Mosaic of Autoimmunity: The Novel Factors of Autoimmune Diseases

By Yehuda Shoenfeld

The Mosaic of Autoimmunity: The Novel Factors of Autoimmune Diseases describes the multifactorial origin and diversity of expression of autoimmune diseases in humans. The term implies that different combinations of factors in autoimmunity produce varying and unique clinical pictures in a wide spectrum of autoimmune diseases. Most of the factors involved in autoimmunity can be categorized into four groups: genetic, immune defects, hormonal and environmental factors. In this book, the environmental factors are reviewed, including infectious agents, vaccines as triggers of autoimmunity, smoking and its relationship with rheumatoid arthritis, systemic lupus erythematosus, thyroid disease, multiple sclerosis and inflammatory bowel diseases.

An entirely new syndrome, the autoimmune/inflammatory syndrome induced by adjuvants (ASIA), is also included, along with other diseases that are now recognized as having an autoimmune etiopathogenesis.

• Highlights the concept of the mosaic of autoimmune manifestations
• Includes new visions on unsuspected molecules
• Provides updated knowledge to physicians helping patients with autoimmune diseases
• Presents thorough, up-to-date information on specific diseases, along with clinical applications

• Language: English
• Publisher: Academic Press
• Release date: Feb 8, 2019
• ISBN: 9780128143087

Book preview

Mosaic of Autoimmunity

The Novel Factors of Autoimmune Diseases

Editors

Carlo Perricone

Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy

Yehuda Shoenfeld

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Laboratory of the Mosaics of Autoimmunity, Saint-Petersburg University, Saint-Petersburg, Russian Federation

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Section I. Introduction

Introduction

Funding

Chapter 1. The Mosaic of Autoimmunity in History

Introduction

Pre-Mosaic Immunology, 1950–80

The Decade of the Mosaics, 1980–90

Post-Mosaic Immunology 1990–2018

Chapter 2. The Novel Aspects on the Mosaic of Autoimmunity

Section II. Cellular and Molecular Mechanisms

Chapter 3. B Cells: A Main Player in the Development of Autoimmunity

B Cells Are Antigen-Presenting Cells

Activated B Cells in Autoimmunity

Proinflammatory B Cells and Autoimmunity

In Summary

Chapter 4. B Regulatory Cells in Autoimmunity

Introduction

IL-10–Producing B Regulatory Cells

CD5highIL-10high B Regulatory Cells

Other Regulatory Molecules/Cytokines

Conclusion

Chapter 5. T Cells in Autoimmune Diseases

Introduction

Genetic Predisposition and T Cell Genetic Variants in Autoimmune Diseases

T Cells in the Pathogenesis of Autoimmune Diseases

Molecular Pathways in Pathogenic Autoreactive T Cells

Epigenetics and Autoimmunity

Concluding Remarks

Chapter 6. Th17 Cells

Historical Aspects

Th17 Cell Development and Plasticity

Th17 Cells and Health

Th17 Cells and Systemic Autoimmune Diseases

Concluding Remarks

Chapter 7. Natural Killer Cells in Autoimmunity

Natural Killer Cells

Natural Killer Cells and Autoimmunity

Natural Killer in Autoimmune Diseases

Natural Killer Cells, the Paradigm of Pregnancy and Autoimmunity

Chapter 8. Dendritic Cells: The Orchestrators of the Inflammatory Response in Autoimmune Diseases

Introduction

Evidence of the Participation of DCs in the Pathophysiology of Various Autoimmune Diseases

Tolerogenic Dendritic Cells

Conclusions

Chapter 9. The Complement System

Introduction

Pathways of Complement System Activation

Regulation of the Complement System

Complement System as Mediator of Tissue Damage

Complement System and Autoimmunity

Complement System and Autoimmune Diseases

Complement-Targeted Therapy

Chapter 10. Autoantibodies in Disease Criteria for Systemic Autoimmune Diseases: Developments in the Last Decade

Introduction

Rheumatoid Arthritis

Systemic Lupus Erythematosus

Sjögren’s Syndrome

Systemic Sclerosis

Mixed Connective Tissue Disease

Autoimmune Myositis

Antiphospholipid Syndrome

ANCA-Associated Vasculitis

Conclusion

Chapter 11. Anti-DFS70 Antibodies: A New Protective Autoantibodies?

Chapter 12. Genetics and Autoimmunity: Recent News

Introduction

The Human Leukocyte Antigen System

Human Leukocyte Antigen Genes and Autoimmune Diseases

Genetic Bases of Rheumatoid Arthritis

Genetics of Systemic Lupus Erythematosus

Genetics of Systemic Sclerosis

Genetics of Sjögren’s Syndrome

Genetics of Psoriatic Arthritis

Chapter 13. Epigenetics

DNA Methylation/Demethylation

Histone Modifications

MicroRNAs

Long Noncoding RNAs

Conclusion and Perspectives

Chapter 14. Citrullination and Autoimmunity

Introduction

Citrullination and Inflammation

Citrullination and Cell Death

Conclusion

Chapter 15. Cytokines and Chemokines

Cytokines: An Overview

The JAK-STAT Pathway

Cytokines in Autoimmune Diseases

Cytokine-Modifying Therapies for Autoimmune Diseases

Cytokines as Therapeutic Agents for Autoimmune Diseases

Chemokines: An Overview

Chemokine Receptors and Cell Classification

Chemokines in Rheumatoid Arthritis

Conclusion

Chapter 16. Autophagy and Autoimmunity

Introduction

Autophagy Mechanisms

Autophagy in Innate and Adaptive Immunity

Autophagy in B and T Lymphocytes

Autophagy in Systemic Lupus Erythematosus

Autophagy in Rheumatoid Arthritis

Autophagy in Multiple Sclerosis

Autophagy in Sjögren’s Syndrome

Autophagy in Inflammatory Bowel Disease

Conclusion

Chapter 17. Laboratory Diagnostics

The Diagnostic and Prognostic Value of Autoantibodies

The Predictive Value of Autoantibodies

The Protective Role of Autoantibodies

The Methods to Detect Autoantibodies

Organization of the Autoimmune Laboratory

Chapter 18. Diagnostic: Imaging

Introduction

The Past: Imaging in the Assessment of Inflammatory and Degenerative Arthropathies

