Recurrent ADEM term was used previously for recurrence of previous ADEM signs and symptoms after 3  months, without new lesions or clinical new areas of involvement but original lesions may have enlarged on MRI of the brain. In IPMSSG 2013 criteria, recurrent ADEM was subsumed into multiphasic ADEM as if truly relapsing with similar clinical and radiographic features. Multiphasic ADEM is the second (or more) episode, which occurs at least 3 months after the initial episode and may consist of clinical and MRI findings of new or recurring lesions, without the constraints of time elapsed since the steroid therapy completion. Encephalopathy is a cornerstone in ADEM and cases without alteration in mental status should have an expanded differential for other relapsing inflammatory conditions of the CNS.

3  Origins and etiologies 3.1  Postinfectious ADEM The most frequently reported type of ADEM is postinfectious, accounting for > 70% of cases [7–9]. However, in more than 70% of cases, no identifiable infection can be identified [23]. The most typical clinical history reported is one in which patients contract a benign bacterial or viral infection, from which full recovery occurs, and subacute-onset neurologic symptoms occur between 2 and 8 weeks after infection [8]. Although bacterial cases of postinfectious ADEM are reported, the majority are viral. Previously reported viral infections associated with postinfectious ADEM include mumps, rubella, influenza A or B, hepatitis A or B, herpes simplex virus (HSV) types 1 and 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein–Barr virus (EBV), human immunodeficiency virus (HIV), human T-lymphotropic

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­ irus-1 (HTLV-1), human herpesvirus 6 (HHV-6), rocky mountain spotted fever, coronaviv ruses, enteroviruses, West Nile virus (WNV), and coxsackievirus type B [18,24,25]. Of note, novel SARS-CoV-2 (COVID-19) has been associated with the development of ADEM as well [26]. Bacterial associations in postinfectious ADEM include Mycoplasma pneumoniae, Borrelia, group A Beta hemolytic Streptococcus, Chlamydia, Leptospira, Campylobacter, and Legionella [11,18]. The variety of infections associated with ADEM has guided our understanding that ADEM is less related to an acute or smoldering infection and is in fact more related to the inflammatory and autoimmune response to infection [27].

3.2  Postvaccination ADEM Postvaccination ADEM accounts for less than 5% of cases of ADEM and seems to occur more frequently after primary vaccination than revaccination [3,6,8,18,28]. Reports of postvaccination ADEM incidence for live measles vaccine is 1–2 per million, whereas postinfectious ADEM followed by measles virus infection is 1 in 1000 [29]. Vaccines that have been historically linked with postvaccination ADEM include rabies, measles-mumps-rubella (MMR), diphtheria-tetanus-polio (DTP), hepatitis B, pertussis, smallpox, Japanese B encephalitis, and influenza [11,29–34]. Postvaccination ADEM was initially thought to be related to the vaccine’s viral component or the contaminated CNS tissue in which the vaccine was cultured with evidence to support this being that postvaccination ADEM rates decreased after the development of recombinant protein-based vaccines [28]. However, the diffuse number of vaccines that have been linked to ADEM also calls to question whether it is the immune response to vaccines that may cause this pathology or the specific antigen presented.

4  Immunopathogenesis The exact immunopathogenesis of ADEM remains obscure. Studies evaluating this disorder date back nearly three decades ago, although the recent identification of MOG antibody being highly associated with ADEM, especially in children, has propagated increased interest in this disease entity. Some of the first reported pathologic lesions attributed to ADEM were macrophage-driven infiltration along venules in the CNS, indicating a peripherally driven inflammatory process that gained privilege access to the brain [35]. Lesions, as is noted clinically and radiographically, are typically of the same age and are without well-defined borders, discriminating this disease entity from other relapsing forms of CNS inflammatory disorders, such as MS. Although not definitively proven, breakdown of the blood–brain barrier may potentiate the inflammatory cascade triggered by antigenic presentation [36–38]. There is no unique animal model of ADEM although the animal model of experimental autoimmune encephalomyelitis (EAE) and Theiler’s murine encephalomyelitis model have provided a mechanism for investigating the pathophysiology of this obscure disease. EAE is an induced autoimmune encephalomyelitis that has been induced in animals by exposing them to neural antigens such as myelin basic protein (MBP), MOG, and proteolipid in combination with Freund or other adjuvants, which are used to break down the blood–brain barrier, allowing for immune cells with non-privileged CNS access to pass through. The presence of these myelin-based antigens together with Freund’s adjuvants leads to the occurrence of diffuse encephalomyelitis of the white matter.

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An early and natural target of investigation of ADEM was clarifying the relationship between vaccination and postvaccination ADEM given the clinical ubiquity of the former. In review of both rabies and Japanese encephalitis vaccinations, it was found that viral strains were incubated in goat, rabbit, and/or mouse CNS tissues, causing contamination by host animal neural tissue in which they were propagated [39]. Patients with ADEM who were vaccinated with Rabies Semple strain vaccine were found to have antibodies against MBP, raising the possibility of an antigenic trigger for immune activation. This is also supported by the fact that with the introduction of recombinant protein-based vaccines, the incidence of postvaccination ADEM has significantly lowered [28]. This data provided evidence to suggest that ADEM results from a triggered autoimmune response against myelin or other antigens either via molecular mimicry or by activation of T-cell processes. Molecular mimicry is a process wherein the host immune system recognizes unique determinants of an infectious or antigenic trigger as being similar to its own antigenic determinants, prompting the host immune system to attack both the antigen and the host tissue [40,41]. As antigenic epitopes can be shared between host neural proteins, inoculated pathogen or vaccine, by sharing certain structural or partial amino acid sequence homologies [42]. These antigens are not considered as “foreign” based on structural homology and continue to treat the offending exposure and cause harm to host tissue simultaneously [43]. These pathogens are locally processed leading to activation of T cells, which in turn, activates ­antigen-specific B cells with the goal of producing antibodies to prevent future infections [43,44]. This latter process explains why the conversion to relapsing clinical phenotypes is observed in patients who develop ADEM. Thus, mimicking antigens, similar in as few as one epitope may initiate a primary cross-reactive response resulting in the recognition of numerous homologous or near homologous epitopes in the host that cause an autoimmune/inflammatory process. With regard to auto-reactivity in the CNS, it is hypothesized that routine immune surveillance may then lead to local reaction against a presumed foreign antigen (e.g., a host’s epitope with homology to foreign antigen) [45]. However, alternative mechanisms of entry, mediated by antigen-presenting cells and dendritic cells have also been proposed [46,47]. This concept, also referred to as epitope spreading, is thought to occur concurrently with and propagate other avenues of the inflammatory response [48]. The identification of this phenomenon has been previously reported in children with MS, which is likely the most similar inflammatory disease to ADEM although ironically, this was not observed in monophasic variants, possibly indicating that epitope spreading may only be observed in patients with more aggressive inflammatory disease [49]. In Theiler’s murine encephalomyelitis model of EAE, direct inoculation of genetically susceptible mice with Theiler murine encephalomyelitis virus produces biphasic disease, in which initial phase occurs with infection and apoptosis of the neurons in the gray matter of brain [50,51]. Induction of CNS inflammation and demyelination is mediated primarily by CD4 + T helper cells, which infiltrate the CNS with further recruitment of monocytes, macrophages, lymphocytes, and antibodies, to cross the blood–brain barrier, causing infiltration and result in inflammation. Although CD4 + T cells are thought to primarily drive the initial process of CNS inflammation, CD8 + T cells are also involved and may in fact be boosted by autoantibody generation through B-cell-mediated mechanisms [52,53]. Pathogenic cytokines and chemokines involvement in ADEM are variable with elevated interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, MIP-1, tumor necrosis factor-alpha (TNF-α), and interferon

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gamma (IFN-γ), have been previously been reported in the serum and the cerebrospinal fluid (CSF) [54,55]. In addition, other studies have identified upregulation of chemokines that attract neutrophils (CXCL1 and CXCL7), monocytes (CCL3 and CCL5), T helper (Th)-1 cells (CXCL10), and Th-2 cells (CCL1, CCL22, and CCL17) [56]. Although multiple members of the inflammatory cascade are elevated in ADEM, it is unclear if these are driven by macrophage/ microglial activation and/or Th-1/Th-2 upregulation [55,57]. Pathological abnormalities of ADEM are described as diffuse perivenular inflammation and demyelination throughout the CNS. It includes a spectrum of sleeves of inflammation surrounding small vessels and demyelination in both CNS gray and white matter, microscopic or gross hemorrhage and lymphocytic meningeal infiltration, which is mild. Hemorrhage, although previously thought to only occur in rare and severe variants of ADEM, may not be restricted to fatal cases related to acute hemorrhagic leukoencephalitis [58]. Perivenular demyelination contains myelin-laden macrophage-dominant inflammatory infiltrates, which may not be present in hyperacute or acute lesions [59]. Histologically these lesions appear of similar age [3,4,8,12,17,60]. Meningeal inflammation with lymphocytes and subpial inflammation of cortical microglia is also noticed [61–64]. Additionally, perivascular edema, endothelial swelling, and vascular endothelial infiltration—unlike vasculitis—are noticed. Relative axonal preservation can be observed as well [1,65].

5  Clinical features The symptoms of ADEM are polyfocal and variable in manifestation based on location, extent, and severity of the lesions [1,8,20,33,60,66]. Given the heterogeneity in immune mechanisms, it is unsurprising that the degree of demyelination causing clinical symptoms can be quite variable. Prodromal symptoms often present include fever, malaise, irritability, generalized weakness, headache, nausea, and emesis, which eventually lead to the onset of acute neurologic symptoms within weeks [8,9,25]. Neurologic manifestations include pyramidal dysfunction, ataxia, acute hemiparesis, optic neuritis (ON) with painful eye movement, decreased visual acuity, relative afferent pupillary defect, cranial nerve deficits, speech impairment, cerebellar ataxia, and seizures [8,9,15,18,24,25,28,29]. Abnormal involuntary movements and aphasia are noticeable but less frequent. Neurological symptoms can become rapidly progressive within 2–5 days, with 15%–25% of patients requiring intensive care unit admission, respiration might be compromised with brainstem involvement, requiring intubation [5]. The short time frame between symptom onset and resolution of the most severe neurologic symptoms corresponds well with the activation of the inflammatory cascade of chemokine signaling of immune cells into the CNS and likely macrophage/microglial activation. Encephalopathy requires separate discussion since it is a major hallmark of this condition. Encephalopathy does not have clearly described characteristics, however, demonstrates a variable range of manifestations such as alteration in sensorium, drowsiness, lethargy, coma, behavioral changes, irritability, aggression. This symptomatic component, a marker of diffuse cerebral dysfunction, again may be representative of global inflammatory activation in the CNS, which is different from other classical relapsing inflammatory disorders of the CNS.

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6  Neurodiagnostic features 6.1  Neuroimaging Magnetic resonance imaging (MRI) is the best modality to identify ADEM. The studies may initially be normal at presentation and a delay of 5–14 days may be noticed between the onset of symptom and the changes noticed on MRI scans. Classic ADEM inflammatory lesions observed on T2-weighted and fluid-attenuated inversion recovery images are bilateral, multiple, diffuse, round, or oval lesions with poor demarcation [60,67]. The majority of the lesions are disseminated but solitary lesions may occur in 10%–30% of cases [68]. These lesions are typically present in the subcortical and central white matter, although gray matter involvement including basal ganglia and thalamus is common as well as cortical gray-white matter junction, cerebellum, and brainstem [60]. Presence of diffuse bilateral lesion pattern, absence of 2 or more periventricular lesions, absence of black hole on T1-weighted images are important differentiating features. These criteria could be helpful with an 81% sensitivity and 95% specificity to differentiate the first attack of MS from monophasic ADEM [60]. Despite the claim that all lesions should be of a same age and uniformly enhanced, gadolinium enhancement is present in up to 30% of the lesions in ADEM, as the disease evolves over several weeks [9]. Evidence of restricted diffusion on diffusion-weighted imaging (DWI) sequences may be associated with recurrence or significant difficulties in a prolong course, particularly in brainstem lesions [69]. The imaging findings are important to note in ADEM as the large confluent swaths of white and gray matter indicate both neuronal and glial disturbances, highlighting the diffusivity of the inflammatory activation in ADEM, specifically with regard to cytokine and T-cell-mediated activation. In addition, the presence of gadolinium enhancement on imaging correlates with blood–brain barrier (BBB) breakdown, which is firmly in line with the concept of epitope spreading through a barrier with strict passage restriction. A clinical and inflammatory correlate that relates to imaging is that even after a single inflammatory event in the CNS, such as ADEM, brain volume is permanently negatively augmented wherein ultimate brain volumes are lower than the age-adjusted neurotypical controls, highlighting the diffuse impact of CNS demyelination in young patients [70,71]. This impact is even more pronounced in individuals with relapsing forms of ADEM and MS. Finally, magnetic resonance spectroscopy studies have shown that myo-inositol (a biomarker of astrocyte function) peak and myo-inositol to creatine ratio are both diminished in acute ADEM (mI/Cr + 0.5), while elevated in chronic stage of the disease, which is different than MS that demonstrates an increase in myo-inositol to creatine ratio in both acute and chronic lesions [69,72].

6.2  Cerebrospinal fluid studies Although research into the chemokine and cytokine abnormalities in ADEM have been explored as previously noted, it is not clinically necessary to obtain these tests. CSF’s white blood cells may be normal in > 50% of the patients with ADEM and when pleocytosis (> 5 white blood cells/μL) is present, it is typically mild (0–268 WBC/μL) and classically associated with lymphocytic skew. In up to two-thirds of patients, increased CSF protein to about 0.40–0.60 g/L is observed, with normal glucose in nearly all cases [67,73,74]. IgG index may be elevated but

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oligoclonal bands are typically negative, and when positive, should prompt the consideration of clinically isolated syndrome or MS [15,18,67,74,75]. Although this line of testing is clinically useful, the neurodiagnostic studies of ADEM workup are not specific for the disease entity and thus must be interpreted in the clinical context of the patient’s presentation and radiographic findings. As research continues to expand, it is possible that chemokine and cytokine profiles in ADEM may yield improved biomarker identification of this inflammatory disease.

6.3  Electroencephalogram Nonspecific abnormal electroencephalogram (EEG) findings are noticed with ADEM and may include mild to severe generalized slowing, focal slowing, and epileptiform discharges. EEG is not routinely done except when there is a probability of seizures or the need to further differentiate the case from functional etiologies if other studies are negative.

7  Treatment and prognosis ADEM is an immune-mediated disorder and thus the goal of the treatment is to suppress an irregularly activated immune mechanism. Spontaneous improvement has been documented with incomplete recovery. In the absence of randomized clinical trials, treatment is based on observational studies and expert opinions. High-dose corticosteroids are the first-line treatment and about two-thirds of the patients treated with this medication showed improvement [76]. High-dose steroids shorten the duration of disease symptoms and may potentially prevent further relapses [77,78]. Although the exact mechanisms by which steroids improve ADEM is unknown, it is presumed to be multifactorial including decreased edema, decreased T-cell recruitment, and minimization of chemokine and cytokine signaling pathways. Intravenous immunoglobulin (IVIg) has been used as a second-line agent in cases of unresponsiveness to steroids. IVIg use has been documented in case reports and case series studies [79]. Plasmapheresis, which mechanistically removes pathologic autoantibodies with the potential to improve T-cell regulation has been used in refractory patients and has shown an acceptable efficacy [80,81]. ADEM has a favorable prognosis in over 80% of patients, with recovery to baseline in 4  weeks or more [9,18,21,25,73,74,76,78,82]. Mortality rates remain quite low, averaging between 1% and 3% of all cases [8,11,18]. Long-term sequelae include focal motor deficits, ataxia, or hemiparesis. Long-term cognitive deficits affecting IQ scores, attention, speech, and behavioral abnormalities are being noticed [66,83,84]. Disease severity and the extent of radiographic findings appear to be correlated with the prevalence of neurocognitive deficits [84]. Although traditionally thought of as a monophasic disease, ADEM has now been linked to a variety of relapsing conditions with similar, but ultimately unique pathophysiology.

8  ADEM as a herald for relapsing neuroinflammatory disorders 8.1  ADEM and multiple sclerosis (MS) MS is a chronic relapsing autoimmune demyelinating disorder. Although classically diagnosed in adulthood, natural history studies have identified that a herald inflammatory

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event of ADEM in childhood may be the initial presentation of this disease entity [85]. The risk of disease development of a relapsing condition following ADEM is inversely correlated with age at onset and lower when encephalopathy (as is the case with ADEM) is present [86]. Given the significant overlap between the heterogeneous mechanisms of disease activity observed in both ADEM and MS, it is unsurprising that the two diseases would be linked in a subset of individuals [1,65,87,88]. From an immune pathology standpoint, ADEM is noted to have confluent demyelinated areas in white matter of the brain and spinal cord with perivascular infiltrates with lipid-laden macrophages more than lymphocytes, CD8 + and CD4 + T cells, reactive astrocytes, besides the axonal loss [1,65,87,88]. Compared to ADEM, MS tends to predominantly involve the white matter, have heterogeneous lesion age (as opposed to uniform age in ADEM), and have significantly more perivenular macrophage and CD8 + T-cell activity as opposed to ADEM, which is classically CD4 + T-cell-driven and has similar rates of macrophage and lymphocyte presence [89–91]. Axonal damage in patients with MS is the hallmark of the disease [91,92], with limited confluent and extensive perivascular IgG deposition noted, highlighting the Tand B-cell-driven processes that seem to be less extensively present in the ADEM [1].

8.2  ADEM and neuromyelitis optica spectrum disorder (NMOSD) NMOSD is a rare relapsing inflammatory demyelinating disorder associated with autoantibodies against the aquaporin four (AQP-4) receptor [93–95]. AQP-4 is a water channel protein present within plasma membrane of foot processes of astrocytes along with the BBB [96]. Although defined by the AQP-4 antibody in the serum, between 20% and 25% of patients with NMOSD either do not have AQP-4 antibodies or have other antibodies such as MOG [95]. The clinical manifestations of NMOSD are quite unique in comparison to both ADEM and MS, while it primarily affects optic nerves (causing optic neuritis), longitudinally extensive transverse myelitis, and brainstem syndromes, often inducing significant disability [97–99]. Although NMOSD is considered an autoantibody-mediated syndrome due to the AQP-4 antibody biomarker, in-depth analysis of the pathophysiology of this disease has revealed that it is actually induction of the complement cascades that causes the pathology observed in NMOSD [100,101]. T-cell activation and chemokine signaling have also been observed in NMOSD, although this is thought to play a minor role in the pathology observed [102–105]. Although ADEM has both T-cell activation and abnormal chemokine/cytokine signaling similar to NMOSD, the activation of the complement cascade is only reported in rare and severe forms of ADEM such as acute hemorrhagic leukoencephalitis [106]. Interestingly, the predilection for NMOSD to involve the optic nerves, brainstem, and spinal cord is likely related to AQP-4 receptor expression [107], which recruits complement, T cell, and local inflammatory signaling at these sites, while also increasing BBB’s permeability [108]. Immunopathogenesis shows humoral immunity plays a critical role in the development of inflammatory lesions, manifested by associations with systemic autoimmunity and response to peripheral therapeutics such as plasmapheresis [88,109]. Compared to ADEM, axonal injury tends to be severe with confluent and extensive perivascular IgG and complement deposition [1]. Although there is clearly a unique pathophysiology associated with NMOSD, the clinical features are so different that the clinical utility of biomarkers and pathologic differentiation is less critical.

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8.3  ADEM and MOG spectrum disorders In the past decade, the identification of the role of MOG antibody in inflammatory disorders has changed the way we evaluate and treat disorders of the CNS inflammation. The presence of MOG antibodies is elevated in pediatric patients with ADEM, although the presence of these antibodies is not specific as they have also been described in MS, transverse myelitis, optic neuritis, NMOSD, and other demyelinating disorders [110–112]. Children diagnosed with ADEM in less than 10 years of age with demyelinating disorders have much higher rates of MOG antibodies, with a reported rate of as high as 65% [82,113,114]. There is a higher likelihood of MOG antibody positivity in younger patients with an initial demyelinating event of ADEM [114]. Interestingly, a study by Hacohen et al. (2015) identified that MOG antibody seropositivity had a positive predictive value of 91% for non-MS-related disease, indicating a potential difference in inflammatory mechanism of action [115]. Clinically, patients with MOG antibody seropositive ADEM have a similarly heterogeneous presentation with regard to neurologic symptoms, although rates of optic neuritis (ON) are reported to be higher either concurrently or as a relapsing phenotype [113–116]. Interestingly, as additional attacks occur (and age increases), encephalopathy is less frequently appreciated although new neurologic signs and radiographic lesions are present. When considering the immunopathology associated with MOG antibody spectrum disorders, it is important to consider the role of MOG in previously reported studies on ADEM as this was not routinely clinically assessed prior to the mid-2010s. The increased rate of relapse observed in patients with continued MOG antibody positivity has provided insight into a more diffuse and multifaceted inflammatory nature. Complement cascades are also activated in MOG antibody-driven disease, which also has systemic implications on inflammation [117]. Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, is occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD [118]. Pathology studies have also revealed a CD4 + T-cell-dominated inflammatory reaction at inflammatory sites with granulocytic infiltration and complement deposition as well [119]. Cytokine signaling cascades, as with ADEM, MS, and NMOSD are also perturbed [120]. Although MOG antibodies are expressed nearly exclusively in the periphery, intrathecal inflammation is also present, with increased Th17 mediated cytokine responses as well as increased intrathecal B-cell responses in patients with positive MOG antibody versus negative ADEM, respectively [121,122]. In addition, MOG antibody insults occur by both antibody-mediated and T-cell-mediated mechanisms, possibly explaining the variability in phenotypes, neurodiagnostic studies, and therapeutic responses [123]. Data continue to evolve in MOG antibody-positive disease, while these initial findings have guided current therapeutic practices.