The Present: Other Than Arthritis

Conclusions

Section III. The Classical Factors Associated with Autoimmunity

Chapter 19. Hormones and Autoimmunity

Introduction

Sex Hormones

Prolactin and Autoimmunity

Hormonal Contraception and Autoimmunity

Epigenetic Influence on Sex Disparities in Autoimmune Diseases: The Example of SLE and RA

List of Abbreviations

Chapter 20. Human Microbiota and Autoimmune Diseases

Introduction

Microbiota Evaluation Methods

Constitution of the Microbiota

Microbiota and Immune System

Dysbiosis and Autoimmune Diseases

Microbiota Therapeutic Manipulation

Chapter 21. Infections: Viruses and Bacteria

Microbe–Host Interactions: A Chess Game Played by Two

Germ-Free Animals Reveal the Need for Microbiota to Achieve Gut Immune Homeostasis

Host–Microbe Interactions: A War of Worlds or a World War?

Discriminating Between the Good and Bad Microbiome

Autoimmune Rheumatic Diseases as Models to Study Interactions Between Viral Pathogens and Microbiome

List of Abbreviations

Section IV. The Novel Environmental Factors Associated with Autoimmunity

Chapter 22. Geoepidemiology of Autoimmune Diseases

Introduction

Rheumatoid Arthritis

Systemic Lupus Erythematosus

Spondyloarthritis

Conclusions and Future Perspectives

Chapter 23. Seasonality and Autoimmune Diseases

Introduction

Multiple Sclerosis and Seasonality

Systemic Lupus Erythematosus and Seasonality

Type 1 Diabetes and Seasonality

Inflammatory Bowel Disease and Seasonality

Rheumatoid Arthritis and Seasonality

Autoimmune Liver Diseases and Seasonality

Autoimmune Thyroid Diseases and Seasonality

Systemic Sclerosis and Seasonality

Conclusion

Chapter 24. Ultraviolet Radiation: Both Friend and Foe in Systemic Autoimmune Diseases?

Introduction

Effect of Ultraviolet Radiation on Human Skin

The Role of Ultraviolet Radiation in Triggering and Exacerbating Systemic Autoimmune Diseases

Phototherapy for the Treatment of Systemic Autoimmune Diseases

Chapter 25. Vitamin D

The Physiology of Vitamin D

Vitamin D Deficiency

The Emerging Role of Vitamin D in Immunomodulation

Genetic and Epigenetic Effects of Vitamin D

Vitamin D and Autoimmune Diseases

Chapter 26. Vitamin D, Pregnancy, and Autoimmunity: An Ongoing Mystery

Introduction

Vitamin D Metabolism and Biological Functions

Vitamin D Deficiency

Vitamin D and Pregnancy

Vitamin D and Autoimmune Diseases

Current Recommendation for Vitamin D Supplementation

Conclusion

Chapter 27. Smell and Autoimmunity—State of the Art

Introduction

Olfactory System Anatomy

Genetics and Olfaction

Olfaction and Autoimmune Diseases

Conclusion

Highlights

List of Abbreviations

Chapter 28. Breastfeeding and Autoimmunity: A Lesson for Life

Introduction

Human Milk Among the Stages of Lactation

Breast Milk and Immune System Modulation

Breastfeeding and Autoimmune Diseases

Conclusions

List of Abbreviations

Chapter 29. Vaccines, Adjuvants, and the Mosaic of Autoimmunity

Introduction

Autoimmune Diseases Induced by Vaccination: Case Reports and Series

Autoimmune Diseases Induced by Vaccination: Epidemiological Surveys

Animal Models of Autoimmune Diseases Induced by Adjuvants

The Concept of Personalized Vaccinology

Chapter 30. Silicone

Introduction

Silicone Breast Implants

Symptoms and Signs of Silicone-Mediated Disease

Laboratory and Radiological Findings and Other Diagnostic Procedures in Silicone-Induced Disease

ASIA, Autoimmune Diseases, and ALCL

Pathophysiology of Silicone Breast Implants–Related Disease(s)

Disease Management

Conclusion

Chapter 31. Nutritional Aspects of the Mosaic of Rheumatic Autoimmune Diseases a Recipe for Therapy?

Introduction

The Good Kind of Fat (n-3 Fatty Acids)

Rubbing Salt in the Wound

Some Like It Hot—Spicy Food (Capsaicin)

The Ancient Indian Gold—Curcumin

Summary

Chapter 32. Gluten and Autoimmunogenesis

Introduction

Gut Ecoevents That Might Drive Systemic Autoimmunity

Gluten Might Be Beneficial in Nonceliac Autoimmune Diseases

Conclusions

Chapter 33. Psychological Stress and the Kaleidoscope of Autoimmune Diseases

Introduction

Rheumatoid Arthritis and Stress

Stress and Multiple Sclerosis

Stress and Inflammatory Bowel Diseases

Stress and Systemic Lupus Erythematosus

Stress and Autoimmune Thyroid Disease

Stress and Type 1 Diabetes Mellitus

Systemic Sclerosis and Stress

Stress and Pemphigus

Conclusion

Chapter 34. Coffee and Autoimmunity: More Than a Mere Hot Beverage!