9  Conclusion While heterogeneous with regard to either the clinical manifestations and immune-­ mediated pathology, ADEM is a display of a dysregulated immune system. The postinfectious, postvaccination, and parainfectious etiologies of this disorder all uniquely contribute

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to ­different mechanisms of the disease such as molecular mimicry, epitope spreading, and induction of inflammatory cascades. It is likely that a more severe immune dysregulation leads to long-term relapsing and remitting conditions observed in association with ADEM.

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C H A P T E R

13 Pulmonary manifestations of autoimmune diseases Tess Moore Calcagnoa and Mehdi Mirsaeidib,⁎ a

Department of Medicine, University of Miami, Miami, FL, United States Division of Pulmonary, Critical Care and Sleep, College of Medicine-Jacksonville, University of Florida, Florida, FL, United States ⁎ Corresponding author

b

Abstract Cells in the innate and adaptive immune system falsely mounting an inflammatory response to the host tissue form the essence of autoimmune diseases. The pathogenesis of how the innate and adaptive immune system becomes dysregulated and carries out this process is complex. Loss of immune tolerance both centrally and peripherally as well as genetic and environmental susceptibilities together contribute to the cycle of aberrant tissue inflammation and disease. Pulmonary disease can occur as a byproduct of autoimmune inflammation. For example, antibody complexes can deposit in the pulmonary epithelium initiating the inflammatory cascade, a pathway that will be discussed in great detail. Autoimmune diseases can occur as a byproduct of pulmonary disease. For example, pulmonary infection can serve as the antigen needed to trigger the onset of an ongoing autoimmune disease. Tissue damage in the lung resulting from an autoimmune disease most commonly manifests as pulmonary hypertension and a variety of interstitial lung disease subtypes, whereas lung disease involved in the initial pathogenesis of an autoimmune disease most commonly includes an antecedent infection of malignancy. Autoimmune leading to pulmonary or pulmonary leading to autoimmune is a temporal distinction in disease pathogenesis. In this chapter, we will discuss both temporal relationships organized by the organ system as a way to encompass a wide range of topics relating autoimmune disease to pulmonary disease. We will also explain the etiology, pathogenesis, genetic factors, and clinical manifestations of each disease discussed.

Keywords Autoimmune disease, Pulmonary disease, Translational immunology, Immune pathogenesis

1  Introduction Autoimmune diseases present as dysregulation of the adaptive immune response. Autoimmune diseases arise when the host tissue is attacked by autoreactive lymphocytes within the adaptive immune system. Autoimmune diseases involve both B- and T-cell

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13.  Pulmonary manifestations of autoimmune diseases

r­ esponses but start from autoreactive T-cell formation. Specifically, autoimmune diseases develop from both self-reactive CD4 + T lymphocytes and self-reactive antibodies. Environmental exposures, infectious exposures, and genetically inherited human leukocyte antigen (HLA) expression all contribute to the development of autoimmune diseases. The process of autoimmune disease development in the context of pulmonary autoantibody deposition is outlined in Fig. 1. Self-tolerance is usually lost secondary to predisposing genetic factors, exposure to infectious diseases, or exposure to environmental triggers [1]. Lymphocytic T cells go through the first round of negative selection in the thymus with an autoimmune regulator (AIRE) gene-assisted presentation of autologous antigens from diverse locations in the body [2]. Peripheral mechanisms of negative selection occur when self-reactive T cells escape deletion in the thymus. Clonal anergy occurs when T cells encounter an antigen without costimulatory receptor interaction. Additionally, immunological ignorance occurs when T cells do not properly interact with their peptide antigens/major histocompatibility complexes (MHCs). Immunological ignorance may be evaded by increasing antigen availability secondary to infection; this can be the precipitating event in some autoimmune processes [3]. In B cell lines, central tolerance is induced by receptor editing and regulatory B-cell suppression of effector

FIG. 1  Pathogenesis of an autoimmune disease and pulmonary deposition of autoantibodies. Human leukocyte antigen (HLA) genotype, environment, and infection influence autoantigens’ display on the major histocompatibility complex (MHC) proteins of antigen-presenting cells (APCs). Autoreactive CD4 + T cells are activated by APCs, resulting in an inflammatory cascade that leads to the stimulation of autoreactive B cells. This process leads to the clonal expansion of plasma cells, which produce antibodies that target the pulmonary epithelium, ultimately leading to the destruction of the lung tissue and the pathogenesis of pulmonary disease. This figure is generated with BioRender.com.

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T cells. Regulatory factors such as Treg and Breg cells, which normally control the immune response, will be out of balance in the development of disease [4,5]. Autoimmune diseases should be differentiated from autoinflammatory diseases, which are diseases with chronic inflammation without any evidence of adaptive immune system involvement [6]. Autoimmune diseases are classified based on the molecular physiology and location of disease presentation (Table  1). This chapter will focus on pulmonary manifestations of TABLE 1  Autoimmune diseases and their pulmonary manifestations. System

Disorder

Immune target

Pulmonary manifestations

Endocrine

Addison’s disease

21-Hydroxylase

Antecedent pulmonary infection (pulmonary tuberculosis)

Graves’ disease

Thyrotropin receptor

Pulmonary hypertension

Adult Still’s disease

Nonspecific

Interstitial lung disease

Antiphospholipid syndrome

β2GPI

Pulmonary embolism

Prothrombin

Pulmonary hypertension

Sarcoidosis

Nonspecific

Restrictive defect

Systemic

Pulmonary hypertension Pulmonary aspergillosis Systemic sclerosis

Nonspecific

Interstitial lung disease (nonspecific interstitial pneumonia) Pulmonary hypertension

IgG4-related disease

Nonspecific

Parenchymal disease Airway disease Mediastinal disease

Rheumatoid arthritis

Citrullinated proteins

Interstitial diseases (most commonly, usual interstitial pneumonia) Pleural effusions

Systemic lupus erythematosus

Double-stranded DNA (most common)

Pleural disease Pneumonitis Interstitial lung disease Diffuse alveolar hemorrhage Pulmonary hypertension Bronchial airway disease

Sjogren’s syndrome

Salivary/lacrimal glands

Obstructive airway disease Interstitial pulmonary fibrosis Interstitial pneumonia Continued

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TABLE 1  Autoimmune diseases and their pulmonary manifestations—cont’d System

Disorder

Immune target

Pulmonary manifestations

Connective tissue/ musculoskeletal

Polymyositis/ dermatomyositis

Myofibrils

Nonspecific interstitial pneumonia

Psoriasis

Dermatological and others Interstitial pneumonia with groundglass and/or reticular opacities

Relapsing polychondritis

Cartilaginous tissue

Vascular

Airway wall thickening Dyspnea, cough, discomfort, hoarseness, stridor

Mixed connective tissue U1 small nuclear disease ribonucleoprotein

Interstitial lung disease varying in pattern from other connective tissue diseases

Undifferentiated connective tissue disease

Connective tissue (nonspecific)

Nonspecific interstitial pneumonia

Takayasu and giant cell arteritis

Aorta and its branches

Takayasu: pulmonary hypertension, cough, dyspnea Giant cell: pulmonary infarction and nonspecific symptoms

Kawasaki disease

Medium vessels

Unresolving pneumonia with associated fever in child

IgA vasculitis (Henoch– Small vessel Schönlein purpura)

Hemorrhage, pneumonitis

ANCA-positive small vessel vasculitis

Varies based on subtype

Small vessel

Upper airway disease Airway occlusion/narrowing Nodules/infiltrates Alveolar hemorrhage Thromboembolic disease Asthma Patchy/bilateral heterogeneous consolidations

Nervous system

Achalasia

Enteric neurons

Cough, wheezing, hoarseness

Stiff person syndrome

GABA receptor-associated protein

Dyspnea with a restrictive pattern

Guillain–Barré syndrome

Ganglioside surface components of peripheral nerves

Antecedent pulmonary infection (COVID-19, pulmonary tuberculosis)

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TABLE 1  Autoimmune diseases and their pulmonary manifestations—cont’d System

Gastrointestinal

Others

Disorder

Immune target

Pulmonary manifestations

Neuromyelitis optica spectrum disorder

Aquaporin-4 water channel

Antecedent pulmonary infection (pulmonary tuberculosis)

Lambert–Eaton syndrome

Presynaptic voltage-gated calcium channel

Antecedent small cell lung cancer paraneoplastic development

Multiple sclerosis

Myelinating oligodendrocytes

Late-stage respiratory failure, aspiration, sleep fragmentation

Myasthenia gravis

Acetylcholine receptors Muscle-specific kinase

Late-stage respiratory failure Isolated respiratory failure Idiopathic pulmonary fibrosis Dyspnea

Celiac disease

Enterocytes

Lane–Hamilton syndrome – idiopathic pulmonary hemosiderosis

Ulcerative colitis

Colon, rectum

Crohn’s disease

Antecedent airway disease, tracheobronchial involvement, Entire gastrointestinal tract nonspecific interstitial pneumonia

Castleman disease

Lymph nodes

Diffuse parenchymal lung disease

Cold agglutinin disease

Red blood cells

Pulmonary embolism

a­ utoimmune diseases categorized by primary organ system involvement. The focus will be on both autoimmune disease processes associated with the development of pulmonary symptoms and pulmonary disease processes associated with the development of autoimmune symptoms.

2  Endocrine 2.1  Addison’s disease Addison’s disease is a primary adrenal insufficiency usually caused by autoreactive humoral and cellular insults against the adrenal cortex. A humoral insult is seen through the production of anti-21 hydroxylase antibodies, which are found in 86% of patients with primary adrenal insufficiency [7]. The presence of HLA-DR3/DQ2 and HLA-DR4/DQ8 alleles increases susceptibility to Addison’s disease likely through the presentation of the 21-­hydroxylase autoantigen to the cellular immune system. The HLA locus codes for MHC class I act as a ligand for natural killer (NK) and T-cell receptors [8]. Patients with Addison’s disease can present in adrenal crises, marked by low levels of adrenocorticoids, leading to hemodynamic instability and life-threatening complications. After diagnosis, patients are maintained on glucocorticoid and mineralocorticoid oral replacement therapies [9]. A pulmonary infectious insult can lead to the development of Addison’s disease. Pulmonary tuberculosis is still a prevalent issue in immunocompromised patients and in

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­ atients in ­developing countries who have a higher likelihood of exposure. Although the p etiology of the disease is usually autoimmune adrenalitis, tuberculosis should not be overlooked as a possible cause in 7%–20% of patients. Namikawa et al. reported a case of a patient who developed Addison’s disease from active pulmonary tuberculosis. A CT image of the patient revealed cavitation in both lungs with bilateral concurrent adrenal enlargement [10]. It is possible that tuberculosis infection acts as an environmental trigger, which in combination with genetic predisposition leads to the formation of autoantibodies and autoreactive T cells through epigenetic modifications.

2.2  Graves’ disease Graves’ disease is a common cause of hyperthyroidism characterized by the presence of thyrotropin receptor antibodies (TRAbs) and orbitopathy symptoms. A breakdown of central and peripheral tolerance in both humoral and cellular immune responses is required for TRAb development. Specifically, intrathyroidal T cells and B cells play an important role in TRAb development. Epithelial cells in the thyroid, which normally do not act as APCs, aberrantly express thyroid antigens (thyrotropin receptor, thyroglobulin, and thyroperoxidase), which activate intrathyroidal B and T cells [11]. The alpha subunit on the thyrotropin receptor in its multimeric form is important for proper maturation of unique and autoreactive IgG antibodies [12]. Monoclonal IgG1 antibodies against the thyroid-stimulating hormone (TSH) receptor are heterogeneous and can stimulate, block, or neutralize the TSH receptor antigenic target [13]. Stimulatory TRAb accounts for clinical hyperthyroidism through stimulation of Gs and Gq G protein-coupled receptor pathways in the thyroid gland [14]. There is a link between pulmonary hypertension (pH) and hyperthyroidism [15]. Mercé et  al. reported cardiac abnormalities in patients with hyperthyroidism over a period of 24 months and found a mean pulmonary arterial systolic pressure of 38 mmHg in 39 patients, with 41% of patients meeting the criteria for elevated pulmonary arterial systolic pressure [16]. The mechanism of pulmonary hypertension in the setting of hyperthyroidism is not clearly elucidated but may be related to excess thyroid hormone or autoimmune pulmonary vascular remodeling. A study by Sugiura et al., looking at pulmonary hypertension specifically in patients with Graves’ disease, supports autoimmune remodeling as a possible etiology [17].

3  Systemic inflammatory diseases 3.1  Adult-onset Still’s disease (AOSD) Adult-onset Still’s disease (AOSD) is an autoimmune inflammatory disorder used to classify adult patients who present the same way as pediatric patients with juvenile idiopathic arthritis (JIA) but do not meet the criteria for rheumatoid arthritis (RA) [18]. It is a systemic disease presenting in a monophasic, intermittent, or chronic time pattern characterized by widespread symptoms including quotidian fever, evanescent rash, polyarthritis, myalgia, nonsuppurative pharyngitis, hepatomegaly, pericarditis, and macrophage activation syndrome (MAS) [19].

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The etiology is unknown, but it is suggested to be influenced by genetic susceptibility and exposure to infectious triggers. Human leukocyte antigen (HLA)–antigen associations including HLA-DRB1*12 and DRB1*15 have been reported [20]. Haplotypes of interleukin (IL)-18 with genetic polymorphisms (IL-18S01, S02, and S03) were found in 28 patients with AOSD [21]. Multiple viral and bacterial triggers have been suggested to play a role in the initiation of AOSD, but no trigger has been clearly isolated. Regardless of the initiating factors, it is certain that involvement of the innate immune system is paramount to the pathogenesis of AOSD. Toll-like receptor (TLR) pathways, specifically the TLR7-MyD88 pathway, are overexpressed in AOSD patients, leading to a few cytokine upregulations (including MyD88, TRAF6, IRAK4) [22]. Additionally, elevated levels of IL-6 and IL-18 seen in patients with AOSD contribute to overactivation of neutrophils and dendritic cells (DCs) in the inflamed organ [23]. Cytokine oversecretion may impair cytotoxicity of NK cells. Decreased frequency and cytotoxicity of NK cell populations are seen in AOSD patients [24]. Interstitial lung disease (ILD) is a rare clinical manifestation of ASOD occurring in patients with a severe phenotype. Takakuwa et al. reported 78 patients with ASOD and concurrent ILD; a chest CT in this population displayed thickening of the intralobular septa, bronchovascular bundles, or visceral pleura. Clinically, patients with concurrent ILD showed higher relapse rates of the disease but the same 3-year survival rates [25]. It is possible that the initial microorganism autoimmune trigger gains entry to the body through the lungs, causing localized immune activation by bronchial and alveolar epithelial cells and subsequent development of ILD.

3.2  Antiphospholipid syndrome (APS) Antiphospholipid syndrome is an autoimmune syndrome clinically characterized by venous or arterial thrombosis and/or pregnancy complications in the presence of an antiphospholipid (aPL) antibody. Presentation is separated into the thrombotic phenotype and the obstetric phenotype. It can occur as a primary autoimmune condition or secondary to systemic lupus erythematous (SLE). The most common antigenic targets for both phenotypes include β2GPI and prothrombin [26]. In thrombotic APS, it is proposed that antiphospholipid antibodies bind to endothelial cells and inhibit eNOS transcription through the action of transcription factors, namely, Kruppel-like factor (KLF)2 and KLF4 [27]. Vasoconstriction in the vascular epithelium occurs because of decreased eNOS, increasing the risk of thrombus development. Additionally, in thrombotic APS, neutrophils spontaneously release neutrophil extracellular trap (NET) and increase adhesion through upregulation of CD64, CEACAM1, beta-2 glycoprotein, and MAC-1 [28,29]. The pathogenesis of obstetric APS is likely a combination of antibody-dependent increased complement activation and impairment in trophoblast adhesion [30,31]. Pulmonary manifestations of APS are referred to as “antiphospholipid lung syndrome” and most commonly include pulmonary thromboembolism and pulmonary hypertension [32]. The initial and most frequently reported symptom found in 38% of APS is often pulmonary thromboembolism secondary to deep vein thrombosis [33]. The prevalence of pulmonary hypertension in patients with primary APS is 3.5% [34]. The presence of pulmonary hypertension is indicated by APS, which is believed to be secondary to the development pulmonary microemboli and disordered proliferation in the vessel lumen [35]. Pulmonary

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hypertension and pulmonary thromboembolization are a continuation of the same pathophysiology seen in thrombotic APS, just localized to the lung.

3.3  Sarcoidosis Sarcoidosis is a multiorgan disease characterized by CD4 + T helper 1 (Th1) T-lymphocyteand macrophage-forming noncaseating granulomas. The etiology is still largely unknown; however, genetic, environmental, and infectious etiologies have been considered. Probable infectious triggers include Mycobacterium and Propionibacterium; genetic susceptibility is linked to HLA-DR11, 12, 14, 15, and 17, as well as intron 16 of the angiotensin-converting enzyme gene [36]. There are multiple reports of environmental triggers for sarcoidosis including silica, talc, and man-made fibers [37]. The etiology of sarcoidosis is likely the result of genetically inherited HLA subtypes in combination with exposure to an environmental or infectious agent that leads to overactivation of Th1 T lymphocytes via MHC class I presentation. It is challenging to categorize sarcoidosis as autoimmune inflammation. However, given the well-known role of environmental and infectious triggers in exacerbating pulmonary disease, this label may be justified. Sarcoidosis-induced granulomas manifest in any organ, but pulmonary sarcoidosis is the most common site for sarcoidosis-related mortality, morbidity, and healthcare use. Pulmonary sarcoidosis is mainly presented as a restrictive ventilatory defect with dry cough and dyspnea. It is diagnosed by bronchoalveolar lavage, transbronchial fine needle aspiration of involved lymph nodes, or tissue biopsy. Severity can range from an asymptomatic condition to a complicated and progressive life-altering disease. Complications that can worsen sarcoidosis include development of pulmonary hypertension, pulmonary fibrosis, and superimposed pulmonary aspergillosis [38].

3.4  Systemic sclerosis (SSc) Systemic sclerosis is a heterogeneous autoimmune connective tissue disorder characterized by universal widespread fibrosis and thickening of the skin and other organs secondary to excessive collagen deposition. The etiology involves development of autoantibodies and autoreactive T cells, vascular abnormalities, and eventual fibroblast dysfunction, leading to progressive and widespread fibrosis. Genetic associations are considered permissive and allow for progression of the disease in the setting of infectious triggers, such as cytomegalovirus (CMV) and Epstein–Barr virus (EBV). Onset is linked to both HLA and non-HLA gene variations [39]. Genome-wide association studies show HLA class II to be the most significant region associated with SSc, and immunochip analysis shows association with modifications in interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) protein [39]. Following infectious insult in genetically susceptible individuals, overactivation of the adaptive immune system leads to the production of autoantibodies, which serve as markers for diagnosis and disease progression. Endothelial cell damage from autoantibody deposition facilitates vascular inflammation and profibrotic cytokine release, which leads to collagen release from myofibroblasts [40]. SSc is subclassified based on major organ involvement and extent of skin damage. Organ involvement can manifest as musculoskeletal, gastrointestinal system, cardiac, renal, neuromuscular, genitourinary, or pulmonary manifestations.

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Pulmonary manifestations, occurring in 80% of patients with SSc, most commonly include ILD and pulmonary arterial hypertension (PAH) [41]. An extensive pulmonary workup is performed in all patients with SSc to rule out minimally symptomatic or asymptomatic organ damage. ILD presents early in diffuse SSc and typically presents as a late complication in limited cutaneous SSc. It is diagnosed using high-resolution CT imaging alongside pulmonary function tests and laboratory findings. A nonspecific interstitial pneumonia (NSIP) pattern is commonly seen on imaging in patients with SSc [42]. Anti-scl-70, anti-U3 ribonucleoprotein, anti-U11/U12 RNAP, and anti-Th/To antibodies are associated with an increased risk of ILD [43]. Patients with SSc are continually evaluated for the development of PAH as it is the leading cause of death in this population. The protocol for detection of PAH in patients with SSc is debated. The DETECT trial was a cross-sectional study using right heart catheterization to diagnose PAH in patients with SSc with only a 4% false-negative rate [44]. The pathogenesis localized to the pulmonary tissue likely involves autoimmune infiltration and subsequent collagen overgrowth in the pulmonary vasculature.