Introduction

The Role of Coffee Intake in Immune System Modulation

Coffee and Rheumatoid Arthritis

Coffee and Thyroid Autoimmune Disease

Coffee and Type 1 Diabetes Mellitus

Coffee and Multiple Sclerosis

Coffee and Psoriasis

Coffee and Systemic Lupus Erythematosus

Coffee and Autoimmune Liver Diseases

Coffee and Inflammatory Bowel Diseases

Coffee and Celiac Disease

Conclusions and Final Recommendations

Chapter 35. Obesity in Autoimmune Diseases: Not a Passive Bystander

Introduction

Connecting Obesity and Autoimmunity

Adipokines: Metabolic and Immunological Properties

Obesity and Immune-Mediated Diseases

Conclusion

Take-Home Messages

LIST OF Abbreviations

Chapter 36. Physical Activity and the Mosaic of Autoimmunity. Get Moving to Manage the Disease

Introduction

Physical Activity and Rheumatoid Arthritis

Physical Activity and Multiple Sclerosis

Physical Activity and Systemic Lupus Erythematosus

Physical Activity and Type 1 Diabetes Mellitus

Physical Activity and Inflammatory Bowel Disease

Physical Activity and Fibromyalgia

Physical Activity and Systemic Sclerosis

Physical Activity and Psoriasis

Conclusion

Chapter 37. Smoke and Autoimmunity: The Fire Behind the Disease

Introduction

Smoke and Rheumatoid Arthritis

Smoking and Anticitrullinated Peptide Antibody—The Evil Duo

Smoking and Inflammatory Bowel Disease

Smoking and Crohn’s Disease

Smoking and Ulcerative Colitis

Smoking, Ankylosing Spondylitis, and Spondyloarthritis

Psoriasis and Psoriatic Arthritis

Smoking and Behçet’s Disease

Smoking and Systemic Lupus Erythematosus

Smoking and Multiple Sclerosis

Smoking and Autoimmune Liver Disease

Smoking and Systemic Sclerosis

Smoking and Thyroid Autoimmunity

Smoking and Thyroiditis

Graves’ Disease, Ophthalmopathy, and Smoking

Smoking and Type 1 Diabetes

Smoking and Other Immune-Mediated Diseases

Conclusions

Chapter 38. Cannabinoids in Autoimmune and Rheumatic Diseases

Endocannabinoid System and Phytocannabinoids

Cannabinoids and Immune System

Rheumatoid Arthritis

Psoriasis

Systemic Sclerosis

Fibromyalgia

Osteoarthritis

Systemic Lupus Erythematosus

Multiple Sclerosis

Type 1 Diabetes Mellitus

Inflammatory Bowel Diseases

Conclusions

Chapter 39. The Role of Plastics in the Spectrum of Autoimmune Disease—Bisphenol A

Introduction

Impact of Bisphenol A on the Immune System

Autoimmune Diseases Associated With Bisphenol A Exposure

Conclusion

Chapter 40. Prolactin and the Mosaic of Autoimmunity

Introduction

Prolactin, the Hormone and the Cytokine

Prolactin and the Mosaic of Autoimmunity

Bromocriptine and Autoimmunity

Conclusions

Highlights

List of Abbreviations

Chapter 41. Cancer and Autoimmune Diseases

Introduction

Rheumatoid Arthritis

Psoriatic Arthritis, Ankylosing Spondylitis, and Other Seronegative SponDyloarthropathies

Adult-Onset Still’s Disease

Primary Sjogren Syndrome

Systemic Lupus Erythematosus and Cancer

Cancer and Systemic Sclerosis

Cancer Associated With Polymyositis and Dermatomyositis

Cancer and ANCA-Associated Vasculitis

Cancer and Other Autoimmune Diseases

Autoimmune Disorders in Malignancies

Summary

Chapter 42. Autoimmune Syndromes in Cancer

Musculoskeletal-Associated Paraneoplastic Syndromes

Hematological Paraneoplastic Syndromes

Vasculitis Associated With Malignancy

Neurological Paraneoplastic Syndromes

Autoantibodies in Malignant Diseases

Section V. Classical Autoimmune Diseases

Chapter 43. Current Insights Into Systemic Lupus Erythematosus: From Pathogenesis to Biomarkers and Therapeutical Strategies

Introduction

Conclusions

Chapter 44. Antiphospholipid Syndrome

Introduction

Pathogenesis

Clinical Manifestations

Obstetric Manifestations

Diagnosis and Classification

Laboratory Pitfalls

Treatment

Chapter 45. Catastrophic Antiphospholipid Syndrome

Introduction

Classification and Diagnosis

Clinical and Laboratory Features

Management Approach

Conclusions

Chapter 46. Rheumatoid Arthritis

Introduction

Epidemiology

Pathogenesis

Clinical Manifestations

Articular Manifestations

Extra-Articular Manifestations

Clinical Assessment

Diagnosis

Treatment

Biological Agents

Practice and Procedure

Chapter 47. Psoriatic Arthritis

Introduction

Etiopathogenesis

Clinical Aspects

Laboratory and Instrumental Findings

Extra-Articular Manifestations

Therapy

Conclusions

Key Points

Chapter 48. Neurological Disorders

Part A Myasthenia Gravis

Part B Multiple Sclerosis

Conclusions

Chapter 49. Systemic Sclerosis: An Autoimmune Disease Without a Known Pathology and to Be Conquered

Introduction

Genetics and Epigenetics

Pathogenesis of Systemic Sclerosis

IL-17

B Cells

Conclusions

Chapter 50. Sjogren’s Syndrome

Pathogenesis Overview

An Autoimmune Epithelitis

Autoantibodies and Autoantigens

Ectopic Lymphoid Structures

Germinal Centers

Therapy in Sjögren’s Syndrome: Old and New

Chapter 51. Autoimmune/Inflammatory Syndrome Induced by Adjuvants (Shoenfeld’s Syndrome)

Introduction

Historical Aspects

Epidemiology

Clinical Manifestations of ASIA

Etiopathogenesis of ASIA

Treatment

Perspectives and Conclusions

Chapter 52. Reproductive Failure

Chapter 53. Atherosclerosis in Systemic Autoimmune Rheumatic Diseases

Background

Biomarkers of Accelerated Atherosclerosis in Systemic Autoimmune Rheumatic Diseases

Epidemiology and Spectrum of Cardiovascular Disease in Systemic Autoimmune Rheumatic Diseases

Prevention and Therapy

Chapter 54. A to Z of Some New Autoimmune Diseases: From Alzheimer’s to Zinc Deficiency

Alzheimer’s Disease

Atherosclerosis

Autoimmune Hematological Diseases

Autoimmune Encephalitis and Epilepsy

Bullous Skin Diseases

Neuromyelitis Optica Devic

Otosclerosis

Parkinson’s Disease

Zika

Zinc Deficiency

Section VI. Treatment of Autoimmune Diseases

Chapter 55. Neuroimmunology

Introduction

Central Nervous System

Peripheral Nervous System

The Parasympathetic Nervous System

Vagus Nerve

The Sympathetic Nervous System

Sensory Nervous System

Conclusions

Chapter 56. Large-Vessel Vasculitis

Classification Criteria of Large-Vessel Vasculitis

Portrait of the Pathogenesis of Giant Cell Arteritis

Current Model of Giant Cell Arteritis Immunopathogenesis

Arterial Inflammation and Remodeling

Systemic Deregulation of the Immune System

Epigenetics

miRNA

Functional Analyses

Imaging of Vasculitis

Treatment of Large-Vessel Vasculitis

Chapter 57. Personalized Medicine in Autoimmunity: Rheumatoid Arthritis as a Paradigm

Introduction

Rheumatoid Arthritis as a Good Example for Personalized Medicine

Conclusions

List of Abbreviations

Chapter 58. Biologics and Biosimilars

Introduction

Definition of a Biosimilar

Biosimilars: Clinical and Nonclinical Data

Immunogenicity

Switching From a Bio-Originator to a Biosimilar and Vice Versa

Conclusions

Chapter 59. Small Molecules

Cytokine-Mediated Kinase

Mechanisms of Action of Small Molecules Targeting Janus Kinase

Clinical Efficacy and Safety of Small Molecules Targeting Janus Kinase

Clinical Use of Small Molecules Targeting Janus Kinase

Conclusion

Acknowledgments

Competing Interests

Chapter 60. Helminthes and Autoimmunity, a Love Story

Introduction

Clinical Experimental Therapy in Animal and Human Models With Helminth Derivatives

Tuftsin-Phosphorylcholine, a Novel Treatment for Autoimmune Diseases

Conclusion

Chapter 61. Intravenous Immunoglobulin Treatment in Rheumatic Diseases

Introduction

Mechanisms of Action

Intravenous Immunoglobulin Therapy and Rheumatological Conditions

Tolerability

Subcutaneous Immunoglobulin Therapy

Chapter 62. Autoimmunity and Allergic Diseases

Epidemiological Studies of Allergy and Autoimmunity

Pathophysiology of Allergy and Autoimmunity

Inherited and Acquired Immune Abnormalities With Allergy and Autoimmunity

The Importance of Coexistence of Allergy and Autoimmunity

Chapter 63. Proteomic Molecular Fingerprints Using an Epstein Barr Virus-Derived Microarray as a Diagnostic Method in Autoimmune Disease

Introduction

Methods

Results

Discussion

Chapter 64. Drug-Induced Autoimmunity: Statin-Induced Autoimmune Myositis as an Example

Introduction

Pathophysiology of Statin-Induced Autoimmune Myositis

Clinical Features of Statin-Induced Autoimmune Myositis

Diagnosis of Statin-Induced Autoimmune Myositis

Treatment

Conclusion

Chapter 65. Autoimmunity and Primary Immunodeficiency

Breakdown of T Lineage Central Tolerance

Breakdown of T Lineage Peripheral Tolerance

Breakdown of B Lineage Tolerance

Hyperactivation of Lymphocytes and Failure to Terminate an Immune Response

Increased Activation of Interferon Pathways

Defective Removal of Cell Debris

Conclusions

Acknowledgments

List of Abbreviations

Index

Copyright

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List of Contributors

Arnon Afek

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Antonella Afeltra,     Unit of Allergology, Immunology, Rheumatology, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy

Gabriele Gallo Afflitto,     Unit of Allergology, Immunology, Rheumatology, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy

Cristiano Alessandri,     Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy

Stefano Alivernini,     Institute of Rheumatology, Fondazione Policlinico Universitario A. Gemelli - IRCCS – Catholic University of the Sacred Heart, Rome, Italy

Alessia Alunno,     Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy

Howard Amital

Department of Medicine ‘B’, Sheba Medical Center, Tel-Hashomer, Israel

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Laura Andreoli,     Rheumatology and Clinical Immunology Unit, Spedali Civili, and Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

Alessandro Antonelli,     Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

Mariachiara Arisi,     Dermatology Unit, Spedali Civili, and Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

Carolina Artusi,     Lupus Clinic, Department of Clinical Rheumatology and Medical Sciences, ASST Pini-CTO, Milan, Italy

Fabiola Atzeni,     Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

Eleonora Ballanti,     Rheumatology, Allergy and Clinical Immunology – University of Rome Tor Vergata, Rome, Italy

Cristiana Barbati,     Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy

Giuseppe Barilaro,     Department of Internal Medicine, ASST Rhodense, Milan, Italy

Elena Bartoloni,     Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy

Dana Ben-Ami,     Department of Medicine ‘B’, Sheba Medical Center, Tel-Hashomer, Israel