3.5  IgG4-related disease (IgG4-RD) IgG4-RD is an autoimmune fibroinflammatory heterogeneous disease marked by lymphoplasmacytic infiltrates and a storiform pattern of fibrosis with an increased number of IgG4 + plasma cells [45]. The most common subtype of the IgG antibody is IgG1, and the least common subtype is IgG4. The pathogenesis of IgG4-RD is related to increased class switching to IgG4 antibodies by way of expansion of T lymphocytes, which secrete IL-1β and TGF-β1 identified in 101 patients with IgG4-RD [46,47]. Other mediators involved in class switching and recombination to IgG4 include IL-21, IL-27, IL-23, IL-27, and IL-35, all produced by APCs [48,49]. Subsets of the clinical disease are characterized by a diverse array of clinical manifestations usually involving the pancreas, liver, lymph nodes, and glandular tissue. IgG4-related respiratory disease is diagnosed based on serology (IgG4 concentration of ≥ 135 mg/dL), histological evidence of IgG4-expressing B cells, chest imaging, and the presence of other organ involvement [50]. Pulmonary manifestations often include nonspecific clinical symptoms and pathology in the lung parenchyma, airways, and mediastinum. Parenchymal disease presents as diffuse rounded opacities and/or patchy appearing restrictive interstitial manifestations. Airway disease in IgG4-RD could be complicated with tracheobronchial stenosis and bronchiectasis. Hilar lymphadenopathy is another common finding in IgG4-RD [51].

3.6  Rheumatoid arthritis (RA) Rheumatoid arthritis is a chronic systemic autoimmune disease affecting the lining layer of synovia. Genetic susceptibility (most commonly, HLA-DR) and environmental exposures cause widespread synovial inflammation with cartilage and bone destruction [52]. The pathogenesis involves innate immune APC presentation of various citrullinated proteins, causing an adaptive T-cell and antibody response. Environmental antigen exposures such as smoking activate an enzymatic conversion of arginine to antigenic citrulline, leading to formation of anticitrullinated protein antibodies (ACPAs) [53]. In fact, ACPAs are detected in the human serum prior to the onset of joint symptoms, suggesting that the initiation of RA pathogenesis

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may occur outside the joints. Exposure to smoke, silica, and carbon dioxide nanoparticles triggers mucosal TLR response and activation of pulmonary APCs [54]. The 2010 American College of Rheumatology/European League Against Rheumatism guidelines diagnose RA using criteria that detail the presence of synovitis in a least one joint, serological abnormality, number of sites involved, and duration of symptoms [55]. Pulmonary manifestations of RA involve interstitial and plural pathologies. Tanaka et al. studied chest CT images of 63 patients with pulmonary RA and found 4 major patterns including usual interstitial pneumonia (UIP) (26), nonspecific interstitial pneumonia (NSIP) (19), bronchiolitis (11), and organizing pneumonia (5) [56]. Another group reviewed medical records of 230 patients with rheumatoid arthritis-related interstitial lung disease (RA-ILD) in the United Kingdom. Results showed that anti-CCP titers correlate with RA-ILD development, with UIP being the most common pathological classification [57]. Pleural effusions containing a sterile exudate and a high RF titer are usually self-limiting pulmonary manifestations, which do not require thoracentesis; concurrent RA treatment will treat the effusion [58]. Genetic studies sequencing genomes of patients with interstitial lung disease plus inflammatory arthritis found four unique deleterious variants of the Coat Complex Subunit Alpha (COPA) gene, a gene involved in the retrograde transport from the Golgi to the endoplasmic reticulum. Expression of deleterious variants leads to endoplasmic reticulum stress and autoimmune Th17 overactivation, potentially explaining the link between RA and its pulmonary manifestations [59].

3.7  Systemic lupus erythematosus (SLE) Systemic lupus erythematosus (SLE) is a multisystemic relapsing–remitting autoimmune disease commonly affecting young women with a complex etiology involving genetics, environment, immune, and humoral factors. SLE may develop from a genetically inherited complement component 1q deficiency, leading to decreased scavenging of immune complexes. It can also develop from the inheritance of multiple gene variants important to DNA degradation, apoptosis, and clearance of self-proteins [60]. The presence of autoantibodies including antinuclear, anti-double-stranded DNA, anti-Ro, anti-La, anti-Sm, anti-nuclear ribonucleoprotein, and antiphospholipid antibodies is observed prior to symptomatic onset in most patients [61]. Other immune abnormalities that may contribute to the pathogenesis of SLE include a decrease in suppressor T-cell function and an increase in circulating interferon-alpha (IFN-α) [62,63]. Aberrant cellular immunity can be explained in SLE by rewiring of the T-cell receptor, T-cell mitochondrial dysfunction, alternative splicing of T-cell genes, and skewed production of cytokines altering T-cell population ratios [64]. Clinical manifestations of SLE include renal dysfunction from immune complex deposition, organ damage through cell surface antibodies, thrombus formation from antiphospholipid antibodies, and skin lesions from local inflammation and anti-DNA antibodies. SLE may be initiated by taking procainamide, hydralazine, and some other medications. Antihistone antibodies are the hallmark feature of drug-induced lupus, present in 95% of cases [65]. Lung involvement usually occurs later in the course and is likely to result from the same complex immune pathogenesis. Pulmonary manifestations of the disease present as pleural, parenchymal, vascular, or airway pathology. Pleural disease that can usually be resolved with antiinflammatory treatment is common, with pleural fluid showing low complement levels

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and positive antinuclear antibodies. Acute lupus pneumonitis is associated with high expression of anti-double-stranded DNA (anti-dsDNA) antibodies in the alveoli, and it is associated with higher morbidity. Chronic interstitial lung disease associated with anti-SSA antibodies presents in long-standing diseases as ground-glass cellular infiltration with fibrotic disease on chest CT images. Diffuse alveolar hemorrhage is usually a rare complication presenting concurrently with another organ pathology. Pulmonary hypertension is a rare complication possibly influenced by thrombus formation from antiphospholipid antibodies [66,67]. Bronchiolar airway disease that manifests as abnormal pulmonary function testing in up to two-thirds of patients with SLE has been described [68].

3.8  Sjogren’s syndrome (SS) Primary Sjogren’s syndrome is a systemic autoimmune disorder characterized by lacrimal and salivary gland dysfunction as well as extraglandular dysfunction including pulmonary manifestations. Salivary gland epithelial cells serve as active participants in the initiation of the adaptive immune response through increased expression of MHC class II and production of chemokines (CXL13, CCL17, CCL21, and CCL22) [69]. Additionally, salivary gland epithelial cells display increased constitutive expression of TLR1, TLR3, and TLR4 (which serve as innate and adaptive immune system activators) in patients with SS compared to healthy controls [70]. A genetically predisposed individual (commonly, HLA-DR variation) is exposed to a viral antigen, which triggers salivary gland epithelial cell activity and subsequent formation of autoreactive B cells through expression of type I and type II interferons. T helper cells are also activated through the release of IL-12 [71]. A probable viral antigen for the development of SS is EBV; EBV in ectopic lymphoid structures produced anti-Ro 52/anti-La 48 antibodies in mice [72]. Therefore, the initial pathogenesis likely starts with salivary gland epithelial cell activation. The European League Against Rheumatism conducted a systematic review on extraglandular manifestations of SS and found pulmonary involvement—either bronchial or parenchymal—in 16% of patients with clinical features including dyspnea (62%), cough (54%), sputum (14%), and fever (2%) [73]. Taouli et al. described CT scans and pulmonary function tests of patients with primary SS and found airway disease in 54%, lymphocytic interstitial pneumonia in 14%, and interstitial pulmonary fibrosis in 20% [74]. Further studies should be conducted to determine whether pulmonary glandular epithelial cells behave in the same manner as salivary glandular epithelial cells and also whether this could be the reason for bronchial or parenchymal involvement in SS.

4  Connective tissue/musculoskeletal/integumentary 4.1  Polymyositis (PM)/dermatomyositis (DM) Polymyositis (PM) and dermatomyositis (DM) are characterized by autoimmune myopathy, which differs in both clinical presentation and etiology. PM is caused by a cellular immune system-mediated destruction of myofibrils via MHC-1 upregulation and ­consequent

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CD8 + T-cell destruction. DM is caused by a humoral immune system and membrane-­ attacking complex-mediated ischemia of the microcirculation supplying myofibers. In both conditions, 25%–30% of patients have autoantibodies against histidyl-tRNA synthetase (­anti-Jo-1) antibodies. In addition, in both conditions, cytokines are believed to play an important role in the early steps of the pathogenesis. Alpha-chemokines (CXCL9 and CXCL10) and beta-­chemokines (CCL2, CCL3, CCL4, CCL19, and CCL21) are elevated in muscle tissues in both conditions [75]. Interleukin-1 likely mediates a direct effect on muscle fibers in both conditions, and IL-1 inhibition has been shown to be effective in treatment [76,77]. Clinical presentation based on the Bohan and Peter criteria includes symmetric proximal muscle weakness, elevated serum muscle enzymes, myopathic changes on electromyography, and the presence of a cutaneous rash only in DM [78–80]. The most common pulmonary manifestation in patients with PM and DM is interstitial pneumonitis. Arakawa et  al. correlated CT scan changes of NSIP associated with PM and DM with pulmonary function tests. The initial CT presentation included reticular and/or ground-glass consolidation, which improved with treatment in 13 patients; improvement in chest CT findings correlated with improvements with FVC and diffusion capacity for carbon monoxide [81].

4.2  Psoriasis Psoriasis is an autoimmune dermatological disease with both varied dermatological and extradermatological findings. Extradermatological manifestations include articular inflammation (also known as psoriatic arthritis), nail psoriasis, and increased risk for metabolic abnormalities such as hyperlipidemia, hypertension, and coronary artery disease. Psoriasis is caused by uncontrolled keratinocyte proliferation secondary to prolonged inflammation from aberrant innate and adaptive cutaneous immune responses. Varying degrees of innate and adaptive immune contribution are seen in each subtype, with T-cell mediation playing a more important role in plaque versus pustular variations. The TNFα–IL23–Th17 axis has been implicated in the formation of autoreactive cellular immunity [82]. It has been proposed that both IL-23 and TNF-α induce naive CD4 T-cell differentiation into IL-17, producing Th17 cells, which, when under the control of proinflammatory cytokines, become pathogenic autoreactive T cells [83]. Pulmonary manifestations in the setting of psoriasis are uncommon, but interstitial pneumonia has been reported. Kawamoto et al. retrospectively examined chest CT images of 392 patients with psoriasis treated with a biological agent and found interstitial pneumonia (IP) characterized by bilateral ground-glass and/or reticular opacities in the lower lung in 2% of patients. Disease activity of IP was found to be correlated with IL-23/IL-17 activity since inhibition of these cytokines improved IP [84].

4.3  Relapsing polychondritis (RP) Relapsing polychondritis (RP) is a multisystemic autoimmune disorder targeting proteoglycans causing inflammation in the cartilaginous tissue including the ear, nose, joints, and tracheobronchial tree. HLA-DR4 has been identified in studies as a major genetic influencer of RP. The pathophysiology is complex and is believed to involve improper formation of type

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II collagen, martrilin-1, and cartilage oligomeric matrix autoantibodies. Like most autoimmune diseases, RP develops after a trigger such as trauma [85], pregnancy [86], or exposure to infections like Mycobacterium tuberculosis and myxoma virus, which serve as molecular mimics to cartilaginous autoantigens [87]. RP manifests clinically in patients as auricular chondritis (90%), nasal chondritis (53%), laryngo-tracheobronchial involvement (10%), and arthropathy (50%–60%). Other less common manifestations include ocular, neurological, renal, dermatological, and cardiovascular symptoms [88]. Pulmonary involvement is well documented in patients with RP because the tracheobronchial tree contains cartilaginous autoantigens. Tracheobronchial tree involvement leads to airway symptoms that are present in 20%–50% of patients with RP. Most commonly, symptoms include dyspnea, cough, chest discomfort, hoarseness, and stridor. Radiographic imaging most commonly shows anterior airway wall thickening. Bronchoscopy findings include trachea-­bronchomalacia, subglottic stenosis, and focal stenosis. Treatment for airway symptoms most commonly includes immunomodulating therapy and endoscopically placed stents in patients refractory to medical therapy [89].

4.4  Mixed connective tissue disease (MCTD) MCTD is an autoimmune disorder characterized by a mixture of features from autoimmune disorders previously described in this chapter including SSc, SLE, and PM to the presence of antibodies targeting U1 small nuclear ribonucleoprotein particles (U1 snRNPs) [90]. The pathogenesis of MCTD is distinct and not considered to be the same as those of the autoimmune diseases discussed previously. MCTD is caused by HLA-DR4 and HLA-DR2 expression and facilitation of T-cell-dependent production of 68kD anti-U1 snRNP antibodies [91]. ILD is the most common pulmonary manifestation of MCTD. Saito and co-workers compared pulmonary CT imaging of 35 patients with MCTD with patients with other forms of connective tissue disorders such as SLE, SSc, PM, and DM. Ground-glass opacification and honeycombing patterns were comparatively lower, whereas septal thickening was significantly higher (P  85%), airway narrowing/occlusion (60%), nodules and infiltrates (> 80%), alveolar hemorrhage (5%–10%), and thromboembolic disease (7 cases per 100). MPA lung manifestations include upper airway disease ( 95%), patchy/bilateral heterogeneous consolidations (70%–90%), and rare alveolar hemorrhage [119].

6  Nervous system 6.1  Achalasia Achalasia is marked by autoimmune inflammatory degeneration of nitric oxide-­producing inhibitory neurons within the myenteric plexus of the esophageal wall, leading to progressive dysphagia, regurgitation, and chest pain [120,121]. The smooth muscle in the distal esophagus and lower esophageal sphincter receives excitatory and inhibitor nerve input from postsynaptic release of acetylcholine and nitric oxide/vasoactive intestinal peptide (VIP), respectively. Loss of inhibitor neurons in achalasia leads to failed relaxation of the lower esophageal sphincter [122]. The pathogenesis of denervation has been theorized to be from either extrinsic neuronal loss (degenerated preganglionic vagus nerve cells and fibers outside the myenteric plexus) [123] or intrinsic neuronal loss (imbalance between postganglionic neurons within the myenteric plexus) [124]. It is more likely to be an intrinsic neuronal loss, specifically a loss of neurons secreting nitric oxide and VIP. The specific etiology of intrinsic denervation is unknown; however, it is associated with variations in HLA-DQ with affected individuals showing circulating antibodies directed against enteric neurons [125,126]. Infectious insults, like herpes simplex virus 1 (HSV-1), may precipitate the development of autoreactive T cells and subsequently autoreactive antibodies [127].

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Esophageal achalasia leads to decreased emptying from the lower esophagus into the stomach. Clinically, it often manifests as dysphagia, regurgitation, and gastroesophageal reflux disease, which does not improve with standard acid-suppressive treatments [128]. Pulmonary manifestations arise because of decreased esophageal transit and mechanical esophageal enlargement. Impairment in the ability to swallow increases the patient’s risk for microaspiration and pulmonary sequelae. Achalasia has also been associated with the development of pulmonary mycobacterial infection. A case report of an 11-year-old boy with achalasia, gastroesophageal reflux, and aspiration pneumonia who developed pulmonary NTM infection has been previously published [129]. Dilation of the esophagus can lead to mechanical compression of the tracheal and bronchioles, causing anatomical changes and sensations of dyspnea. In fact, respiratory symptoms at baseline in patients with achalasia are not uncommon. In a study examining laparoscopy myotomy treatment designed to open the lower esophageal sphincter, 41% of achalasia patients had respiratory symptoms including symptoms of cough, wheezing, and hoarseness. These patients displayed a more dilated esophagus and respiratory symptoms responded well to myotomy treatment with a 92.5% remission rate [130]. In a systematic study reporting lung involvement in patients with achalasia, 53.3% of patients had anatomical changes (tracheobronchial compression, parenchymal lung disease, ground-glass opacities, air trapping, and bronchiectasis) on chest CT or functional abnormalities reported by pulmonary function tests [101].

6.2  Stiff person syndrome (SPS) Stiff person syndrome (SPS) is a rare neurological condition marked by spasm of trunk and limb muscles that results in limited mobility and ambulation. It is caused by a decrease in central nervous system (CNS) inhibition of excitatory motor neurons. The pathophysiology is linked to autoimmune comorbidities such as type 1 diabetes and involves destruction of autoantigens at GABAergic synapses. GABA type A receptor-associated protein (GABARAP) is an antigenic target found in the postsynaptic receptor of GABA neurons. Antibodies directed at GABA receptor-associated protein are present in 65% of patients with SPS [131]. Although antibodies to GABARAP serve as a marker for disease, their pathogenic role is still under investigation. Glutamate, GABA, and glycine are essential for creating respiratory rhythm. The primary respiratory center receives phasic inhibitory input from GABA and glycine and excitatory input via glutamate from indirect pontine input [101]. Dyspnea significantly contributing to patient functional impairment has been reported in patients with SPS. A prospective study conducted by Allen et al. found that many patients with SPS reporting dyspnea displayed a restrictive spirometry pattern likely secondary to chest wall constriction and muscle spasm [132]. The sensation of dyspnea seen in SPS is likely related to decreased GABAergic input and uninhibited excitatory pontine stimuli.

6.3  Guillain–Barré syndrome (GBS) Guillain–Barré syndrome (GBS) is an acute ascending autoimmune paralysis usually brought on by an antecedent infection precipitating development of neuronal autoreactivity. Subtypes are classified based on electrophysiological patterns with the most common

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subtype being acute inflammatory demyelinating polyneuropathy (AIDP). The pathogenesis is driven by humoral and cellular immune responses cross-reacting with ganglioside surface components of peripheral nerves [133]. Exposure to a component of an infectious agent leads to the formation of self-reactivated B and T cells through molecular mimicry although a common immunogenetic factor across all GBS cases has not been identified [101]. Possible antecedent infections include campylobacter, coronavirus disease 2019 (COVID-19), human immunodeficiency virus (HIV), Zika virus, and pulmonary tuberculosis. Paralysis and associated symptoms progress and peak at 2 weeks after onset and usually resolve by 8 weeks with favorable prognosis [134]. The lungs act as the first point of entry for some antecedent infectious exposures. COVID-19, a pulmonary infection caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), has been associated with the development of GBS in recent reports. A case report has been published of a 64-year-old COVID-19-positive man who developed flaccid paralysis, decreased reflexes, and swallowing disturbances and was subsequently diagnosed with GBS [135]. A 61-year-old woman presented with rapid quadriplegia attributable to AIDP was diagnosed several days later with COVID-19 infection in the setting of only mild respiratory symptoms [136]. Antecedent pulmonary tuberculosis is also associated with GBS according to a case series analysis conducted in India, which reviewed four patients diagnosed with pulmonary tuberculosis and concurrent GBS. The diagnosis was made using nerve conduction studies, Brighton criteria, and a detailed investigation to rule out other possible infectious triggers [137].

6.4  Neuromyelitis optica spectrum disorder (NMOSD) Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disorder selectively targeting the spinal cord and the optic nerve. Its prognosis is poor, and it is commonly misdiagnosed as multiple sclerosis (MS). However, unlike MS, its pathogenesis involves humoral immunity infliction of both gray and white matter in the CNS. A neuromyelitis optica-specific IgG antibody targeted at the aquaporin-4 water channel (AQP4-IgG) in the astrocytic foot processes of the blood–brain barrier (BBB) can help distinguish NMOSD from MS [138,139]. AQP4-IgG activates complement and recruits eosinophils, neutrophils, and macrophages that disrupt the BBB, leading to neuroexcitation [140]. Development of NMOSD has been associated with other autoimmune disorders also displaying a type II hypersensitivity reaction such as myasthenia gravis and pernicious anemia [141]. NMOSD development is also linked to preexisting pulmonary infection. Pulmonary tuberculosis and the subsequent immune response may also predispose patients to NMOSD. Siddiqi et al. reported a case of NMOSD following pulmonary tuberculosis [142].

6.5  Lambert–Eaton syndrome Lambert–Eaton syndrome is a slowly developing disorder of muscle weakness, autonomic dysfunction, and areflexia from autoantibody destruction of presynaptic voltage-gated calcium channels at the motor endplate. It affects the normal mechanism of acetylcholine (ACh) release from the presynaptic nerve terminal. Normally, ACh is synthesized and stored in vesicles in the presynaptic neuron. Depolarization of the presynaptic neuron activates ­voltage-gated calcium channels. An influx of calcium leads to calcium-dependent synaptic

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release of Ach, which then acts on the postsynaptic neuron to trigger an action potential at the motor endplate. Destruction of presynaptic calcium channels causes a reduction in presynaptic vesicle release of acetylcholine. Since acetylcholine concentration is normal, symptoms improve with high-frequency repetitive nerve stimulation, which increases calcium release [143]. P/Q-type voltage-gated calcium channel antibodies are found in 90% of patients with Lambert–Eaton syndrome [144]. Lambert–Eaton syndrome is related to one of the most common subsets of pulmonary malignancy. Lambert–Eaton is usually a paraneoplastic autoimmune syndrome, which develops in the early stages of small cell lung carcinoma (SCLC). SCLC tumors express antigen components of the exocytosis apparatus in P/Q-type voltage-gated calcium channels, which likely trigger humoral development of autoantibodies [145].