Andreia Bettencourt

Immunogenetics Laboratory, Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal

Unit for Multidisciplinary Research in Biomedicine (UMIB), Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal

Nicola Bizzaro

Laboratory of Clinical Pathology, Azienda Sanitaria Universitaria Integrata di Udine, San Antonio Hospital, Tolmezzo, Italy

Laboratory of Clinical Pathology, Department of Laboratory Medicine, S. Maria degli Angeli Hospital, Pordenone, Italy

Miri Blank,     Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Dimitrios P. Bogdanos,     Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece

Daniela Boleixa

Department of Neurology, Centro Hospitalar do Porto-Hospital de Santo António (CHP-HSA), Porto, Portugal

Unidade de Imunologia Clínica (UIC), Centro Hospitalar do Porto-Hospital de Santo António (CHP-HSA)

Vânia Vieira Borba

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Department ‘A’ of Internal Medicine, Coimbra University Hospital Centre, Coimbra, Portugal

Faculty of Medicine, University of Coimbra, Coimbra, Portugal

Paola Borgiani,     Department of Biomedicine and Prevention, Section of Genetics, School of Medicine, University of Rome Tor Vergata, Rome, Italy

Nicola Luigi Bragazzi,     Postgraduate School of Public Health, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy

Iwona Brzosko,     Independent Laboratory for Rheumatologic Diagnostics, Pomeranian Medical University in Szczecin, Szczecin, Poland

Marek Brzosko,     Department of Rheumatology, Internal Medicine and Geriatrics, Pomeranian Medical University in Szczecin, Szczecin, Poland

Piergiacomo Calzavara-Pinton,     Dermatology Unit, Spedali Civili, and Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

Irene Campi

Division of Endocrine and Metabolic Diseases, Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy

Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

Luca Cantarini,     Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet’s Disease, Rheumatology Unit, University of Siena, Policlinico Le Scotte, Siena, Italy

Rosa A. Carranza-Muleiro

Research Division, Hospital de Especialidades Centro Médico Nacional La Raza, IMSS, Mexico City, Mexico

Instituto Politécnico Nacional, Mexico City, Mexico

Cláudia Carvalho

Immunogenetics Laboratory, Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal

Unit for Multidisciplinary Research in Biomedicine (UMIB), Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal

Francesco Caso,     Rheumatology Unit, Department of Clinical Medicine and Surgery, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy

Fulvia Ceccarelli,     Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy

Ricard Cervera,     Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Spain

Joab Chapman

The Department of Neurology, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel

The Zabludovich Autoimmune Center, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel

Robert and Martha Harden Chair in Mental and Neurological Disease, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Xian Chen,     Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, People’s Republic of China

Maria Sole Chimenti,     Rheumatology, Allergy and Clinical Immunology – University of Rome Tor Vergata, Rome, Italy

Cinzia Ciccacci,     Department of Biomedicine and Prevention, Section of Genetics, School of Medicine, University of Rome Tor Vergata, Rome, Italy

Enrica Cipriano,     Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy

Jan Willem Cohen Tervaert

Division of Rheumatology, University of Alberta, Edmonton, Canada

Maastricht University, Maastricht, The Netherlands

Tania Colasanti,     Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy

Paola Conigliaro,     Rheumatology, Allergy and Clinical Immunology – University of Rome Tor Vergata, Rome, Italy

Fabrizio Conti,     Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy

Louis Coplan,     Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Luisa Costa,     Rheumatology Unit, Department of Clinical Medicine and Surgery, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy

Stefania Croci,     Unit of Clinical Immunology, Allergy and Advanced Biotechnologies, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

María del Pilar Cruz-Domínguez

Research Division, Hospital de Especialidades Centro Médico Nacional La Raza, IMSS, Mexico City, Mexico

Universidad Nacional Autónoma de México, Mexico City, Mexico

Maurizio Cutolo,     Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Polyclinic San Martino Hospital, Genoa, Italy

Shani Dahan

Department of medicine B, Assuta Ashdod Medical Center, Ashdod, Israel

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Jan Damoiseaux,     Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands

Caterina De Carolis,     Rheumatology, Allergy and Clinical Immunology – University of Rome Tor Vergata, Rome, Italy

Antonio Del Puente,     Rheumatology Unit, Department of Clinical Medicine and Surgery, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy

Vinicius Domingues,     Florida State University, College of Medicine Daytona Beach, FL, United States

David H. Dreyfus,     Keren LLC, New Haven CT, United States

Tali Drori

The Department of Neurology, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel

The Zabludovich Autoimmune Center, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel

Michael Ehrenfeld,     Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Gerard Espinosa,     Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Spain

Antonella Farina,     Department of Experimental Medicine, Sapienza University, Rome, Italy

Giuseppina Alessandra Farina,     Rheumatology, Boston University School of Medicine, Arthritis Center, Boston, MA, United States

Gianfranco Ferraccioli,     Institute of Rheumatology, Fondazione Policlinico Universitario A. Gemelli - IRCCS – Catholic University of the Sacred Heart, Rome, Italy

Annacarla Finucci,     Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy

Antonella Fioravanti,     Rheumatology Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy

Katarzyna Fischer,     Independent Laboratory for Rheumatologic Diagnostics, Pomeranian Medical University in Szczecin, Szczecin, Poland

Giulia Lavinia Fonti,     Rheumatology, Allergy and Clinical Immunology – University of Rome Tor Vergata, Rome, Italy

Barone Francesca,     Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, College of Medical & Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital, Birmingham, United Kingdom

Franco Franceschini,     Rheumatology and Clinical Immunology Unit, Spedali Civili, and Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

Jozélio Freire de Carvalho

Institute for Health Sciences, Federal University of Bahia, Salvador, Brazil

Rheumatology Division, Aliança Medical Center, Salvador, Brazil

Keishi Fujio,     Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Grettel García-Collinot