6.6  Multiple sclerosis (MS) Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disorder believed to be caused by autoreactive lymphocytic damage to myelinated oligodendrocytes in the CNS. Gene loci HLA-DR12/DQ6, interleukin-2 receptor alpha gene, and interleukin-7 receptor alpha gene are documented risk factors for disease development [146–148]. The pathogenesis involves peripheral activation of CD4 + autoreactive T cells after a loss of self-tolerance to myelin basic protein. Transmigration of myelin-reactive T cells across the BBB occurs through attraction of chemokines. Once in the CNS, peripherally active T cells are activated in the presence of autoantigen-specific brain parenchyma [149]. The histological findings in demyelinating lesions are heterogeneous with some displaying T-cell-mediated pathology, some displaying T-cell-mediated plus antibody-mediated pathology, and some displaying toxin/viral-induced oligodendrocyte demyelination. Specific autoreactive T cells or antibodies identified against named target antigens have not been found [150]. Clinical presentation takes on a relapsing–remitting pattern or a progressive pattern of disease severity. The relapsing–remitting pattern is more common at first but usually develops into a secondary progressive pattern. Diagnosis is made if symptoms vary over time and space, as defined in the McDonald criteria [151]. Optic neuritis, peripheral neuritis, muscle spasms, issues with mobility, and pain are common presenting symptoms [152]. Pulmonary manifestations of MS occur in later stages of the disease and present as either acute or chronic respiratory failure, aspiration, and sleep fragmentation. Respiratory symptoms develop later in the disease after demyelination of brain stem regions that are responsible for neural impulses in bulbar muscles. Respiratory complications including respiratory failure and pneumonia are the most common causes of mortality [153].

6.7  Myasthenia gravis (MG) Myasthenia gravis (MG) is a disorder of muscle weakness developing from autoantibody destruction of acetylcholine receptors (AChRs) at the muscle endplate or destruction of muscle-­specific kinase (anti-MuSK). MG is studied as the prototype of an autoimmune disease. Antibodies bind to and neutralize the host target receptor in what is considered a type II immune reaction. AChR antibodies are present in 80% of patients with MG, and the activity of antibodies correlates with the severity of disease [154]. Anti-Musk IgG antibodies also cause

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downstream destruction of AChR in mice, showing the causal link to the development of MG [155]. The development of antibodies usually starts with proliferating B cells in the lymphoid tissue inside germinal centers, but, in MG, autoreactive antibodies are developed in a hyperplastic thymus, the usual location of T-cell maturation. IFN-I and IFN-III subtypes induce AChR expression in thymic epithelial cells and increase the expression of CXCL13 and CCL21, which are involved in germinal cell development [156]. TLR4 signaling in the thymus of MG patients increases CCL17 and CCL22 expression, leading to upregulation in Th1/Th17 AChR-specific T cells and thus creating a dysregulated immune microenvironment inside the thymus [157]. MG can manifest as two clinical presentations: one only affecting ocular muscles and the other more generalized one affecting the bulbar and limb musculature. Pulmonary manifestations of MG usually occur later into the progression of the disease when respiratory muscle motor endplates are affected. However, dyspnea and primary respiratory failure can occur in isolation of other systemic manifestation. Dyspnea in the setting of peripheral lung receptor activation has been well characterized [158–161]. An autoimmune pulmonary insult can initiate this sequence, as pictorially represented in Fig. 2. Isolated dyspnea and respiratory failure in the setting of myasthenia gravis could partially be explained by this mechanism.

FIG. 2  Mechanism of dyspnea in an autoimmune pulmonary disease. An autoimmune pulmonary insult (e.g., autoantibody deposition) leads to the development of dyspnea through activation of peripheral pulmonary receptors, which communicate with the medullary respiratory center through vagal afferent neurons. Medullary modulation by vagal afferent neurons leads to increased rate of breathing, increased volume of breathing, and the sensation of breathlessness. These physiological changes occur via slow adapting stretch spindles and rapidly adapting irritant receptors in the lungs. Capillary fluid leakage activates the slow adapting stretch spindles, whereas histamine, bradykinins, and irritants activate the rapidly adapting irritant receptors. These receptors cause physiological changes associated with a dyspneic state by way of vagal afferent neurons that input and synapse in the medulla. This figure is created with BioRender.com.

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Kim et al. reported a patient with MG presenting as isolated respiratory failure. The patient had acute respiratory distress, focal atelectasis progressing to reduced lung volume on chest X-ray, and increasing respiratory decline requiring mechanical ventilation. A diagnosis of MG was made using electromyography, which showed decrement in response to repetitive nerve simulation [162]. Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease usually leading to severe morbidity from subsequent respiratory failure. Chogtu et al. presented a patient with IPF who developed concomitant MG; the restrictive component of IPF combined with the paralytic component of MG makes management more challenging [163].

7  Gastrointestinal 7.1  Celiac disease (CD) Celiac disease is a gastrointestinal autoimmune disorder affecting 1% of the population caused by an overactive immune response to gluten, leading to enteropathy and malabsorption of nutrients in the small intestine. The only treatment for CD is to avoid gluten-­containing grains in the diet. Similar to most autoimmune disorders, genetic and environmental factors influence development of the disease. HLA-DQ2 and HLA-DQ8 are implicated in genetic susceptibility and likely present gluten as an antigen to activate T lymphocytes, which will self-react against tissue transglutaminase. Gluten proteins are made up of both monomeric gliadins and polymeric glutenins, which are only partially digested by brush-border endopeptidases. Partially digested fragments transverse through the epithelium and are deaminated by the enzyme tissue transglutaminase. Deaminated gliadin fragments are highly immunogenetic and expressed on MHC II receptors encoded for by HLA-DQ2 and HLA-DQ8 [164]. Alterations in the brush border of the bowel membrane after exposure to rotavirus in the first year of life, breastfeeding, and alterations in the microbiota are potential causes of CD [165,166]. Clinical presentations subside with implementation of a gluten-free diet; they are heterogeneous and are categorized as intraintestinal and/or extraintestinal. Intraintestinal symptoms include malabsorption, diarrhea, weight loss, constipation, nausea, and vomiting. Extraintestinal symptoms include iron deficiency anemia, paresthesia, osteopenia/osteoporosis secondary to malabsorption, transaminitis secondary to increased intestinal permeability, and loss of reproductive function [167]. Extraintestinal pulmonary manifestations of CD are rare; however, Lane–Hamilton syndrome is a recently characterized condition in which patients have idiopathic pulmonary hemosiderosis (IPH) with associated CD. Berger et al. reported a case of Lane–Hamilton syndrome: the woman presented with dyspnea, severe anemia, and lung infiltrates with negative gastrointestinal complaints. A diagnosis was made using lung biopsy in the setting of positive antigliadin antibody. Treatment included a gluten-free diet and steroids followed by no recurrence at 4 years [168].

7.2  Inflammatory bowel disease (IBD) Inflammatory bowel disease (IBD) encompasses two separate autoimmune diseases of the gastrointestinal tract, namely, ulcerative colitis and Crohn’s disease. The pathogenesis of both diseases has been shown to be related to the differentiation of ­mucosal

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Th17 cell populations and microbiota dysbiosis. Mucosal T-cell populations include T cells, which are terminally differentiated into Th1, Th2, Th17, and regulatory T cells. Th17 cells are terminally differentiated through activation with cytokines IL-6 and IL-21. Differentiation of Th17 cells is dependent on microbiota populations [169]. Dysbiosis seen in IBD may lead to a proinflammatory host response through variations in the degree of Th17 differentiation. 7.2.1  Ulcerative colitis (UC) Ulcerative colitis (UC) is an inflammatory disorder affecting the distal rectum to the proximal colon developed from a combination of genetics, environmental exposures, epithelial defects, and immune dysregulation. HNF4A and CDH1 loci increase susceptibility to UC; however, screening is not routinely done. Environmental exposures including oral contraceptives, hormone replacement therapy, and NSAIDS have been positively associated with UC development, while smoking cigarettes is a protective factor. Epithelial defects include underexpression of inflammatory response regulator peroxisome proliferator-activated receptor gamma and alterations in goblet-derived proteins. Immune dysregulation is a complex interaction between innate immunity with increased expression of TLRs and adaptive immunity with a Th2 predominant response [170]. Clinical presentation includes bloody diarrhea, abdominal pain, and rectal urgency diagnosed in combination with endoscopy. Treatment is usually pharmacological and is chosen based on patient-specific symptomology and severity; however, 15% of patients are refractory to medication and require surgical resection [171]. 7.2.2  Crohn’s disease (CD) Crohn’s disease (CD) is similar to UC in that it is a relapsing–remitting inflammatory gastrointestinal disease; however, its transmural noncaseating granulomatous pathology affecting any part of the gastrointestinal tract is distinct. The etiology is a combination of immune, genetic, and environmental factors. The overactive immune responses in combination with the microbiota influence the pathogenesis of CD, which involves CD4 + Th1, Th17, and regulatory T cells [172]. Defective NOD2, a gene, which functions to fight intracellular bacteria, is strongly associated with CD. A locus of genetic susceptibility to CD on chromosome 16 has been studied through linkage disequilibrium mapping, and multiple independent genetic associations were found including NOD2 frameshift and missense variants encoding apoptosis regulator Apaf-1/Ced-4 expressed in monocytes [173]. Presenting symptoms include chronic diarrhea, abdominal pain, weight loss, and extraintestinal symptoms including peripheral arthritis. Diagnosis is made using biopsy from ileocolonoscopic investigation. The mainstay of treatment is pharmacological therapy starting with corticosteroids and mesalamine escalating to TNF inhibitors for refractory patients [174]. Extraintestinal pulmonary symptoms of IBD have been reported; in fact, symptoms of airway disease may precede intestinal symptoms and accompany intestinal exacerbations. Manifestations include tracheobronchial involvement with several cases of concurrent bronchiectasis, bronchitis, tracheobronchitis, bronchiolitis, interstitial lung disease with diverse radiographic presentations, and accompanying exudative eosinophilic pleuritis [175].

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8  Other diseases 8.1  Castleman disease (CD) Castleman disease is the name for a spectrum of conditions with overlapping clinical features and unique but related etiologies and histological findings. Castleman disease, also known as angiofollicular or giant lymph node disease, is a lymphoproliferative disorder defined histologically by hyperplastic lymphoid tissues associated with herpesvirus 8 (HHV8), HIV, non-Hodgkin lymphoma, and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome. The pathogenesis of HHV8related CD is well defined. HHV8 is a gamma herpesvirus, which infects endothelial cells, monocytes, and B cells. HHV8 goes through both a latent (nonreplicating) stage and a lytic (replicating) stage. There is expression of HHV8 cytokine genes (vIL-6, vMIR1, vMIR2) during the latent phase, which is normally only expressed in the lytic phase [176]. Such expression is important to the aberrant immune response seen in CD. Symptoms differ among pathological variants of CD (plasmablastic variant, multicentric CD, plasma cell variant, and hyaline vascular variant), but all variants involve enlargement of mediastinal and hilar lymph nodes. Radiographic manifestations sometimes also manifest in pleural and lung spaces [177]. Pulmonary manifestations are not pathognomonic for CD; however, diffuse parenchymal lung disease (DPLD) has been reported in this population. A retrospective analysis of 262 CD patients conducted by Huang et al. identified 22 patients with concurrent DPLP. Clinical symptoms of DPLP included coughing (72.7%), fever (68.2%), and dyspnea (59.1%) with associated lymphadenopathy (81.8%), pulmonary nodules (72.7%), cysts (59.1%), and groundglass opacities (54.5%) on high-resolution CT imaging [178].

8.2  Cold agglutinin disease (CAD) Cold agglutinin disease (CAD) is an autoimmune IgM-mediated hemolytic anemia caused by binding of IgM to RBC membranes in cooler peripheral circulation, leading to complement activation, C3b surface binding, and subsequent hemolysis. Possible postinfectious triggers include mycoplasma, EBV, legionella, varicella, citrobacter, and influenza. Most commonly, patients present with chronic anemia requiring transfusion about 50% of the time. Coldinduced circulatory symptoms such as Raynaud’s syndrome, livedo reticularis, and cutaneous necrosis have also been reported in patients with CAD [179]. Pulmonary manifestations of CAD are not common; but, Onishi et al. reported a case of an 86-year-old man with CAD who presented with pulmonary embolism (PE). The patient presented with typical PE symptoms (chest pain and shortness of breath). A diagnosis of CAD was made after incubating blood samples at 37 degrees after noticing elevation in the mean corpuscular hemoglobin (MCH) value, which normalized with incubation [180].

9  Conclusion Autoimmune diseases involve the overactivation of both humoral and cellular immune responses that are often triggered by infections, environmental exposures, and overactive 287



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i­nnate immune responses in genetically susceptible individuals. Many autoimmune processes are associated with the development of pulmonary symptoms and manifestations of which the sensation of dyspnea is commonly reported. Some pulmonary disease processes such as infection and neoplasm are associated with the development of autoimmune diseases. In this chapter, we conducted a comprehensive review of known rheumatological and pulmonary associations including the basic science literature detailing the pathophysiology, up-to-date case reports, and clinical descriptions.

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14 Inflammatory bowel diseases: Sex differences and beyond Alessandra Sorianoa,g,*,†, Marco Sorianob,†, Marina Beltramia, Francesca Sanguedolcec, Andrea Palicellid, Maurizio Zizzoe, Stefano Ascanif, Magda Zanellid, Theresa T. Pizarrog a

Department of Internal Medicine, Gastroenterology Division and IBD Center, Azienda Unità Sanitaria Locale – IRCCS, Reggio Emilia, Italy b‘Luigi Vanvitelli’ University and School of Medicine, Naples, Italy cPathology Unit Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Foggia, Foggia, Italy dPathology Unit, Azienda Unità Sanitaria Locale – IRCCS, Reggio Emilia, Italy eSurgical Oncology Unit, Azienda Unità Sanitaria Locale – IRCCS, Reggio Emilia, Italy fPathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, Terni, Italy gPathology Department, Case Western Reserve University, Cleveland, OH, United States ⁎ Corresponding author

Abstract Mechanisms behind sexual dimorphism in immune-mediated diseases are an underinvestigated area of research. In both the two main prototypes of inflammatory bowel diseases (IBDs), namely, Crohn’s disease (CD) and ulcerative colitis (UC), the presence of clear-cut sex-based differences is a controversial issue with a number of factors that need to be considered, including diet, ethnicity, age, and hormone levels. The gut microbiome has a critical role in shaping the immune response, and increasing evidence shows that the gut microbiome itself differs according to sex. In recent years, the link between gut microbiome perturbation and IBDs has become clearer; however, much less is known about how it may drive a sex-based immune response in the context of the disease. In this chapter, we analyze current evidence on the potential role of sex-based interplay between immune responses and the gut microbiome in IBDs, aiming to unravel whether these sex-based differences might differently impact the pathogenesis and course of the disease in the host.

Keywords Inflammatory bowel diseases, Crohn’s disease, Ulcerative colitis, Sex, Gut microbiome, Hormones, Immunity, Innate immunity, Adaptive immunity, Animal models †

Both authors contributed equally to this work.

Translational Autoimmunity, Vol. 4 https://doi.org/10.1016/B978-0-12-824466-1.00010-8

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1  Introduction The terms “sex” and “gender” are often used interchangeably in research, but this might lead to some “conceptual” misunderstanding/misinterpretation. The term “sex” strictly refers to biological differences between females and males based on sex hormones, chromosomes, and reproductivity, whereas “gender” refers to socially constructed features, such as behaviors, roles, and activities related to social and cultural aspects, including gender minorities. In recent years, increasing attention has been paid to the so-called “gender medicine” as one of the pivotal aspects for dealing with gender differences in the era of precision medicine, with several international research programs providing dedicated funding. Although the term “gender medicine” might be considered partially improper due to the already cited conceptual differences between the terms “sex” and “gender,” the definition of this new area of study, in any case, reveals novel scientific awareness on how sex and gender may potentially exert a deep impact on diseases. Sex biases observed in many diseases has long been considered as fully host-intrinsic as well as a feature of some autoimmune disease prototypes such as systemic lupus erythematosus (SLE) and type 1 diabetes mellitus (T1DM). In a seminal paper published in 2013, Markle et al. [1] showed for the first time that commensal gut microbiota directly modulates sex hormone levels as an extrinsic factor, thus—at least partially—contributing to the sex bias observed in a nonobese diabetic (NOD) mouse model, which is a mouse model with genetic susceptibility to T1DM. A diversion of gut microbiota composition between females and males was observed at the time of puberty. After puberty, female NOD mice developed spontaneous autoimmune T1DM at twice the rate of males, but, under axenic (germ-free) conditions, both sexes showed equal incidence of the disease; thus, that protection from T1DM was lost in male mice. By performing gavage of female NOD weanlings with the gut microbiota from NOD males, the authors demonstrated elevated serum testosterone levels, which eventually conferred protection against the development of T1DM through full development of T and B responses. Additionally, when recipient females were treated with flutamide to antagonize androgen receptor signaling, this protective effect appeared abrogated. These results confirmed the hypothesis that a “metastable” state of maleness was beneficial to young females and also raised the possibility of considering gut microbiota manipulation and transplantation in disease treatment purposes [2]. In their editorial on the paper titled “Welcome to Microgenderome,” Flak and colleagues [2] aimed to eventually crystalize the interplay between commensal gut bacteria and sex hormones observed in T1DM. The concept did not catch on in the following years, and, to date, studies on the gut microbiota as a modulator of immune-mediated diseases, particularly inflammatory bowel diseases (IBDs), in a sex-based manner remain very few. This can be attributed to several reasons, including the difficulty in interpreting data in animal models where hormonal changes are more rapid, especially in the female sex. Additionally, there is still no general consensus on which features depict a “healthy microbiome” [3], a consensus on best practices in microbiome research is missing, there is lack of data standardization [4], and a clear commonly agreed-upon definition of the term “microbiome” itself is still debatable. According to the most widely accepted definition as originally postulated by Whipps and co-workers [5], the “microbiome” includes not only the communities of microorganisms but also the whole spectrum of molecules produced by the microorganisms, their structural

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elements, metabolites, and molecules produced by coexisting hosts, structured by the surrounding environmental conditions. The microbiota is defined as the assemblage of living microorganisms present in a defined environment. Regardless of several challenging issues that still render the field of “microgenderome” difficult to approach, in recent years, some important key concepts have started to become clearer: (1) there are highly distinct differences between the two sexes in terms of immune responses in both physiological and pathological conditions that, at least partially, justify the different prevalence between sexes observed in several immune-mediated disorders, including IBDs; (2) among the environmental modulators of immune-mediated disorders, the gut microbiota is capable of directly and indirectly influencing immune responses; (3) there is increasing evidence that the gut microbiota per se differs between females and males (in both physiological and pathological conditions); (4) mechanistic causal relationships between commensal microbiota and host immune response are strongly supported by the use of germ-free animal models [3]; and (5) in a genetically susceptible host, a perturbed gut microbiome—referred to as dysbiosis—represents a key contributor to IBD pathogenesis, at least through shaping local and systemic immune responses [6]. With these assumptions, taking into consideration that differences in the immune response are clearly sex-based and also assuming that the gut microbiome is per se different between females and males, one might argue that immunity-gut microbiome interaction may exert an impact on the onset and progression of IBDs in a sex-dependent manner. This remains an underrepresented area of investigation, which needs further efforts in research. A sex-based approach to IBD patients is strongly warranted to pursue the goal of personalized medicine. Unraveling the impact of the gut microbiome on sexual dimorphism in IBDs— through basic, translational, and clinical research—could add pivotal insights that potentially may revolutionize the disease approach itself, including prediction of treatment response (i.e., to biological drugs or to other microbiome-targeted experimental treatments such as fecal microbiota transplantation (FMT)), outcome measures, and surveillance strategies. In this chapter, we investigate whether the gut microbiome in turn might impact the pathogenesis and course of IBDs in the host in a sex-dependent manner. In order to do this, we will refer to seminal papers about sex differences in immune responses, in IBDs, and in the gut microbiome per se. We mainly set up our critical review of the available basic and translational research literature, remaining mainly focused on sex, rather than gender, as most of the factors responsible for sexual dimorphism in the gut microbiota are determined by biological sex. We will refer to the microbiome and microbiota of the gastrointestinal tract using the two terms according to the above-cited and most widely accepted definitions.