Research Division, Hospital de Especialidades Centro Médico Nacional La Raza, IMSS, Mexico City, Mexico

Instituto Politécnico Nacional, Mexico City, Mexico

Elena Generali,     Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy

Maria Chiara Gerardi,     Department of Internal Medicine and Medical Specialties, Rheumatology, Sapienza University of Rome, Rome, Italy

Roberto Gerli,     Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy

Smadar Gertel,     Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Eitan Giat,     Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Elisabetta Greco,     Rheumatology, Allergy and Clinical Immunology – University of Rome Tor Vergata, Rome, Italy

Elisa Gremese,     Institute of Rheumatology, Fondazione Policlinico Universitario A. Gemelli - IRCCS – Catholic University of the Sacred Heart, Rome, Italy

Eyal Grunebaum

Developmental and Stem Cell Biology Program, Research Institute, Food Allergy and Anaphylaxis Program, Hospital for Sick Children, Toronto, ON, Canada

University of Toronto, Toronto, ON, Canada

Roberta Gualtierotti

Lupus Clinic, Department of Clinical Rheumatology and Medical Sciences, ASST Pini-CTO, Milan, Italy

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

Maria Domenica Guarino,     Rheumatology, Allergy and Clinical Immunology – University of Rome Tor Vergata, Rome, Italy

Hanan Guzner-Gur

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Shu-Gui He,     Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, People’s Republic of China

Cristina Iannuccelli,     Department of Internal Medicine and Medical Specialties, Rheumatology, Sapienza University of Rome, Rome, Italy

Luis J. Jara

Direction of Education and Research, Hospital de Especialidades Centro Médico Nacional La Raza, IMSS, Mexico City, Mexico

Universidad Nacional Autónoma de México, Mexico City, Mexico

Pierre-Yves Jeandel,     Department of Internal Medicine, Archet-1 Hospital, University of Nice-Sophia-Antipolis, Nice, France

Dr Shaye Kivity

Department of Medicine A, Ramat-Gan, Israel

Sackler School of Medicine, Ramat Aviv, Israel

The Zabludowicz Center for Autoimmune Diseases, Ramat-Gan, Israel

Przemyslaw J. Kotyla,     Department of Internal Medicine Rheumatology and Clinical Immunology, Medical University of Silesia Katowice, Poland

Alec Krosser,     Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Andrea Latini,     Department of Biomedicine and Prevention, Section of Genetics, School of Medicine, University of Rome Tor Vergata, Rome, Italy

Matilde Leon-Ponte,     Developmental and Stem Cell Biology Program, Research Institute, Food Allergy and Anaphylaxis Program, Hospital for Sick Children, Toronto, ON, Canada

Aaron Lerner

B. Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

AESKU.KIPP Institute, Wendelsheim, Germany

Roger Abramino Levy

Department of Rheumatology, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil

Global Medical Expert, GSK, Upper Providence, PA, United States

Benjamin Lichtbroun,     Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Ramona Lucchetti,     Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy

Qianjin Lu,     Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, China

Domenico P.E. Margiotta,     Unit of Allergology, Immunology, Rheumatology, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy

António Marinho

Unidade de Imunologia Clínica (UIC), Centro Hospitalar do Porto-Hospital de Santo António (CHP-HSA)

Unit for Multidisciplinary Research in Biomedicine (UMIB), Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal

Michel A. Martínez-Bencomo

Research Division, Hospital de Especialidades Centro Médico Nacional La Raza, IMSS, Mexico City, Mexico

Universidad Nacional Autónoma de México, Mexico City, Mexico

Torsten Matthias,     AESKU.KIPP Institute, Wendelsheim, Germany

Gabriela Medina

Clinical Research Unit, Hospital de Especialidades Centro Médico Nacional La Raza, IMSS, Mexico City, Mexico

Universidad Nacional Autónoma de México, Mexico City, Mexico

Pier Luigi Meroni,     Immunorheumatology Research Laboratory, IRCCS Istituto Auxologico Italiano, Milan, Italy

Michael Lichtbroun

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Gustavo Guimarães Moreira Balbi

Department of Rheumatology, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil

Department of Rheumatology, Hospital Universitário, Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil

Francesco Muratore

Rheumatology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

Università di Modena e Reggio Emilia, Modena, Italy

Luca Navarini,     Unit of Allergology, Immunology, Rheumatology, Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy

Giuseppe Novelli,     Department of Biomedicine and Prevention, Section of Genetics, School of Medicine, University of Rome Tor Vergata, Rome, Italy

Viviana Antonella Pacucci,     Department of Internal Medicine and Medical Specialties, Rheumatology, Sapienza University of Rome, Rome, Italy

Rosario Peluso,     Rheumatology Unit, Department of Clinical Medicine and Surgery, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy

Monica Pendolino,     Department of Internal Medicine and Medical Specialties, Rheumatology, Sapienza University of Rome, Rome, Italy

Dolores Pérez,     Zabludowitz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Carlo Perricone,     Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy

Roberto Perricone,     Rheumatology, Allergy and Clinical Immunology – University of Rome Tor Vergata, Rome, Italy

Luca Persani

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

Division of Endocrine and Metabolic Diseases, Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy

Luca Petricca,     Institute of Rheumatology, Fondazione Policlinico Universitario A. Gemelli - IRCCS – Catholic University of the Sacred Heart, Rome, Italy

Nicolò Pipitone,     Rheumatology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

Guilherme Ramires de Jesús,     Department of Obstetrics, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil

Gustavo Resende,     Rheumatology Division, Clinical Hospital, Federal University of Minas Gerais, Belo Horizonte, Brazil

Chen Rizenbah

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Ignasi Rodríguez-Pintó,     Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Spain

Noel R. Rose,     Department of Pathology, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, United States