2  Sexual dimorphism in IBDs: Not as “nuanced” as it seems 2.1  Evidence from human studies Clinically, IBDs are not considered among the strongest models of polygenic and multifactorial immune-mediated diseases in which sex differences clearly stand out at least in 297



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terms of phenotypic manifestations. Phenotypic differences between sexes in IBDs have been depicted as “nuanced” for a long time. The current knowledge is that, similar to other ­immune-mediated diseases, the female sex is a risk factor for the development of Crohn’s disease and ulcerative colitis is more prevalent among male patients. Nonetheless, different from other immune-mediated diseases with a clear-cut sex-based difference such as SLE or T1DM, Crohn’s disease and ulcerative colitis do not show extreme sex-based differences in either incidence or prevalence [7]. However, in data interpretation, it cannot be ignored that ethnicity, geographical location, dietary habits, and thus different microbiome “signatures” may exert their own influence as environmental factors. A slight female predominance in adult Crohn’s disease has been found in western population-based studies but not in Asian cohorts. Less consistent data support modest predominance of the male sex in the adult population with ulcerative colitis. In terms of disease severity, epidemiological studies have shown more severe Crohn’s disease in women than in men and by contrast more severe ulcerative colitis in men than in women. Pediatric Crohn’s disease shows an increased male predominance. Population-based studies aiming to investigate IBD prevalence among different populations have already been reviewed elsewhere [7–15]. More recently, with growing attention on the so-called “gender” medicine as part of a personalized disease approach, sex differences in IBDs have been claimed for disease presentation, course and complications, response to medical therapies, surgical rates, adherence to therapy, and psychological and psychiatric disorders, albeit in some areas data still remain conflicting. Sex hormones—including oral contraceptives—have been shown to influence the immune system and contribute to both development and exacerbation of IBD symptoms in women [7]. Estrogen receptor beta (ERβ) expression was decreased in intestinal biopsy samples from patients with IBD; the authors demonstrated increased epithelial resistance in vitro in T84 cell monolayers stimulated with an ERβ-specific agonist. These findings suggested a protective role for estrogen and/or ERβ signaling in the intestinal epithelium [16]. As for clinical extraintestinal manifestations, nowadays, we know that rheumatological conditions and iron-deficiency anemia tend to be more frequent in women than in men, apart from ankylosing spondylitis [17–19]. Primary sclerosing cholangitis (PSC) is more common in IBD males; by contrast, females with PSC and concomitant IBD appear to be at decreased risk of liver transplantation, malignancy, and death. The risk of developing colorectal cancer, small bowel neoplasia (including adenocarcinoma), neuroendocrine tumors, and lymphoma has been found to be higher in males with colitis-associated IBD. Colorectal cancer itself is more common among men than among women with chronic ulcerative colitis with a high degree of inflammation. Conversely, females seem to be at higher risk of cardiovascular complications including stroke and have higher incidence of periodontitis and oral cancer [7,20]. Among serum biomarkers and autoantibodies, mannan epitope of Saccharomyces cerevisiae antibodies (g-ASCAs), atypical perinuclear antineutrophil cytoplasmic antibodies (a-ANCAs), and antilaminaribioside (ALCA) are useful for distinguishing between Crohn’s disease and ulcerative colitis patients, whereas increasing antibody responses have shown an association between more complicated disease behavior and surgery rates in Crohn’s disease; however still, no information is available about such rates and differences according to sexes [6].

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2.2  Evidence from animal models Over the last several years, sex differences in IBD animal models have been extensively studied. Female sex bias has been shown in two well-established mouse models of ileitis, namely, SAMP1/YitFc (SAMP) and TnfΔARE/+ strains. In both models, ileitis occurs earlier and/or more severely in female mice [21–23]. An exogenous estrogen administration was found to determine effective expansion of mucosal regulatory T-cell (Treg) population in male SAMP mice that eventually corresponded to improvement of ileitis, whereas female SAMP mice were found resistant to these effects [23]. A mechanistic explanation of this phenomenon was attributed to signaling downstream of ERβ, an isoform that can antagonize classic ERα signaling in vitro and in vivo in cellular types expressing both estrogen receptors [24]. Additionally, it has been demonstrated that apart from contributing to the expansion of Treg populations, ERβ signaling contributes to intestinal permeability and maintenance of colonic epithelial cell differentiation and function [25,26]. The loss of function of ERα showed a protective effect on female mice with dextran sulfate sodium (DSS) colitis, whereas male mice deficient in ERα (Esr1−/−) showed disease exacerbation. These findings also suggested that skewing estrogen signaling toward ERβ can lead to substantial protection from experimental colitis in female mice [27]. Further proof of concept came from a study in which colonocytes from mice lacking ERβ (Esr2−/−) were found to be hyperproliferative and with lower levels of differentiation markers and adhesion molecules than wild-type (Esr2+/+) controls [25]. However, it should be taken into account that estrogen’s biological effects are complex and at least “biphasic”; thus, hormonal assessment may strongly vary according to the model system. This represents an important issue related to the difficulties in producing reliable evidence on in vivo hormonal effects. Moreover, it cannot be excluded that supraphysiological concentrations of estrogens may play a direct role in lymphocyte functions [7]. For example, in vivo treatment of female mice with supraphysiological doses of estrogen exacerbated experimental colitis in mice exposed to DSS but showed a protective effect from dinitrobenzene sulfonic acid (DNBS)-mediated colitis. This might be due to different T-cell responses mediating the two models of colitis [28,29]. Other evidence on sexual dimorphism in IBDs comes from epigenetic studies, aiming to investigate whether specific X-linked genes can contribute to sex-based differences. Using experimental IBD mouse models, studies have identified a core 1 β3-GalT-specific molecular chaperone (Cosmc), which encodes an X-linked chaperone important for glycocalyx formation as an IBD risk factor [30]. In a study on experimental IBD mouse models, the loss of one Cosmc allele in intestinal epithelial cells of male mice resulted in enhanced colitis activity, whereas female mice were partially protected. Susceptibility loci on chromosome X were found through genomic microsatellite DNA analysis of ileitis-prone SAMP mice, once again pointing to the importance of genetic contributors to sex-based differences [31].

3  Gut microbiome in IBD: Where do we stand? By definition, IBDs represent a group of chronic immune-mediated diseases mainly consisting of Crohn’s disease and ulcerative colitis, whose etiopathogenesis remains partially unknown. Apart from genetic predisposition and ~ 200 host genetic loci that have been found

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to be associated with key immunological pathways, it is clear that environmental factors (i.e., western diet, habits, smoking, medication, circadian rhythm, stress) and gut microbiome perturbation—referred to as dysbiosis—affect the host immune response during both IBD onset and progression [6,7]. Thus, IBDs are considered multifactorial diseases, whereas an uncontrolled activation of intestinal immune cells overrides in a genetically susceptible host [32]. Increasing evidence supports the hypothesis that IBDs are diseases that originate at the epithelial barrier level, whose defects are responsible for microbial dysbiosis, with subsequent accumulation and local activation of immune cells [33–36]. A disbalance between proinflammatory and ­antiinflammatory signals is eventually responsible for chronic immune-mediated inflammation at the local level, with potential fibrosis, stenosis, epithelial-mesenchymal transition, or cancer as the main complications in the long term [20,37]. Altered trafficking of immune cells and pathogenic immune cell circuits represent crucial drivers of mucosal inflammation and tissue destruction. The impairment of intestinal barrier function determines the translocation of commensal microorganisms into the bowel wall, which is the “first hit” activating innate immune cells as well as cytokine and chemokine production. Subsequently, gut homeostasis is impaired and the recruitment of additional immune cells activates adaptive immunity. Cytokines and chemokines produced by activated immune cells contribute to epithelial cell damage, determine and aggravate impairment of barrier function, perpetuate dysbiosis, and, thus, gut inflammation [32]. Evidence of dysbiosis as a pivotal contributor to the etiopathogenesis of IBD is becoming stronger. Although a causal role is yet to be determined, IBD is considered a model for the study of microbiome-related disorders. IBD has also been defined as a “polymicrobial” disease, whereas the triad of dysbiosis, altered immune response, and impairment of the intestinal mucosal barrier contributes to aberrant host-microbial interactions [6]. The gut microbiota contributes to T-cell development and immune tolerance, as widely demonstrated in animal models. For instance, CD4 + Treg cells, which express FOXP3 transcription factor and act as negative regulators of inflammation, are decreased in the colons of germ-free mice as compared to those of conventional mice [38]. When germ-free mice are colonized with fecal microbiota from IBD patients, RORγt + Treg cells decrease and intestinal T helper (Th)17 cells increase [39]. A total of 20 bacterial strains have been isolated from an ulcerative colitis patient based on their ability to induce a Th17 response in mice in another study. The authors demonstrated that the host Th17 response is activated by intestinal microorganisms through mechanisms of adhesion to epithelial cells [40]. Microbial factors influence Treg cell differentiation, as in the case of commensal Bacteroides fragilis or some Clostridium species. In the case of IBDs, it has been found that the gut microbiota from new-onset Crohn’s disease and ulcerative colitis patients is markedly lacking Clostridiales organisms [41,42]. Additionally, for homeostasis maintenance between the gut microbiota and the immune system, it should be taken into account that immune cells have sex hormone receptors and that there is increasing evidence that all the three subtypes of T helper cells—namely, Th1, Th2, and Th17—directly respond to the changes in concentrations of sex hormones. For example, estradiol affects the reduction of Th17 number, increases the activity of Th2 at high concentrations, and increases the number of Treg cells [43]. Overall, mouse studies investigating sex differences between organ-specific Treg frequencies in various diseases showed contradictory results; in humans, it seems that Treg levels are higher in adult males than in

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females [43]. Nonetheless, this remains an area of investigation that can potentially open new perspectives on gut microbiota-immune system interaction according to sexes in health and disease, including IBDs. With this aim, one of the useful tools is represented by multiomics techniques. Longitudinal multiomics data sets have been recently collected as part of the integrative Human Microbiome Project (iHMP) [44]. In all, 132 individuals with and without IBDs were followed up for 1 year; stool samples, biopsy samples, blood specimen, and clinical data were also collected. Molecular profiles of host and microbial activity were generated in order to understand functional dysregulated mechanisms of the gut microbiome in the course of IBDs (i.e., taxonomic shifts, change in the gene expression of some bacterial species, change in metabolite production). All these data were gathered in the Inflammatory Bowel Disease Multiomics Database, which is publicly available [45]. Data extrapolation according to sexes from such larger data sets might undoubtedly add insights into sexual dimorphism in the gut microbiome of IBD patients.

4  Sexual dimorphism in the gut microbiome Over the past decade, increasing evidence has been in favor of sex-specific differences in the gut microbiome per se [46–50]. Sexual dimorphism in the gut microbiome is also a relatively recent area of research. Most of the studies on this issue have been performed in rodents and have provided evidence that sex differences in microbiota composition might contribute to differences observed in both intestinal immunity and peripheral immunity. Yurkovetskiy et  al. [51] demonstrated that NOD mice microbiota did not differ between males and females before puberty and also that castration of males reversed sex differences observed after puberty. In another study, no differences in colonic bacterial community composition were found in prepubescent C57BL/6 mice through deep sequencing of the colonic luminal contents, but whole genome profiling of both colonic and small intestinal tissues from prepubertal mice revealed multiple genes with sexually dimorphic expression, ­including those involved in immunity and inflammatory pathways, thus suggesting an intrinsic sex-specific regulation of the gut microbiota, even independently from sex hormones [52]. In summary, it is clear that after puberty, female mice have an increased microbiota diversity as compared to male mice, and, when focusing on bacterial composition, the abundance itself changes between sexes [46]. The gut microbiota plays a role in entheropathic circulation of nonovarian estrogen in men and postmenopausal women, thereby modulating local and systemic hormones levels [53]. In rodent models, the gut microbiota modulates local production of testosterone, conferring protection against the development of type 1 diabetes in males through altered IFN-γ- and IL-1β-mediated signaling [1,51]. Androgens seem to confer male protection against the development of lupus in lupus-prone mice via influencing gut microbiome composition [54]. The sex of the microbiota also seems to affect metabolic outcomes, which could be modulated by change in testosterone levels [51,53]. It has been observed that strain-specific sex differences are anyway present in mice models, which means that genetic background might also have a role. This contributes to difficulties in correct data interpretation. Org et al. [55] investigated gut microbiota composition in 89 different inbred strains and found specific sex differences in microbiota composition for each strain. Despite these interstrain differences in that study, the total cohort of the phylum

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Actinobacteria and Tenericutes appeared more abundant in male than in female mice. At the genus level, Erwinia, Anaeroplasma, and Allobaculum were more abundant in males, whereas Ruminococcus, Dorea, Coprococcus, and SMB53 were more abundant in females than in males. Diet is an additional factor that can dramatically influence mice microbiota in a sex-­ dependent manner. Western diet is one of the environmental factors included among those responsible for IBD etiopathogenesis. Sheng et al. [56] investigated the effects of a western diet defined as a high-fat and high-carbohydrate diet for 4 months on C57BL/6 mice and found a significant reduction in the relative abundance of Erysipelotrichaceae in only males, whereas the relative abundance of Lachnospiraceae was found to be exquisitely reduced in females. The sex–diet interaction was investigated in a study including mice, fish, and humans, underscoring sex-specific effects on the gut microbiome in two species of fish. In humans, sex-specific differences on Fusobacterium spp. levels were also found [47]. Interestingly enough, if the statistical models did not account for sex, dietary effects were not present, confirming once again the importance of considering sex as a pivotal variable—and not as a confounding factor—in statistical analysis in gut microbiota studies [47,57]. In the case of humans, data remain anyhow conflicting, as some studies did not find any significant difference according to sex in the gut microbiome in terms of diversity. Similar to animal models, diet, body mass index, genetic background, age, and sex hormones (including variation in reproductive conditions in women) are considered the most influencing factors that render data standardization and interpretation extremely difficult. Results produced from seminal studies performed in the last decade may be summarized with a higher level of the Bacteroides-Prevotella phylogenetic group, higher abundance of some Bacteroidetes, Clostridia, and Proteobacteria, and higher relative abundance of Bacteroidetes in men as compared to women. More recent data from 6 studies analyzing 1020 healthy individuals from 23 different populations across 4 continents have revealed similar abundance of Firmicutes and Bacteroidetes in both males and females [48,49,58,59]. Relative abundance of some species has been observed in correlation with the amount of saturated fatty acid intake in females and not in males, providing evidence once again on how diet can affect the human gut microbiome in a sex-dependent manner. The adipose tissue produces sex hormones and can also influence sex differences in the gut microbiota [53,60]. If sex differences in the gut microbiome exist per se, with the gut microbiome being a pivotal environmental factor for IBD development, one might argue that the gut microbiome can contribute to IBD development according to sex, thus justifying, at least partially, the phenotypic differences observed in female and male IBD patients. This might be further supported by the fact that the immune response by itself is different between females and males and is shaped by the gut microbiome [43]. Indeed, as the immune response is different between sexes, it seems highly probable that its interplay with the gut microbiome is generally different as well. In the two seminal papers already mentioned, Markle et al. [1] and Yurkovetskiy et al. [51] basically provided evidence on the role of sex as a gut microbiome influencer outside the reproductive tract and in a sex hormone-dependent manner. Further evidence comes from microbiota transfer studies from conventional specific pathogen-free (SPF) mice to germ-free mice. Germ-free male recipients of male microbiota showed higher percentages of RORγt + Foxp3 + cells in Peyer’s patches and mesenteric lymph nodes as compared with germ-free male recipients of female microbiota [61]. Germ-free females showed higher baseline antibodies as compared to males and similar to conventional females, suggesting

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that some differences in immunity are even independent from microbiota [62]. However, the same authors also showed that germ-free males have lower baseline antibody titers, which increased following the transfer of female microbiota, thus determining a boost in IgA levels and suggesting on the other hand a microbiota-induced effect on antibodies in males. Female microbiota appeared to be less proinflammatory when transplanted, as confirmed by the analysis of local genes and pathways [62]. All differences manifested after 4 weeks since the transplant. Double-negative T-cell precursors were higher in mice receiving female microbiota as compared to those receiving male microbiota, but no sex differences were found in the three subsets of T helper (Th) lymphocytes, namely, Th1, Th2, and Th17, in Peyer’s patches, mesenteric lymph nodes, and the spleen. In the same study, examination of differential gene expression in the gut mucosa demonstrated more pronounced transforming growth factor-beta (TGF-β), IL-1β signaling, and type 1 interferon pathway regulation in males as compared to female mice, thus providing evidence in favor of a sex-based gut microbiota-­ immunity interplay [62].

5  Impact of the gut microbiome on sexual dimorphism in IBDs: Future perspectives and applications, from bench to bedside All the evidence analyzed so far support the role of sex hormones as the third main component in the complex interaction between the gut microbiota and immunity. As hormones are able to influence intestinal permeability, they probably play a major role in driving the gut ­ microbiota-immunity interplay in a sex-based manner. Estrogens have been shown to decrease intestinal permeability in animal models, according to cyclic changes in the ­estrogen-progesterone shift [63,64]. In clinical practice, IBD women experience symptoms, which vary according to their menstrual cycle, suggesting that this might be related to ­hormonal fluctuations [65]. Thus, we should consider more carefully that hormonal levels and variations in our patients might have an impact on the clinical course of IBDs on both genders. Redefining translational and clinical research in IBDs according to sex-based differences in the gut microbiome might have a deep impact on treatment strategies and on adopting a real personalized approach in this field. This could be possible by integrating metagenomic data in large-scale populations studies with metatranscriptomics and metabolomic data analysis that add further insights into transcriptional changes and metabolic pathways, respectively [6]. Knowledge of an IBD patient’s gut microbiome composition according to his/her sex and its correlation with metabolomic pathways of response to treatment can help in understanding how to predict response to therapy with antiintegrin, anti-TNF, or other biological/synthetic immunomodulators [6,66–68]. In order to do that, one of the first steps is to conduct high-­ powered metaanalyses on publicly available gut microbiome databases so as to identify specific microbial strains according to the patient’s sex [7]. Thereafter, we need to understand how such microorganisms and microbial products affect the immune status of the host in health and disease and also how their activity is influenced by sex hormone levels. We need to identify functional differences between strains and provide for further animal studies and models as proof of concept. However, the research approach should remain focused on identification of human disease-relevant microbial factors to be tested in mouse models, rather than vice versa, as IBD is a polymicrobial disease linked to reduced gut microbial diversity [6].

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Nowadays, we know that dietary changes have strong influence on gut microbiota composition and can either prevent or promote gut inflammation. Diet modifies the gut microbiome differently in males and females, as demonstrated by different studies, but we are still far away from being able to assess dietary changes in a personalized and sex-based manner. A prospective study on 170,776 women investigated the long-term intake of dietary fibers and found that intake of the highest quintile was associated with 40% reduction of Crohn’s disease risk. A protective effect of dietary fibers related to increased production of short-chain fatty acids—and thus to increased immune tolerance and activation of Treg cells—might be argued in that population [69,70]. Finally, FMT application in IBDs is a matter of deep interest and there is an emerging consensus that it might be potentially considered as a treatment at least in ulcerative colitis patients [71]. However, the sex of the donor and the recipient has not being considered during the screening for suitability so far [53], and we still do not know whether the sex of the donor can influence FMT’s rate of success. This might be of extreme relevance to personalize methods of cultivation and transplant in IBDs. Interestingly, in a recent study on FMT treatment of Clostridium difficile infection, female sex was associated with FMT failure [72].

6  Conclusion We have referred to seminal papers aiming to show that sex differences are present in the gut microbiome; they influence its composition and function and also its interaction with the immune system. Furthermore, sex differences in the gut microbiome are at least partially modulated by sex hormones. How this complex interplay affects sexual dimorphism in IBDs, in terms of pathogenesis, disease onset, clinical course, and response to treatment and prognosis, remains an underrepresented and challenging area of investigation. We have underscored several limitations related to the study of such an interplay, whose insights can represent a pivotal step forward in personalized medicine in IBDs. We need to take into account that most of the seminal studies have mainly been performed on the gut microbiota from laboratory rodents, whose results may not be generalizable to humans due to strong differences between rodent and human gut microbiota at the genus level [53]. Rigorous experimental techniques are required as individual rodent gut microbiota may vary even when cohoused and may render results inconsistent [53]. However, as IBD is currently considered a polymicrobial disease, the research approach should remain focused on identification of human disease-relevant microbial factors to be tested in mouse models, rather than starting from evidence in animal models to be transferred to humans [6]. Finally, this chapter focuses on studies aimed to identify and deepen on bacterial communities, while how fungi and viruses interact with them in the whole gut microbiome remains to be clarified and represents another fascinating field for future gut microbiome research in IBDs.

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15 Autoimmunity of the liver Angelo Armandia, Giovanni Clemente Actisb, and Davide Giuseppe Ribaldonea,⁎ a

Department of Medical Sciences, Division of Gastroenterology, University of Turin, Turin, Italy b The Medical Center Practice Office, Turin, Italy ⁎ Corresponding author

Abstract Autoimmune hepatitis (AIH) is a chronic inflammatory disease, in which a loss of tolerance against liver antigens is considered the main pathogenic mechanism. AIH is probably triggered by environmental agents (medications, toxins, other immune-mediated disorders) that act upon genetically susceptible individuals. The global burden of AIH is increasing worldwide, potentially due to multiple environmental factors that impact the genome structure. A loss of immune tolerance and exposure of cryptic antigens from damaged hepatocytes are believed to be the strongest driver for the onset and maintenance of an immune-mediated chronic inflammatory injury. The whole clinical spectrum is characterized by unspecific elements, including serum autoantibodies and diverse disease features at liver histology. Considering its increasing prevalence, many efforts are being taken to treat patients who do not adequately respond to standard immunosuppressive treatments as well as to find novel noninvasive biomarkers that can reliably substitute liver histology in assessing liver fibrosis and in predicting hard long-term outcomes.

Keywords Autoimmune hepatitis, Immune tolerance, Immunosuppressive treatment, Autoantibodies, Liver fibrosis

1  Introduction Autoimmune hepatitis (AIH) is a chronic inflammatory disease in which a loss of tolerance against liver antigens is considered the main pathogenetic mechanism, probably triggered by environmental agents acting on genetically susceptible individuals. AIH was first described by Waldenström in 1950 as a form of chronic hepatitis affecting young women and characterized by elevated gamma globulins and amenorrhea, with a progressive course to cirrhosis [1]. A beneficial effect of steroid therapy was observed, making

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this form of hepatitis the very first one to be potentially cured by medical therapy. Afterward, Mackay et al., in 1956, collected evidence of the connection between AIH and other systemic autoimmune syndromes, which together with the presence of circulating antinuclear antibodies (ANAs) led to the term “lupoid hepatitis” [2]. Subsequent evaluation of the histological pattern of hepatocellular damage, the presence of specific antibodies against human and animal cell protein structures, and clinical features led to the characterization of AIH as a single, heterogeneous hepatic syndrome with different underlying etiologies but gathered by few recognizable pathogenic alterations [3]. The disease can arise at any age, with a female predominance. An association with other immune-mediated diseases is frequently observed, such as rheumatoid arthritis (RA), autoimmune thyroiditis, ulcerative colitis (UC), and type 1 diabetes mellitus (T1DM) [4]. If untreated, AIH subtly progresses to cirrhosis, potentially causing the onset of hepatocellular carcinoma (HCC) and portal hypertension, eventually leading to liver transplantation and death. Sometimes, AIH can first present as acute hepatitis or even fulminant hepatic failure [5]. Together with ANAs, other marker antibodies have been recognized as being related to AIH, thus allowing a subclassification of the disease: AIH type 1, which constitutes the originally described disease, affecting young adult women, is characterized by ANAs and/or antismooth muscle antibodies (SMAs), which mainly target actin, troponin, or tropomyosin [6]; AIH type 2, which predominantly affects children and adolescents, is characterized by antiliver kidney microsomal antibodies type 1 (LKM-1), which target cytochrome P450 CYP2D6 and, with lower frequency, UDP-glucuronosyltransferase (UGT) [7]; and AIH type 3, which shares the clinical and epidemiological patterns with AIH type 1, is characterized by antibodies against a soluble liver antigen (anti-SLA), which targets a transfer-ribonucleoprotein (tRNP) particle that is involved in the incorporation of selenocysteine in peptide chains [8]. An additional presence of antiliver cytosol antibody type 1 (anti-LC1) and LKM-1 in type 3 may be detected although the significance is still uncertain [9]. This serological heterogeneity, despite the association with slight differences when comparing the subtypes of the disease, does not influence the decision of whom to treat and which therapy to adopt. In addition, the serum antibody pattern can change during the course of the disease. Indeed, no diagnostic feature is specific to AIH. The main histological finding is the high necroinflammatory activity located at the periportal zone of the hepatocyte (interface hepatitis) associated with a lymphomonocytic infiltrate inside the lobules [10]. These histological features are also found in liver diseases of other etiologies, while the detection of circulating antibodies is not exclusively suggestive of an immune-mediated damage. ANAs and ASMAs are found in other hepatic and extrahepatic diseases as nonspecific serological stigmata of the inflammatory damage in healthy people, particularly in the elderly and in women. In chronic hepatitis caused by the hepatitis C virus (HCV) or the hepatitis D virus (HDV), diverse circulating antibodies that do not show clinically relevant significance may appear. Similarly, in the spectrum of nonalcoholic fatty liver disease (NAFLD), ANAs may be detected in sera. Moreover, even the assumption of drugs with high hepatic extraction (e.g., carbamazepine, phenobarbital, hydralazine) can cause autoimmune reactions. Moreover, even in immune-mediated diseases, antibodies may be the result of a large immune response, such as epiphenomena. On the other hand, the absence of antibodies does not rule out the immune-mediated etiology of liver disease, as shown by the prompt response

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to steroid therapy in cases of seronegative AIH. Therefore, more suggestive parameters are needed to first suspect and then confirm the presence of an immune-mediated hepatic syndrome, classified into different clinical entities. In this complex scenario, understanding the pathogenic mechanisms of AIH is of crucial relevance, especially in the therapeutic field. The growing knowledge of the molecular basis of AIH should lead to better long-term control of the disease and also to a novel, more precise therapeutic target that would replace nonspecific immunosuppressive agents, burdened by prominent side effects, in particular with long-term use. However, as AIH is often recognized during the late course of the disease, it is challenging to obtain information about the immunological derangements that are primarily responsible for initiating the chronic damage. In addition, as there is no known hepatocellular antigen that is recognized as the main target of the autoimmune response (thus, challenging the term “autoimmune” hepatitis itself), the etiology of the disease (which therefore should be better addressed as “immune-mediated” hepatitis) relies on environmental factors that act on a susceptible individuals with genetic and/or epigenetic background. The onset of a form of hepatitis that is caused by autoreactive immune responses is quite intriguing per se, as the liver is a privileged organ from an immunological point of view. Transplanted livers are less rejected than other solid organ transplants [11]. AIH together with other forms of immune-mediated liver diseases that primarily affect the biliocyte (primary biliary cholangitis and primary sclerosing cholangitis) have a lower frequency as compared to other systemic or organ autoimmune diseases. This immune privilege of the liver may depend on the avoidance of tissue damage in one of the first organs that faces hexogen neoantigens, especially derived from the gut and its microbiota via portal drainage, both in healthy individuals and in those affected by intestinal diseases, in which a breakdown of the mucosal barrier makes the antigen overflow a more frequent occurrence [12]. Thus, a high immune tolerance threshold in the liver is necessary, considering its function in detoxifying drugs and toxins that may frequently cause hepatocyte disruption with consequent exposure of intracellular (cryptic) antigens or may hesitate in intermediate reactive metabolites acting as antigens and would stimulate the immune ­system [13].

2  Pathogenesis AIH occurs both in children and in adults of all ages and all ethnicities (Table 1). Based on epidemiological data, AIH-1 has two peaks of incidence: the first one between 10 and 18 years of age and the other around the age of 40 years, with up to 20% of individuals being diagnosed after the age of 60. AIH-2 mainly affects children, including infants less than 1 year of age, adolescents, and young adults up to 25 years of age, being rare at older ages [14,15]. As with other autoimmune syndromes, there is a female preponderance, with a male-to-female ratio of around 1:4, regardless of the subtype of AIH, with an increase in the number of male patients over the last few decades [16,17]. Such different trends over the decades may be explained through the complexity of autoimmunity that involves both genes and the environment. There is still no convincing evidence to explain the preponderance of females in autoimmune disorders, despite the strong

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TABLE 1  Subtypes of autoimmune hepatitis. Feature

AIH-1

AIH-2

Diagnostic antibodies

ANA (homogeneous)

LKM-1

Suggestive antibodies

SMA

LKM-3, LC-1

Age at diagnosis

Any age (2 peaks: 10–18 years and 40 years)

Childhood

Prevalence

10–25/100.000 individuals

Less than 0.5/100.000 individuals

Polymorphisms in the HLA region

DRB1*0301, DRB1*0401, DRB1*405, DRB1*404, DRB1*1301, DRB1*0301

DRB1*07, DRB1*03, DRB1*15

Concomitant autoimmune diseases

Occurrence in almost 20% of cases: autoimmune thyroiditis, atrophic gastritis, and inflammatory bowel disease

Strongest association with extrahepatic disorders: vitiligo, autoimmune thyroiditis, type 1 diabetes mellitus, and Addison’s disease

Disease severity

Mild to moderate

Moderate to severe, acute liver failure

Treatment response

Good response to steroids and standard immunosuppressive regimens

Less response to steroids

ANA, antinuclear antibody; HLA, human leukocyte antigen; LC1, liver cytosol antibody type 1; LKM, antiliver-kidney microsomal antibody; LKM-1, type 1 LKM; LKM-3, type 3 LKM; SMA, antismooth muscle antibody.

epidemiological evidence of a female-driven global burden. Nonetheless, some intriguing hypothesis, focused on gender-restricted mechanisms, have been made, namely, different expressions and distribution of sexual hormones, fetal microchimerism during pregnancy, and skewing of X chromosome inactivation or X chromosome abnormalities. In addition, deviations from the expected random cellular mosaicism in women, as well as haploinsufficiency of X-linked genes, can contribute to female-specific loss of self-tolerance and subsequent genetic imbalance [18]. Although there are few data on the global burden of AIH-2 (presently estimated to be less than 0.5 cases per 100.000 individuals), there is strong evidence that the prevalence of AIH-1 is increasing worldwide [19]. Data from studies conducted in Northern Europe have estimated a prevalence ranging from 10 to 25 case per 100.000 individuals, with a higher prevalence in Denmark and Sweden, followed by The Netherlands and Finland. In the Pacific area, the prevalence is estimated to range from 5 to 25 per 100.000 individuals, being higher in Japan and New Zealand [17,20]. In the United States, the estimated prevalence is 0.4 per 100.000 adults and AIH constitutes 3.2% of liver transplant cases [21,22]. Even in Asia, where chronic viral hepatitis represents the major burden, prevalence of AIH has increased, reaching numbers of cases that are similar to the rest of the world. Autoimmune diathesis has increased worldwide. Therefore, despite the initial sexual diverse susceptibility, the environmental changes that have taken place during the last century may have affected both sexes equally, shaping the epidemiology toward milder differences. Industrialization has caused a profound imbalance in dietary intake and work habits as well

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as in altered sleeping patterns. These factors, and probably many others that are not yet understood, slowly impact the whole genome. Genome and environment always need to head toward the same direction, and the discordance caused by multiple environmental modifications cannot be long tolerated. Changes in lifestyle, particularly in diet, could trigger genetic susceptibility. Dysbiosis, the alteration of the balance of the intestinal microbiome, could be the link in the chain that unites lifestyle changes with the onset of the disease [23]. Thus, new patterns of gene expressions are needed for adaptation, and, sometimes, they become pathogenic for the individual. Large genome-wide association studies (GWASs) have demonstrated that a primary susceptibility to develop AIH is linked to polymorphisms in the human leukocyte antigen (HLA) region, encoding the major histocompatibility complex (MHC), a crucial extracellular structure involved in the mechanism of the proper recognition of the self [24]. The distribution of these polymorphisms may explain the different prevalence of AIH across different populations. In Europe and North America, HLA-DR3 (HLA DRB1*0301) and HLA-DR4 (HLA DRB1*0401) genotypes predispose to the onset of AIH; these genotypes are characterized by a lysine residue at position 71 of the DRB1 polypeptide. Interestingly, in Argentina, Mexico, and Japan, there is a wide distribution of HLA DRB1*0405 and HLA DRB1*0404 in the AIH population; these genotypes are characterized by an arginine residue at position 71. Accordingly, it seems that the presence of either lysine or arginine in position 71 of the DRB1 polypeptide of the MCH complex would result in a less functioning protein, leading to susceptibility in binding autoantigen-specific peptides [25,26]. Other genotypes associated with AIH type 1 are HLA DRB1*1301 and HLA DRB1*0301 in South America. For AIH-2, HLA DRB1*07, HLA DBRB1*03, and HLA DRB1*15 have been described [27]. Moreover, AIH-2 can be part of an autosomal recessive monogenic polyendocrine syndrome, named the autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED) syndrome, which in up to 20% of cases is a syndrome resembling AIH-2 with detectable circulating LKM-1 antibodies [28]. The implied dysfunctional gene is AIRE, encoding for the autoimmune regulator protein that permits the presentation of tissue-restricted antigens to T lymphocytes inside the thymus in order to eliminate autoreactive T cells (negative selections) and to positively select antigen-specific regulatory T cells (Tregs). Interestingly, mouse models with analogous AIRE mutations develop a syndrome that includes corticosteroid-responsive hepatitis, probably caused by a deficit in peripheral Tregs (deficit in positive selection) [29]. GWASs conducted in non-HLA genes have not shown the same strength as that of HLA loci in determining susceptibility to AIH. Notwithstanding this evidence, the familiar clustering of AIH is relatively low [30]. In addition, increased prevalence of male individuals being affected by AIH, as well as the worldwide increase of the disease, has increased awareness that epigenetic factors or, more incisively, environmental factors are crucial determinants in the genesis of immune-mediated injury of hepatocytes [31]. Experimental murine models have provided insightful evidence of the involvement of the gut microbiota in the pathogenesis of AIH, as well as other liver diseases, as one of the main characteristics of the gut-liver axis [32]. The intestinal microbiome has sex-specific compositional differences, and this may be one of the first hypotheses of the female preponderance of immune-mediated diseases. In addition, AIH microbial dysbiosis seems to be constituted by lower bacterial diversity and reduced uniformity among the species, with altered relative abundances in 11 bacterial genera; in particular, richness in Veillonella, Streptococcus, Klebsiella,

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and Lactobacillus genera is associated with AIH. In particular, relative abundance in Veillonella is related to disease activity due to augmented production of lipopolysaccharides (LPS), one of the most relevant bacterial proinflammatory products. Expansion of facultative anaerobes (Streptococcus, Klebsiella, Lactobacillus) underlines a shift to a more aerotolerant microenvironment, leading to a decreased production of short-chain fatty acids, which are synthetized by anaerobic intestinal microbiota and exert an antiinflammatory effect. Expansion of facultative anaerobic bacteria seems to be relevant in maintaining a proinflammatory environment, together with increased gut permeability and thus increased translocation of bacterial products into the portal flow, as shown by the decreased expression of intestinal protein occluding [33]. One of the most commonly accepted pathogenic mechanisms in autoimmune disorders is molecular mimicry. In genetically predisposed individuals, immune responses directed toward hexogen antigens may be shifted to structurally similar self-proteins. Naive T cells that are evoked by antigen-presenting cells (APCs) in an MHC-restricted manner become primed and initiate the clonal expansion that is responsible for liver injury. Viral infections are the most frequent agents that may cause molecular mimicry together with xenobiotics. This is easily shown in AIH-2, where LKM-1 antibodies are directed toward cytochrome P4502D6. Some amino acid sequences inside the cytochrome share high homology with proteins synthetized by HCV and some members of Herpesviridae (herpes simplex virus, ­cytomegalovirus, Epstein-Barr virus). Conversely, it has been reported to be a false positive for HCV-specific antibody testing in patients with untreated AIH, without any other sign of viral infection [34,35]. Thus, one initial infective insult may cause the onset of an aberrant immune response that is maintained over time in a proinflammatory manner. In addition, an autoreactive response once initiated can expand to other homologs self-antigens, a phenomenon known as epitope spreading, which is responsible for the systemic nature of immune-­mediated disorders, where anatomically distant organs are equally affected through immunological cross-reactivity [36]. Mouse models of AIH-2 have confirmed that the spreading attitude of molecular mimicry, as an autoreactive response, primarily directed toward exposure to cytochrome P4502D6 within a viral vector caused the synthesis of LKM-1 antibodies; afterward, the immune response was directed toward less-dominant homologous sequences within the same antigen [37]. A growing evidence of epigenetic modulation of DNA has been presented to the complex world of nontranscriptional, interconnected small regulatory particles of RNA (microRNA). In AIH, some epigenetic changes may affect the severity and outcome of liver disease. MicroRNAs such as miR-21 and miR-122 have shown correlation with AIH as they can suppress antiinflammatory genes, thus resulting in a more aggressive phenotype [38]. In addition to viral infections, other environmental agents may act as the primary stimulus to the onset of aberrant immune responses. Formation of neoantigens and unmasking intracellular cryptic self-antigens are the putative underlying mechanisms that are involved. Idiosyncratic drug-induced liver injury (DILI) can be the result of direct toxicity or the effect of a subsequent metabolic or immunological derangement [39]. In fact, hepatocyte damage may trigger a sensitization response to nuclear or cytoplasmic antigens that leads to both cell-mediated and humoral immune responses, resembling AIH. The histological pattern of inflammatory infiltrations is also the same (plasma cells mainly located in the periportal area), challenging the correct diagnosis. Most DILIs, however, resolve spontaneously after drug withdrawal, with prompt response to steroid therapy and low occurrence of relapse

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and, importantly, show no correlation with HLA allele patterns [40,41]. Drugs best known to cause DILIs are nitrofurantoin, minocycline, methyldopa, dihydralazine, tienilic acid, and amoxicillin. The synergic effect of direct toxicity and immune system evocation is best shown by the anesthetic halothane, which can cause acute hepatitis associated with AIH-related antibodies [42]. These antibodies are directed against both neoantigens induced by oxidative stress and well-known protein targets in AIH, such as cytochromes. This is also demonstrated with tienilic acid, which is known to induce antibodies against cytochrome CP4502C9 (known as LKM-2) [43]. According to the exposure of hidden hepatocyte antigens, every inflammatory liver damage may potentially lead to stimulation of bystander immune cells in a proper genetic manner. In cirrhosis and HCC, which are two conditions of hepatic tissue subversion, antibodies against cryptic residues of α-fetoprotein have been reported [44]. Similarly, alcohol hepatitis and NAFLD may induce antibodies resembling those present in AIH. However, these antibodies, although relevant in the pathophysiological field, seem to be only one epiphenomenon of the concurrent active inflammatory damage, as they are not related to a more severe course of the disease nor do they appear to have sustained an immune damage both in the liver and in extrahepatic districts [45].

3  Pathophysiology The liver hosts different kinds of specialized resident APCs, such as sinusoidal endothelial cells (that have the ability to switch their phenotype according to the inflammatory stimuli driven by cytokines), Kupffer cells, and dendritic cells as well as macrophages and B cells. Their role is to process antigens and present them to naive CD4 + T helper (Th) cells, appropriately assembled within the type 2 MHC complex and appropriate costimulatory signals. Their subsequent maturation is driven by a specific cytokine pathway to which naive T cells are exposed. In the liver, antigen presentation occurs locally, without exposing antigens to local lymph node stations, leading to an immunological background characterized by tolerance [46], as shown by some experiments conducted in mice, where both CD8 + and CD4 + T cells may be primed and activated entirely within the liver [47,48]. Animal studies have also shown that tolerance can be induced through oral or portal venous introduction of antigens but not through the liver, thus excluding the systemic venous route [49]. Moreover, Kupffer cells constitutively express immunoregulatory molecules, such as CD274, and are known to secrete immunosuppressive interleukin (IL)-10 in response to proinflammatory stimuli driven by bacterial LPS [50]. Therefore, an immunological analysis of liver samples is essential in AIH, rather than evaluation of peripheral blood because critical phenotypic differences between liver-infiltrating leukocytes and circulating leukocytes have been found [51]. The majority of AIH patients are treated with immunosuppressive drugs, sometimes even before a precise diagnosis has been made, and this can alter the peripheral immunophenotype. The mononuclear infiltrate of AIH is mainly constituted by CD4 + T cells, as the CD4/CD8 T-cell ratio is higher in AIH than in cholestatic or viral chronic hepatitis. CD8 + T cells are present in inflammatory infiltration but are less frequently and most predominantly found in interface hepatitis. After stimulation, infiltrating lymphocytes produce more IL-4 and IL-10 than those present in other

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15.  Autoimmunity of the liver

liver diseases. Production of other cytokines, such as IL-2 or interferon-gamma (IFN-γ), is not significantly increased as compared to other liver diseases [52,53]. This a fundamental finding in terms of pathophysiology. IL-4 and IL-10 are markers of Th2 cells, which indicates a polarized immune response toward the humoral arm. As a matter of fact, even though B cells constitute a small proportion of the inflammatory infiltrate, they are stimulated by Th2 cells toward maturation to plasma cells, leading to antibody-mediated cellular damage and complement activation. Plasma cells seen in AIH predominantly secrete immunoglobulin (Ig) G, differently from cholestatic diseases, where IgM is more frequently produced. Notably, animal models and clinical experience strengthen the pivotal role of B cells in AIH. Rituximab, the B-cell-depleting CD20 monoclonal antibody, has proved to ameliorate the course of AIH, including the extent of T-cell infiltration [54]. Circulating autoreactive T cells are present in healthy individuals, but their potential tissue damage is contrasted by intrinsic mechanisms of self-tolerance. The main lymphocytes involved in this surveillance are lymphocytes with immunoregulatory function, mainly CD4 + CD25 + Treg cells. They play a surveillance role in both innate and adaptive immune systems by limiting the proliferation of immunoreactive T cells through direct cell-to-cell contact and through secretion of specific cytokines, such as IL-10 and transforming growth factor-beta (TGF-β). In AIH, a numerical and functional defect in Tregs has been observed [55]. Individuals affected by AIH have lower circulating Tregs, more evident at diagnosis and during relapses. Their titer is inversely correlated with serum antibody (especially anti-LKM-1) concentration [56]. Functional studies conducted on Tregs in patients with AIH have shown their lower ability to control the proliferation of both CD4 + and CD8 + lymphocytes. In addition, their functional impairment is shown when considering their lower ability to secrete the immunomodulating IL-10 and their instability is demonstrated upon proinflammatory stimuli given that they can be more rapidly converted into effector cells [57,58]. When considering a tight, bidirectional dialog between multiple cytotypes, the study of the microenvironment is of utter importance, particularly in tumor progression. In AIH, even though Tregs are apparently normal, the intrahepatic environment may exert a defective action on their function. Treg cells require IL-2 for their development, and the lack of intrahepatic production of IL-2 can lead to their poor functionality. Supplementation of IL-2 has been proved to sustain the expression of specific Treg phenotype-immunomodulating molecules [59,60]. In addition, another possible mechanism that underlies this functional and numerical paucity in Treg function has been attributed to another cluster of lymphocytes, namely, Th17 cells. When the cytokine milieu is dominated by strong proinflammatory agents, like IL-1β and IL-6, naive lymphocytes may be driven to the Th17 phenotype [61]. A high number of Th17 cells have been reported in AIH although their role is yet to be clarified. However, some evidence has brought to light their possible role as a mediator in AIH. Both peripheral and intrahepatic augmented amounts of Th17 cells have been reported, together with increased intrahepatic IL-6 expression. Indeed, differentiation into the Th17 phenotype, rather than the Treg phenotype, is hypothetically linked to sustained damage in AIH. Blockade of IL-17 allows the development of the Treg CD4 + CD25 + phenotype in AIH, and, in addition, during resolution of inflammation, Th17 cells are transdifferentiated into Tregs [62,63]. The pivotal role of Treg phenotype defection comes from an animal model characterized by deletion of medullary thymic epithelial cells, which regulate T-cell tolerance through negative selection. The mice do not develop a systemic autoimmune disease but instead a

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syndrome that closely resembles human AIH-1, with periportal hepatitis and production of ANAs and antibodies directed toward liver-specific antigens [64].