Eric Rosenthal,     Department of Internal Medicine, Archet-1 Hospital, University of Nice-Sophia-Antipolis, Nice, France

Mariateresa Rossi,     Dermatology Unit, Spedali Civili, and Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

Lazaros I. Sakkas,     Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece

Carlo Salvarani

Rheumatology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

Università di Modena e Reggio Emilia, Modena, Italy

Piercarlo Sarzi-Puttini,     Rheumatology Unit, L. Sacco University Hospital, Milan, Italy

Raffaele Scarpa,     Rheumatology Unit, Department of Clinical Medicine and Surgery, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy

Yahel Segal,     Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Michael J. Segel

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

The Pulmonary Institute, Sheba Medical Center, Tel-Hashomer, Israel

Carlo Selmi

Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy

BIOMETRA Department, University of Milan, Milan, Italy

Dr Lior Seluk,     Department of Medicine A, Ramat-Gan, Israel

Colafrancesco Serena,     Department of Internal Medicine and Medical Specialties, Rheumatology Unit, Sapienza University of Rome, Rome, Italy

Amir Sharabi

Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Kassem Sharif

Department of Medicine ‘B’, Sheba Medical Center, Tel-Hashomer, Israel

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Netta Shoenfeld,     Sheba Medical Center, Tel-Hashomer, Israel

Yehuda Shoenfeld

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Laboratory of the Mosaics of Autoimmunity, Saint-Petersburg University, Saint-Petersburg, Russian Federation

Flavio Signorelli

Department of Rheumatology, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil

Department of Internal Medicine, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

Ana Martins Silva

Department of Neurology, Centro Hospitalar do Porto-Hospital de Santo António (CHP-HSA), Porto, Portugal

Unit for Multidisciplinary Research in Biomedicine (UMIB), Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal

Berta Martins Silva

Immunogenetics Laboratory, Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal

Unit for Multidisciplinary Research in Biomedicine (UMIB), Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal

Sharon Slomovich,     Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Raz Somech,     Department of Pediatrics, The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Alessandra Soriano,     Unit of Clinical Immunology, Allergy and Advanced Biotechnologies, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

Zoltán Szekanecz,     Division of Rheumatology, Institute of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

Yoshiya Tanaka,     The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan

Sara Tenti,     Department of Medicine, Surgery and Neuroscience, Rheumatology Unit, University of Siena, Policlinico Le Scotte, Siena, Italy

Angela Tincani,     Rheumatology and Clinical Immunology Unit, Spedali Civili, and Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

Barbara Tolusso,     Institute of Rheumatology, Fondazione Policlinico Universitario A. Gemelli - IRCCS – Catholic University of the Sacred Heart, Rome, Italy

Jiram Torres-Ruiz

Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Elias Toubi,     Bnai-Zion Medical Center, Faculty of Medicine, Haifa, Israel

Renato Tozzoli

Laboratory of Clinical Pathology, Azienda Sanitaria Universitaria Integrata di Udine, San Antonio Hospital, Tolmezzo, Italy

Laboratory of Clinical Pathology, Department of Laboratory Medicine, S. Maria degli Angeli Hospital, Pordenone, Italy

Paola Triggianese,     Rheumatology, Allergy and Clinical Immunology – University of Rome Tor Vergata, Rome, Italy

Amelia Chiara Trombetta,     Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Polyclinic San Martino Hospital, Genoa, Italy

George C. Tsokos,     Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Yumi Tsuchida,     Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Zahava Vadasz,     The Division of Allergy and Clinical Immunology, Bnai-Zion Medical Center, Faculty of Medicine, Technion, Haifa-Israel

Guido Valesini,     Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy

Joyce van Beers,     Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands

Pieter van Paassen,     Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands

Guia Maria Vannucchi,     Division of Endocrine and Metabolic Diseases, Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy

Carlos Vasconcelos

Unidade de Imunologia Clínica (UIC), Centro Hospitalar do Porto-Hospital de Santo António (CHP-HSA)

Unit for Multidisciplinary Research in Biomedicine (UMIB), Abel Salazar Institute of Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal

Marina Venturini,     Dermatology Unit, Spedali Civili, and Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

Olga Vera-Lastra

Internal Medicine Department, Hospital de Especialidades Centro Médico Nacional La Raza, IMSS, Mexico City, Mexico

Universidad Nacional Autónoma de México, Mexico City, Mexico

Mathilde Versini,     Institut Arnault Tzanck, Saint Laurent du Var, France

Marta Vomero,     Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy

Abdulla Watad

Department of Medicine ‘B’, Sheba Medical Center, Tel-Hashomer, Israel

Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Haijing Wu,     Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, China

Yong Zeng,     Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, People’s Republic of China

Section I

Introduction

Outline

Introduction

Chapter 1. The Mosaic of Autoimmunity in History

Chapter 2. The Novel Aspects on the Mosaic of Autoimmunity

Introduction

Funding

This work is supported by the grant of the Government of the Russian Federation for the state support of scientific research carried out under the supervision of leading scientists, agreement 14.W03.31.0009, on the basis of SPbU projects 15.34.3.2017 and 15.64.785.2017.

Chapter 1

The Mosaic of Autoimmunity in History

Noel R. Rose     Department of Pathology, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, United States

Abstract

In this chapter, we examine the impact that the publication of The Mosaic of Autoimmunity has had on research and its clinical application in the time before publication of the first edition of the Mosaic book in 1989, its effect on the field around the time of publication, and its continued influence in the future. We consider the effects on immunology generally and in the study of autoimmune disease in particular. Finally, we venture some predictions of the course of research on autoimmune-related diseases that may follow the publication of the new second edition of the Mosaics.