4  Diagnosis It is undeniable that the presence of autoantibodies is a hallmark of AIH and an important factor in diagnostic procedures. Nevertheless, sometimes AIH can develop without serum-­ detectable antibodies, especially in an acute setting, where antibodies may appear after a proper response to empirical immunosuppression [65]. Before accepting the negativity to antibodies, a wider screening should be done, expanding the detection beyond ANA, SMA, and LKM-1 through searching for SLA, p-ANCA, LC1, and LKM-3. On the other hand, ANA, SMA, and LKM-1 antibodies lack sensitivity to AIH, as they may be present in liver diseases of other etiologies. Globally, their diagnostic accuracy reaches 55%–60% [66]. Positivity to multiple antibodies strengthens the suspicion of AIH, in particular a combination of ANA and SMA, which has a specificity of 99% and a diagnostic accuracy of 74%. Only SLA antibodies exhibit a high specificity (98.9%) for AIH [67]. In some cases, autoantibodies seem to correlate with disease activity, whereas serum titers neither correlate with the severity of the disease nor are they able to predict a successful response to immunosuppressive treatment [68]. However, many antibodies are directed toward antigens that are not specific to the liver. In diagnostic evaluations, SMA and LKM-1 antibodies are identified using indirect immunofluorescence to IgG by examining the patient serum on rodent liver-stomach-kidney slides, with preferential staining on large kidney tubules for LKM-1, and on rodent stomach preparation samples for SMA; ANA antibodies are preferentially evaluated on human epithelial type 2 cells. Further examination with ELISA is often imperative to confirm the initial reactivity to immunofluorescence and is necessary for detecting SLA antibodies [69] (Fig. 1). Therefore, it is still not clear whether autoantibodies represent an epiphenomenon of the immune response or have a pathogenic role per se. LKM-1 antibodies show a clearer profile in this sense, as the targeted self-antigen cytochrome P4502D6 is expressed on the surface of hepatocytes, whereas it is intracellular (and thus cryptic) in other cell types [70]. Hepatocytes isolated from patients with AIH are in  vivo coated with antibodies and are destroyed by autologous lymphocytes in in vitro essays [71]. On the other hand, serum transfer fails to induce AIH in animal models [72], and individuals who develop AIH during pregnancy do not transfer the disease to the fetus [73]. It is not known whether autoantibodies appear before the onset of the disease, thus questioning their direct pathogenic role. This point appears to be of crucial interest because, notwithstanding the wide distribution of the targeted antigens, tissue destruction is confined to the liver. This evidence marks the prominent role of liver-specific defective regulatory mechanisms that are primarily involved in the upraise of AIH. One initiating event, acting on proper genetic susceptibility, drives tissue damage, which encompasses the synthesis of autoantibodies. The more we descend to the inflammatory ground, the more overlapped becomes the picture, making it hard to discriminate between real pathogenic factors and simple bystanders (Table 2). Due to lack of accuracy of noninvasive tests, a liver biopsy is presently required for the diagnosis of AIH [14]. It is necessary for both differential diagnosis and fibrosis staging. Even though in most cases, AIH has an indolent course, if untreated, it leads to liver cirrhosis and

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FIG. 1  Autoantibodies in autoimmune hepatitis. Indirect immunofluorescence of representative autoantibodies in autoimmune hepatitis performed on rodent tissues. (A) Homogeneous antinuclear antibody (ANA) staining on rodent kidney tissue. (B) Antismooth muscle antibody (SMA) staining on rodent stomach tissue. (C) Antiliver-kidney microsomal antibody (LKM) staining on rodent kidney tissue. (D) Anti-LKM staining on rodent liver tissue. Property of Department of Medical Sciences, University of Turin, Italy.

portal hypertension. In fact, fibrosis represents the most relevant prognostic factor for longterm liver-related events and any actual noninvasive tests are not accurate enough to replace histology. Interface hepatitis and lymphoplasmacytic infiltrates are significantly associated with AIH, whereas other histological findings like rosette formation or emperipolesis are less significant. Interface hepatitis develops in the portal area and then breaks the limiting plate, infiltrating the liver parenchyma. Plasma cells are highly specific to AIH as they are less frequently associated with other etiologies, whereas interface hepatitis occurs in other liver diseases like chronic viral hepatitis, DILI, primary biliary cholangitis, and primary sclerosing cholangitis. In fact, central zone necrosis or perivenulitis of the central veins is an important histological finding in AIH, especially in acute presentation or in liver failure, even though it may also be present in chronic AIH with or without interface hepatitis. Steatosis is not a main finding, but it can also be present. In about 10% of cases, biliary inflammation may be present without bile duct destruction. Eosinophils may be found in the infiltrate, even though they are more specific to DILIs [74–77].

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TABLE 2  Spectrum of autoantibodies found in autoimmune hepatitis and their clinical significance in supporting the differential diagnosis. Autoantibody

Autoantigen

Clinical significance

ANA

Chromatin, histones, centromeres, ribonucleoprotein complexes

High titers and a homogeneous pattern support the diagnosis of AIH-1 Also found in PBC, PSC, Wilson disease, NAFLD, chronic hepatitis B, and chronic hepatitis C

SMA

Mainly F-actin, but also components Supports the diagnosis of AIH-1, in particular when of intermediate filaments of the binding the kidney tubule and glomerular smooth cytoskeleton muscle Also found in PBC, PSC, DILI, hepatitis C, hepatitis B, and NAFLD

LKM-1

Cytochrome P4502D6

Supports the diagnosis of AIH-2 Also found in chronic hepatitis C and DILI

LKM-2

Cytochrome P4502C9

Present in AIH induced by tienilic acid

LKM-3

UDP-glucuronosyltransferase

Supports the diagnosis of AIH-2 Also found in chronic hepatitis D

AMA

Pyruvate dehydrogenase complex

Highly specific for PBC. Present in a minority of AIH, especially in overlap syndrome

p-ANCA

Lamina proteins of neutrophils (mainly β-tubulin isotype 5)

Supports the diagnosis of AIH-1, especially in overlap syndrome with PSC Also found in PSC and IBD

SLA/LP

Phosphoseryl-tRNA selenium transferase

Specific to AIH-1 and AIH-2 It predicts poorer outcome and relapse after withdrawal of therapy

LC1

Formiminotransferase cyclodeaminase

Specific to AIH-2 It predicts poorer outcome

ASGPR

Asialoglycoprotein receptor

It is specific to liver tissue and correlates with disease severity and relapse after withdrawal of therapy in both AIH-1 and AIH-2 Also found in PBC, DILI, chronic hepatitis C, chronic hepatitis B, and chronic hepatitis D

AIH, autoimmune hepatitis; AIH-1, AIH type 1; AIH-2, AIH type 2; AMA, antimitochondrial antibody; ANA, antinuclear antibody; ASGPR, asialoglycoprotein receptor; DILI, drug-induced liver injury; IBD, inflammatory bowel disease; LC-1, liver cytosol antibody type 1; LKM, antiliver-kidney microsomal antibody; LKM-1, LKM type 1; LKM-2, LKM type 2; LKM-3, LKM type 3; NAFLD, nonalcoholic fatty liver disease; p-ANCA, perinuclear neutrophil cytoplasmic antibody; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; SLA/LP, soluble liver antigen/liver-pancreas antibody; SMA, antismooth muscle antibody; UDP, uridine diphosphate.

In more severe cases, necrosis becomes confluent and may form bridges between the portal area and central veins. This necrotic ground harbors a scar tissue that typically develops from the periportal area and then spreads to the lobule, disrupting the hepatocyte architecture until development of cirrhosis. A certain diagnosis can be made only within a scoring system that involves different features of the disease. Clinical presentation, in an acute setting, does not differ from hepatitis of

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other etiologies. The majority of patients, however, have no symptoms of liver disease, with the exception of fatigue, which is the sole, although nonspecific, symptom of chronic hepatitis. In the event of acute hepatitis, a typical liver-related syndrome may be present including malaise, jaundice, and right upper quadrant pain. Very rarely, AIH can present with liver failure, defined by the presence of jaundice, coagulopathy, and encephalopathy. In most cases, instead, AIH is suspected by elevations in aspartate aminotransferase and alanine aminotransferase and is sometimes accompanied by elevations in alkaline phosphatase and gamma-glutamiltransferase. Dominant alterations in alkaline phosphatase are highly suspected for a cholestatic disease. Total and direct bilirubin may be altered as well, suggesting an advanced state of the disease. At diagnosis, IgG levels are elevated in more than 80% of patients [78]. All these factors converge into the diagnostic criteria that were built in 1993 by the International AIH Group [79]. The scoring system was then revised in 1999 [80] (Table 3), and the simplified diagnostic criteria were published in 2008 [81]. Both revised and simplified TABLE 3  Revised diagnostic criteria for AIH in adults [80]. Parameter

Score

Gender Female

+ 2

Male

0

Ratio of alkaline phosphatase levels to aminotransferase levels > 3

− 2

1.5–3

0

 2.0

+ 3

1.5–2.0

+ 2

1.0–1.5

+ 1

 1:80

+ 3

1:80

+ 2

1:40

+ 1

 15 before therapy and > 17 after treatment. A “probable” diagnosis of AIH requires an aggregate score of 10–15 before therapy and 12–17 after treatment.

criteria include histological findings and altered biochemistry. Regardless of its retrospective nature, this score has widely been validated, showing high levels of sensitivity and specificity [82]. The simplified score is less accurate than the revised score, as the first does not include medical history, concomitant medications, and alcohol use. The simplified criteria are therefore preferred in patients with histological and serological features of AIH. Any patient obtaining “probable” or “nondiagnostic” as a simplified score should be reassessed using the revised score [83].

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5  Therapy Untreated AIH has an extremely poor prognosis. In 1980, one placebo-controlled immunosuppressive treatment trial containing an untreated arm revealed that untreated patients had a 5-year survival of 50% and a 10-year survival of 10%, with significant improvement in survival in the immunosuppressive treatment arm [84]. Cirrhosis developed in 17% of cases within 5 years, especially in the case of bridging fibrosis at presentation. The frequency of remission was about 86% and treatment failure reached 14% in patients with both chronic hepatitis and cirrhosis. Similarly, the presence of cirrhosis did not influence the 10-year survival in patients receiving treatment [85]. Elderly patients show a worse histological grade as compared to children [86]. In the latter, long-term follow-up studies have revealed that longterm treatment is required in up to 70% of cases, as most young patients relapse when therapy is discontinued or if the dose of immunosuppressive drugs is reduced [87]. Therefore, indication for treatment is given to any patient who has an established diagnosis of AIH. A liver biopsy is recommended for confirmation of diagnosis and for grading the activity and staging the fibrosis. Only few exceptions should be considered when approaching the onset of therapy. Potential contraindications of steroids or immunosuppressive drugs should be initially evaluated. In patients with decompensated liver disease on the waiting list for liver transplantation and in patients with cirrhosis and the absence of inflammatory activity, treatment does not appear beneficial, but a close surveillance is mandatory in order to quickly catch the signs of reactivations or flares of the inflammatory disease [14]. Patients bearing a mild disease should equally be treated; expectant management has been proposed; but, even in this setting, the natural history of the liver disease progresses toward end-stage liver disease. Therefore, a tailored therapy is recommended in this case in order to achieve the goal of the treatment. Standard treatment is based on corticosteroids, alone or in combination with azathioprine. Randomized trials conducted through the 1960s and 1970s demonstrated a universal response to corticosteroid therapy, leading to a consistent improvement in survival rates. Accordingly, response to steroid treatment was introduced as a diagnostic criterion. Corticosteroids still remain the treatment of choice for remission induction. An initial dose of 0.5 mg/kg body weight is sufficient in the majority of patients. If bilirubin levels are under 6 mg/dL, azathioprine should be added within 2 weeks of starting therapy, as it is the cornerstone of the maintenance of remission. Diverse trials have shown that addition of azathioprine spares steroids and has better success rates of remission than steroid monotherapy. Azathioprine may be used as a single therapy, starting from lower doses (1 mg/kg body weight) up to the highest dosage (2 mg/kg body weight) or in association with low-dose prednisone (10–2.5 mg/day) without any further increase in azathioprine from the lowest dosage [14]. The decision between monotherapy or combined therapy is driven by side effects and therefore needs to be tailored for each individual, aiming to find the appropriate maintenance dose. Long-term use of steroids is associated with side effects (so-called iatrogenic Cushing’s syndrome), including weight gain, diabetes, osteopenia, aseptic bone necrosis, hypertension, cataract formation, and psychiatric symptoms. These adverse events are found in 44% of patients after 12  months and in 80% of patients after 24  months of treatment. In addition, azathioprine may cause nausea, cholestatic hepatitis, pancreatitis, skin rash, and leukopenia. Bone marrow toxicity is the main reason for the stepwise increase of dosage in association

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with regular blood count. Many side effects are not predictable, as they are based on the high interindividual variability of azathioprine pharmacokinetics. Genetic testing for mutations of thiopurine S-methyltransferase (TPMT) or measuring blood levels of biologically active metabolites 6-mercaptopurine or 6-thioguanine may be useful in predicting the occurrence of side effects [88]. Alternatively, maintenance of remission with a single dosage of prednisolone or prednisone, as well as with 6-mercaptopurine, might be preferred, with half dosages of azathioprine, which may be better tolerated and equally effective. Remission can be achieved in up to 75% of cases after 2 years of therapy [89]. Biochemical remission is defined by normalization of transaminase and IgG serum levels: it has been recognized as a valuable surrogate endpoint. Indeed, the normalization of both transaminase and IgG levels is correlated with improved long-term outcomes and histological regression of fibrosis; however, it is still debated whether biochemical remission is equally or more reliable than histological remission [90]. The latter is instead defined as a hepatitis activity index (HAI) score less than 3 of 18, which is considered a nonprogressive liver disease [91]. The current European guidelines claim against the obligation of performing a liver biopsy before treatment withdrawal, due to both possible sampling errors and optimal predictive values of the serum surrogate markers of remission. Therefore, a liver biopsy during treatment needs to be considered in those cases where an initial diagnosis is questioned. In patients with borderline remission or with discrepancies between transaminase and IgG normalization, a liver biopsy can support the evidence of the remaining disease activity and also bring to light drug-related hepatotoxicity related to azathioprine or the presence of concomitant liver disease, like NAFLD, which can be responsible for the perpetuation of inflammation despite correct drug treatment. In fact, it has to be highlighted that side effects of initial steroid therapy also involve the development of NAFLD; therefore, that should be considered in insufficient responders, especially in the case of a compatible biochemistry (normal values of cholestatic enzymes, altered ALT values superior to AST values) [92]. In all other cases, liver biopsy is not required, including the clear serological evidence of insufficient response to treatment. Histological remission usually occurs later than serological remission. Therefore, a liver biopsy should be performed and it might be delayed up to 1 year after beginning the treatment. Those patients with a more aggressive disease at baseline may even require longer time to achieve remission. Therefore, withdrawal of therapy can only be attempted after 2 years of stable remission on low-dose therapy [93]. Relapse of AIH is almost universal when immunosuppression is erroneously tapered or interrupted in the presence of residual inflammatory activity. It may happen in 50% of patients within 6 months of withdrawal and in 80% after 3 years. Relapse requires the repetition of the initial drug scheme and perhaps the long-term perpetuation of therapy. On the contrary, in patients achieving full remission, liver fibrosis has shown to regress from initial values. In about 10% of patients, immunosuppressive treatments fail to suppress immune-­ mediated liver damage. It requires at least 6 months to be established and happens in about 10% of patients. These individuals are at risk of developing end-stage liver disease and thus further strategies need to be considered. Despite current evidence still being limited, budesonide has shown to be an effective alternative treatment in the corticosteroid field. Budesonide is a synthetic steroid with high hepatic first-pass metabolism that would limit its systemic effects. It has liver extraction of 90%

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and high affinity to the glucocorticoid receptor, and thus its overall bioavailability is much lesser than that of prednisone. The main aim of budesonide in future therapy is to replace prednisone in long-term maintenance therapy and induction therapy to reduce steroid-­ related side effects [94]. However, clinical trials do not universally agree with budesonide’s efficacy [95]. In addition, the biochemical response is much slower with standard therapy with budesonide (9 mg/day), and there is no improvement in those systemic manifestations of immune-related disorders (e.g., arthralgia) that would, instead, benefit from considerable steroid bioavailability. Moreover, it cannot be safely used in cirrhotic patients due to the global functional deficiency of the liver that, unable to correctly metabolize budesonide, in addition to portosystemic shunts, would cause a much higher systemic availability, leading to the same side effects of standard corticosteroids. With these limitations, budesonide is currently licensed for use in AIH in many countries as a first-line treatment strategy in noncirrhotic patients [14]. At present, other drug treatments do not show robust evidence. Probably, the best ­second-line therapy for patients intolerant to azathioprine is mycophenolate mofetil (MMF) [96]. MMF is a noncompetitive inhibitor of inosine monophosphate dehydrogenase, blocking purine synthesis. It exerts a selective action on lymphocyte activation, leading to a marked reduction in both T- and B-cell populations. Data from different studies do not agree with its efficacy. MMF is able to maintain remission in up to 80% of azathioprine-intolerant patients, alone or together with low doses of prednisolone, but it is almost ineffective in patients who do not respond to azathioprine [97]. Other immunosuppressive agents, like cyclosporine A, are burdened by relevant drug toxicity, whereas others, like tacrolimus, have not yet been validated in large randomized trials [98]. Novel biological drugs have been able to act in a more tailored therapy, with concomitant understanding of pathogenetic pathways of the disease. Infliximab (anti-TNF-α) has shown the capability to induce remission in AIH patients for whom no other treatment is effective. However, AIH is one potential side effect of infliximab; thus, its role in difficult-to-treat patients with AIH needs to be further investigated [99]. Rituximab (anti-CD20) is another target therapy that may potentially supplement or replace standard immunosuppression, acting solely on differentiation and proliferation of B cells [100]. These more precise and elegant molecular advantages will change our way of perceiving immune-mediated disorders across all stages of the disease, from the little, still partially obscure molecular derangements to the systemic nature of immune-mediated disorders, which would no longer be addressed as a single-organ disease. Recombinant molecules that impair lymphocyte activation (CTLA4 fused with immunoglobulin) [101] or monoclonal antibodies against B-cell activating factor (BAF) [102] are other examples. The latter, in particular, would also be useful as a noninvasive marker of disease activity. BAF levels fluctuate during disease activity and improve under steroid treatment [103]. Agents acting on oxidative stress, such as agonists of nuclear factor erythroid 2-related factor 2 of antagonist of TGF-β, have shown to improve liver inflammation and hepatic fibrosis in mouse models [104,105]. Given the main role of Tregs in the pathophysiology of AIH, the adoptive transfer of Tregs has been studied in experimental models of AIH [106]. The procedure was able to target the liver, restore peripheral tolerance, and induce remission of AIH. Therefore, it might be useful in maintaining a protracted immunosuppression in patients with relapsing AIH.

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6  Conclusion Given the major role of fibrosis in the prediction of long-term prognosis, many efforts are currently being taken in order to avoid liver biopsy and to develop novel noninvasive biomarkers, in both cross-sectional and longitudinal evaluations. Currently, liver elastography shows the best accuracy and the best negative predictive value in determining liver fibrosis as compared to liver biopsy. Magnetic resonance-based elastography is currently being assessed in larger cohorts of NAFLD patients in order to assess its accuracy in determining liver fibrosis and to understand whether serial assessments can reliably demonstrate progression or regression of fibrosis during follow-up and under experimental treatments [107]. This new technique might also be part of the follow-up process in patients with AIH. Worsening of stiffness values during follow-up is highly predictive of reactivation of the disease or fibrosis progression. Similar to IgG levels, hyperferritinemia has been correlated with liver fibrosis and predicts response treatment [108]. Vitamin D deficiency has been found in some cohorts of AIH patients [109]; given its role in regulating the expression of immune regulatory genes by binding the nuclear vitamin D receptor, it can play a good supporting role in the treatment strategy. Soluble CD163, a macrophage-derived serum marker, is directly related to liver fibrosis and might be a biomarker of treatment response [110]. In the therapeutic field, novel experimental molecules are currently being tested in large cohorts of patients with biopsy-proved nonalcoholic steatohepatitis (NASH). Agents such as cenicriviroc (an antagonist of chemokine receptor 2) or obeticholic acid (an agonist of nuclear receptor FXR) have shown to decrease liver inflammation and improve fibrosis, and, in the near future, they might also be tested in other liver diseases with underlying significant fibrosis [111,112]. Due to the increasing evidence of the role of the microbiota in determining both systemic and hepatic derangements, targeted probiotics or antibiotics, as well as biological agents, acting on T-like receptors to strengthen the intestinal barrier, might be a valuable therapeutic tool [113]. In conclusion, AIH is the perfect paradigm of a liver disease, the knowledge of which represents an evolving landscape. The recognition of the complexity hidden among various cytokine patterns and among different immune cell populations has paved the way for novel diagnostic and therapeutic tools. Studies conducted on animal models have shown the primary involvement of central and peripheral tolerance in the very first spark of AIH. The emerging role of intestinal microbiota will certainly play a crucial part in both pathogenic and therapeutic fields. Genetic and epigenetic changes have highlighted the tight relationship between genes and the environment in determining the onset and severity of immune-mediated damage. Hepatic fibrosis has been recognized as a crucial prognostic factor in liver disease. Noninvasive biomarkers will be an accurate, alternative method to stage fibrosis and predict liver-related events. New treatments targeting molecules that are directly involved in the process of fibrogenesis will be a valuable strategy to alter the natural history of liver disease.

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C H A P T E R

16 Advances in autoimmune cutaneous diseases Silvia Angélica Carmona-Cruz and María Teresa García-Romero⁎ Department of Dermatology, National Institute of Pediatrics, Mexico City, Mexico ⁎

Corresponding author: [email protected]

Abstract Autoimmune diseases reflect a continuum of a proinflammatory state and depend on the target tissues affected; isolated clinical manifestations or systemic involvement may also occur. Recognition of subtle cutaneous changes in the early stages of the disease, such as erythema/edema of the morphea plaques, photosensitivity in some types of cutaneous lupus erythematosus, or the heliotrope erythema of dermatomyositis, can guide the proper diagnosis and promote early initiation of treatment to avoid both functional and aesthetic sequelae as well as close follow-up during the course of the disease. Recent knowledge of new physiopathological mediators in these diseases, such as autoantibodies expressed in different phenotypes of dermatomyositis, has helped understand the variability of clinical course and response to treatment by affected individuals. It has also facilitated the study and potential development of new biomarkers of disease activity to develop new targeted therapies.

Keywords Scleroderma, Dermatomyositis, Systemic lupus erythematosus, Cutaneous, Autoantibodies

1  Introduction Autoimmune diseases that involve the skin are usually diagnosed by cutaneous findings, which are also the initial manifestation in many cases. Early recognition of the characteristic presentation of each disease is the key to early diagnosis. In this chapter, we review the most relevant and novel considerations related to the clinical, diagnostic, and therapeutic aspects of morphea, dermatomyositis, and lupus erythematosus.

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16.  Advances in autoimmune cutaneous diseases

2  Morphea or localized scleroderma 2.1  Introduction Morphea, or localized scleroderma (LS), is an autoimmune disease characterized by inflammation and chronic sclerosis, which can lead to atrophy at the level of the epidermis, dermis, and/or subcutaneous cellular tissue (SCT) [1–3]. Although it shares pathophysiological factors with systemic sclerosis, it is considered a separate entity and does not evolve into the latter. However, morphea can be accompanied by extracutaneous alterations in 20%–70% patients [2,4].

2.2  Epidemiology The estimated incidence of morphea is 0.4–2.7 cases per 100,000 people and its prevalence is reported to be 2 cases per 100,000 people, with a predominance of female patients with a ratio of 2.4:1 [5,6]. In the pediatric population, the age of onset ranges from 5 to 9 years [5]. Congenital morphea is extremely rare, with approximately 25 cases reported in the literature [6].

2.3  Pathophysiology There are multiple factors involved in the pathophysiology of the disease, which include both environmental and genetic factors that cause alterations in the immune response pathways [7,8]. Among the environmental factors, it has been described that morphea lesions can appear in skin areas that were previously exposed to radiation, surgery, insect bites, injection sites, or infections such as herpes zoster [4,8,9]. The association with Borrelia burgdorferi remains controversial. Some studies have reported positive serology for B. burgdorferi in up to 33% of patients with morphea; however, other studies have failed to identify it [10]. There is a genetic susceptibility, such as that granted by human leukocyte antigen (HLA) class I and II (HLA-B*37 and HLA-DRB1*04:04), since their presence has been associated with generalized and linear morphea subtypes [4]. Furthermore, HLA-DRB1*04: 04 has also been associated with the risk of rheumatoid arthritis in patients with morphea [11]. At the immunological level, there is an imbalance between Th1, Th2, and Th17 cell subtypes, which leads to obvious inflammation in the early stages of the disease (predominantly Th1 and Th17) and fibrosis in the later stages (predominantly Th2) [5]. In the initial inflammatory stage, environmental stimuli activate mononuclear cells, causing perivascular invasion to the skin and activation of the immune response with the consequent secretion of proinflammatory cytokines and cell mediators such as interferon (INF)-γ, interleukin (IL)-1, and tumor necrosis factors (TNFs). The elevation of these mediators causes structural and functional changes in the microvasculature at the systemic level and expression of adhesion molecules such as intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM). Subsequently, there is an overproduction of cytokines (IL-4, IL-6, and IL-8) by lymphocytes [5].

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Finally, excessive cell proliferation and deposit of collagen and other components of the extracellular matrix cause hardening and fibrosis of the skin. These changes are considered to be orchestrated by excessive IL-4 and transforming growth factor (TGF)-β production [1,4]. Dendritic cells (DCs) play an important role in pathophysiology. The specific ligand that activates them is not yet known; however, after activation, they produce INF-α and INF-β, which in turn activate myeloid DCs (mDCs). These mDCs activate autoreactive B and T lymphocytes through molecules of the major histocompatibility complex (MHC), leading to skin autoimmunity [4]. The early presence of proinflammatory cytokines such as IL-2 and IL-6 induces a Th17 response. Subsequent inflammation, as well as transition to fibrotic damage, is caused through this route [4]. Epigenetic mechanisms related to the pathophysiology of morphea include micro-­ ribonucleic acid (RNA)s, together with deregulated histone acetylation and deoxyribonucleic acid (DNA) methylation. MicroRNAs are regulators of cell differentiation and proliferation, apoptosis, and immune responses. In relation to fibrosis, it is known that these microRNAs can induce the signaling pathways of TGF-β, proliferation and differentiation of fibroblasts, and deposition of extracellular matrix proteins. In a recent review, Wolska-Gawron et  al., have found that the expression of miRNA-7, 196a, 155, let7a, and 483-5p was associated with the severity of sclerotic lesions; however, more studies are needed to confirm these results and introduce these markers to be considered as biomarkers of the disease [11].

2.4  Clinical manifestations Classic findings include one or more plaques of the hardened skin, with a shiny surface, variable degrees of atrophy, hyperpigmentation, or hypopigmentation. Both size and number vary, and lesions may or may not have a blaschkoid distribution [5]. These plaques can affect any anatomical site. Initially, during the inflammatory phase, lesions are erythematous edematous to violaceous poorly defined plaques, which spread centrifugally (Fig. 1).

FIG. 1  Erythematous-edematous plaque, slightly violaceous, ill-defined, and with centrifugal expansion on the thigh of a girl.

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They are asymptomatic; so, they can go unnoticed. These plaques can appear spontaneously or insidiously for months [2]. Subsequently, during the fibrotic phase, the skin becomes sclerotic and indurated, with a waxy or yellowish-white central appearance; shiny white superficial textural changes and different degrees of dyspigmentation can also be observed [1,7]. At the end of the active stage, atrophy can manifest itself at the level of the epidermis, dermis, SCT, and even muscles. Dermal atrophy is evidenced as shiny-looking skin, visible vessels, and cliff-drop deformity. A “cobblestone” appearance is seen in SCT atrophy. If the atrophy extends beyond the SCT, it causes asymmetry. In lesions with residual damage, pigmentary changes, loss of annexes, itching, and dry skin may develop [1,2]. Deep morphea lesions are not always accompanied by changes in the surface and are usually more easily recognized through palpation than observation [2]. 2.4.1  Extracutaneous manifestations In addition to the skin changes, ophthalmological and/or neurological manifestations have been reported (seizures, headache, cranial nerve palsy, hemiparesis, uveitis, optic neuritis, scleritis, dry eyes) [4]. Musculoskeletal manifestations include joint stiffness, synovitis, myalgia, arthritis, and muscle contractures. In general, joint affection is observed on the sites affected by morphea; however, cases with distant affection have also been described [2,4]. The presence of joint abnormalities without obvious inflammation has been described as a presenting sign of morphea and is known as dry synovitis. It presents with a diffuse decrease in the range of motion of the joints, without elevation of the acute-phase reactants. One must have a high index of suspicion, and magnetic resonance imaging (MRI) supports the diagnosis [12]. In addition, oral morphea can manifest as gingivitis or malocclusion [2,4]. 2.4.2  Clinical subtypes of morphea On the basis of distribution patterns and depth of the lesions, morphea has been divided into five subtypes: circumscribed (plaque morphea), generalized morphea (multiple plaque lesions), linear morphea (of the trunk/extremities, of the head that is also termed ParryRomberg syndrome), pansclerotic morphea, and mixed morphea (a combination of two or more of these subtypes) [5,7,8,13]. Plaque morphea is the most common presentation in adults, and the condition is usually limited to the dermis. Sclerotic plaques are well circumscribed, can be single or multiple, and vary from 1 to 30 cm in diameter (Fig. 2) [5,7,8,13]. Linear morphea occurs in pediatric patients in 40%–70% cases and is the most frequent form in this age group. It has a predilection for the extremities, frontal region of the face, and the thorax (Fig. 3). Up to 50% of patients concomitantly present plaque morphea, thus having the mixed variant. This form of presentation is extremely rare in adult patients [5,7,8,13]. It is important to question and explore other systems, since up to 50% of patients with linear morphea may have neurological and/or ophthalmological alterations (almost exclusively when located in the head) [4,7] or musculoskeletal manifestations when it affects the extremities [1]. Generalized morphea is defined by the presence of four or more plaques larger than 3 cm that converge and involve more than two anatomical sites. This form corresponds to 7­ %–9% of morphea types and has rapid progression and extension. It occurs more frequently in women, and extracutaneous involvement is rare [1,14].

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FIG. 2  Well-defined sclerotic plaque with a shiny, waxy-like surface in the clavicular region of a girl.

FIG. 3  (A) and (B) Linear morphea: sclerotic plaque affecting the back and sole of the foot with a linear distribution.

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FIG. 4  Sclerotic plaque with deep involvement. The significant asymmetry of both the legs secondary to muscular atrophy must be noted.

Pansclerotic morphea is the most aggressive form and predominantly affects children, which is why it is also known as disabling morphea of childhood. This condition has ­extremely deep affection, involving muscles, tendons, and bones (Fig.  4). Contractures, calcification, and ulceration may occur, leading to significant functional disability. On some occasions, it can be associated with neoplasia, cardiomyopathy, and restrictive lung disease [15]. Other less common variants are [1,6,14]: • Morphea guttate: small, whitish sclerotic plaques, slightly indurated, with follicular openings. • Nodular or keloid morphea: nodular lesions reminiscent of keloid scars. • Atrophoderma: multiple discreetly depressed hyperpigmented plaques on the trunk and upper extremities, without evidence of sclerosis. • Parry-Romberg syndrome or progressive hemifacial atrophy: atrophy that extends from the dermis to the bone, with hemifacial involvement or trigeminal distribution. Up to 30% of patients have neurological involvement. • Eosinophilic fasciitis or Shulman syndrome: symmetrical, painful, indurated plaques, exclusively on the extremities. Peripheral eosinophilia and increased erythrocyte sedimentation rate (ESR). • Lichen sclerosus and atrophicus: atrophic plaques that can affect any part of the body but show predilection for the anogenital area. It is frequently found accompanying lesions of plaque or generalized morphea. • Congenital morphea: it manifests itself mainly as linear lesions, which can follow Blaschko’s lines, which is why it has been suggested that its origin is explained by genetic mosaicism. It is usually associated with extracutaneous manifestations in about half of the cases, secondary to a delay in diagnosis.

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2.4.3  Comorbidities and malignancy The association of morphea with other autoimmune diseases has been described, including vitiligo, Hashimoto’s thyroiditis, alopecia areata, type 1 diabetes, and genital lichen sclerosus [3,8]. Some studies have documented an increased risk of developing cutaneous squamous cell carcinoma (cSCC) [16]. Recently, Heck et al. have studied 16 patients with morphea (pansclerotic, linear, and generalized) who developed cSCC, which appeared in the lower extremities (81.3%). The mean duration time between the onset of morphea and the development of cSCC was 21.0 ± 3.7 years. It is suggested that immunosuppressive treatment and tendency to develop fibrosis, erosions, and ulcers in the affected skin predispose individuals to develop cSCC [14].

2.5  Diagnosis The diagnosis is clinical. The entire body of the patient should always be examined for active plaques that may go unnoticed [8]. Photographs provided by the patient/parents are extremely helpful to evaluate progression of the lesions. 2.5.1  Dermoscopy The usefulness of dermoscopy lies mainly in the differentiation of erythema (a marker of activity) from telangiectasia (indicators of damage) in atrophic lesions [2,7]. 2.5.2  Laboratory studies There are no specific studies for the diagnosis. Routine examinations are usually normal, except for slight eosinophilia in the blood count, mainly in the initial stages or in patients with concomitant eosinophilic fasciitis [1,2]. In the inflammatory phase of deep variants, there may be leukocytosis in 37.5%, an increase in ESR in 25%, and an increase in C-reactive protein (CRP) in 35.7% patients, which usually normalize during follow-up [17]. When there are muscle symptoms and myositis is suspected, taking muscle enzymes (creatinine kinase, aldolase, lactate dehydrogenase) and acute-phase reactants are recommended [2,8]. Up to 10% of pediatric patients may have elevated muscle enzymes, which should alert the physician to the risk of growth arrest of the affected limb [7]. Although the presence of autoantibodies is also not specific, up to 30% of patients with linear or generalized morphea may have anti-double-stranded DNA (anti-dsDNA) or antihistone antibodies (AHAs) [1]. Previously, it was believed that the presence of these antibodies did not relate to a worse clinical course; but, in recent studies, it has been observed that some of them are associated with greater extension, depth, and/or extracutaneous involvement. For example, AHA titers have been positively correlated with the number of injuries, their greater extension, and muscle involvement. They are more frequently found in the linear subtype compared to the generalized one [4]. The presence of anti-single-stranded DNA (anti-ssDNA) antibodies has been associated with the presence of joint contractures or a duration of the disease for more than 2 years [4]. In addition, 18%–68% have positive antinuclear antibodies (ANAs) with a speckled pattern. Their presence is related to the severity of the disease in relation to depth (pansclerotic variant), association with extracutaneous manifestations, mainly musculoskeletal, and likelihood of relapses after remission [1,4].

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Rheumatoid factor (RF) can be positive in 3%–16% of patients and has been associated with high rates of arthritis [7,17,18]. The presence of RNA polymerase, topoisomerase, and centromere antibodies (which are associated with systemic sclerosis) should raise suspicion of the latter and an appropriate approach should be initiated [2]. 2.5.3  Histopathology At the histopathological level, the findings correspond to the stage and the depth of the disease. In early forms, we can find perivascular and periadnexial lymphocytic inflammatory infiltrates. On occasion, eosinophils, plasma cells, and mast cells can be visualized; there is endothelial edema, vessels with thickened walls and diminished vascular lumen, and adnexal atrophy [2]. In more chronic lesions, there is a decrease in the inflammatory infiltrate and it may even disappear, the dermoepidermal junction flattens, collagen bundles become aligned in parallel thus exhibiting a packed appearance, and there is loss of adnexal structures (Fig. 5) [1]. In the case of deep morphea, the SCT is mainly affected, but inflammation and damage can extend to the muscular fascia. Furthermore, there is marked sclerosis with hyalinization [8]. 2.5.4  Imaging studies Magnetic resonance imaging (MRI) allows evaluation of the depth of the lesions, as well as differentiating between inflammatory lesions, sclerosis, or atrophy, which is why it has become an extremely useful tool in the evaluation of patients with morphea, particularly in patients with deep involvement (subcutis, fascia, and muscle) [8]. This study showed fascial thickening and enhancement and proposed that up to 38% of patients might have musculoskeletal involvement, which is not clinically apparent [2]. Synovial enhancement without joint effusion and bone edema is evidenced in dry synovitis [12]. Patients with linear morphea or morphea plaques on the head, who report neurological symptoms such as headache or seizures, should be evaluated with brain MRI [2]. Recently, ultrasonography has gained strength as a tool to identify the thickness and activity of m ­ orphea

FIG. 5  Late-stage morphea: atrophy of the epidermis with closely packed collagen bundles and a mild inflammatory infiltrate.

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lesions. It has the advantage of being cheaper and easier to perform, particularly in pediatric patients. Sclerotic lesions show hyperechogenicity, whereas inflammatory lesions are isoechogenic [19]. 2.5.5  Activity markers Currently, there are no standardized clinical data to help determine the activity of the disease. Some clinical characteristics have been proposed that can be helpful to evaluate the severity of the disease with the aim of facilitating management decisions [2]. These features are: 1. The presence of new lesions or expansion of preexisting lesions in the last 3 months. 2. Moderate-to-severe erythema or edema of lesions. 3. Erythematous violaceous borders in lesions. 4. Progressive increase in duration or sclerosis in the lesion. 5. Hair loss associated with lesions. 6. Documentation of disease activity or progression to deep tissues, through activity scales, photographs, MRI, or ultrasound. 7. Skin biopsy showing disease activity. There are some scales that assess disease activity and damage, named as the Localized Scleroderma Severity Index (LoSSI) and the Localized Scleroderma Damage Index (LoSDI), respectively. Both scales make up the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT). The LoSCAT is validated for both pediatric and adult patients [2,17]. The DIET scale (depigmentation, induration, erythema, and telangiectasia) was proposed; however, it has not been validated so far [20]. Sometimes it may not be feasible to use the aforementioned scales in clinical practice, while follow-up with photographs of the lesions during each visit is extremely helpful for identifying their improvement or worsening [2]. Currently, there are studies designed with the aim of identifying biomarkers that provide information about the severity and activity of the disease. During the inflammatory phase of morphea, there is an increase in the expression of adhesion molecules, among which E-selectin stands out. After increased production of other cytokines such as IL-1, TNF-α, or INF-γ, this molecule is strongly expressed on the surface of endothelial cells. It subsequently stimulates T-cell receptors to produce other proinflammatory cytokines. Expression of IL-2 and its binding to the sIL-2R (soluble high-affinity IL-2 receptor), which is located only in activated lymphocytes, has immunomodulatory effects. Wodok-Wieczorek et al. compared a group of 42 patients with morphea (generalized, plaque, or linear) with healthy controls and found that the group with morphea had higher levels of E-selectin and sIL-2R than did controls (P