Keywords

Autoimmune disease; Autoimmune disease clinic; Cytokines; Genetics; Immunopathology; Regulation; Thyroiditis

Introduction

The Oxford English dictionary describes mosaic as the process of producing pictures or patterns by cementing together small pieces of stone, grass etc. of various colors; pictures or patterns thus produced. This is an apt description of the book. Research on autoimmunity and autoimmune disease by its diverse nature involves many colorful little tiles. Each autoimmune disease is an element onto itself. It has its own color and texture conveyed by the clinical signs and symptoms and by its distinct biologic mechanisms. It was the genius of the first edition of The Mosaic of Autoimmunity that Yehuda Shoenfeld was able to assemble these different pieces into a coherent image. The pattern was the culmination of three decades of research both in the laboratory and in the clinic that resulted in a portrait of autoimmune diseases as an important component of modern medical science.

Pre-Mosaic Immunology, 1950–80

Modern day immunology was emerged during the three decades following World War II. The war left science in Europe decimated. In continental Europe, medical scientists were scattered or killed, and the laboratories and medical facilities destroyed. The situation in Great Britain was a bit different from the continent because the country was not actually invaded. Scientists were taken off doing their research and assigned activities to support the war effort. The great names in post–war British immunologic research, Florey, Medawar, Gell, and Humphrey, were able to transition back to fundamental investigation often based on their war time experience.

In Europe, one place where immunology was reborn after the war was Paris. I had the good fortune to spend a sabbatical year at the Pasteur Institute in Paris in 1957 and to experience the renaissance of immunologic research at that distinguished institution. Two units, side by side at the Pasteur Institute, were the nidus from which modern immunology sprang. The molecular biology group under Lwoff defined our understanding of the interaction of genes through the operon. With Monod and Jacob, the group was awarded with the Nobel Prize.

The neighboring unit was headed by Grabar. Although trained as an engineer, Grabar became fascinated by immune reactions in a visit to the United States in the 1930s and established a laboratory after the war with many colleagues who set the stage for what is now referred to as Immunopathology. The major outcome of the Grabar research was the development of new methods that allowed deeper searching and greater insight into the immune response. This research led to another Nobel Prize given to a past member of a group, Dausset, for discovery of the HLA gene family.

Before World War II, immunology was largely a handmaiden of microbiology and infectious diseases. The major occupation of the immunologist was performing serological tests to aid microbiologic diagnosis. Three tests were available in the laboratory for demonstrating antibodies: agglutination, precipitation, and complement fixation. Each of these tests were greatly expanded and refined in the Grabar laboratory. Precipitation tests performed in an agar gel, for example, made it possible to separate and label the antigens and antibodies that were present in a complex sample. Agglutination was made more versatile and sensitive by devising indirect agglutination methods using particulate carriers of the antigen. Complement fixation was transformed by using defined enzymatic markers, giving raise to ELISA and immunofluorescence as signals. This expanded array of laboratory procedures allowed immunologists to discover worlds that had previously been beyond our vision.

My own year in the Grabar laboratory was occasioned by my studies with Ernest Witebsky of organ-specific or tissue-limited antigens. We discovered that organs with highly restricted antigens, such as the thyroid gland, can relatively easily be induced to develop self-destructive autoimmune responses, something that was previously believed to be impossible. Using Grabar’s new methods of separation in agar, I was able to more fully characterize the antibodies to thyroglobulin in both animal and human sera, and to fragment this large antigen into its component epitopes. These studies, which I described publicly at the first International Symposium on Immunopathology organized by Grabar, were included with a flurry of research papers on possible immunologic causes of human diseases. For example, a young hematologist who was coorganizer of the symposium, Peter Miescher, reported that the LE factor present in most patients with lupus represents antibodies to antigens found in the cell nucleus. Other studies on human diseases of unknown etiology identified many examples associated with, and possibly caused by, an autoantibody response. Autoimmune diseases made their debut on the medical stage at the meeting.

Inspired by these studies on the value of autoantibodies in diagnosis, attention of immunologists was redirected to immune responses in which antibodies played no apparent role. The basis for cell-mediated immunity was demonstrated by Landsteiner and Chase and led to the understanding that much of the injury in an autoimmune disease was due to cytotoxic effects of lymphocytes and other inflammatory cells. Research on cell-mediated immune responses progressed rapidly with the discovery of different families of lymphocytes, T cells and B cells, and of their active mediators, cytokines.

Another turning point in research on autoimmune diseases came from the discovery of my own laboratory that susceptibility to thyroiditis in animals was partly genetically determined, and that the major genes were a part of the major histocompatibility complex (MHC). A similar finding in humans was published soon afterward by McDevitt who described a similar MHC association with lupus. Studies on the genetic regulation of autoimmune disease became a major topic of investigation in the 1970s in both experimental animals and humans. Genetics and immunology merged.

In this era, two concepts of theoretical importance advanced our understanding autoimmune disease: the clonal selection theory propounded mainly by Burnet and specific acquired immunologic tolerance described by Medawar and his colleagues.

As the frequency of the autoimmune immune response was more fully appreciated and the harm that can result from an unregulated autoimmune response were more fully appreciated, investigations of the normal regulation of specific immunity, both antibody-mediated and cell-mediated, became a prominent topic for investigation. The idea that both lymphocytes and antibodies can both initiate and regulate autoimmune responses emerged at this time.

A continuing theme throughout this period was the remarkable specificity of the immune response. Crystallographic and other structure–function studies together with more precise genetic analysis allowed greater understanding of the mechanisms of selection of the receptors on antibodies as well as on T cells. T-cell recognition became an issue because it was clear that unrestrained recognition by T cells of antigen in the blood stream can lead to a storm of devastating cytokine responses. T-cell recognition is therefore circumscribed by MHC-restricted antigen presentation. Studies of T-cell recognition have led to the discovery of the critical importance of cells that prepare antigen for T-cell recognition. The action of antigen-presenting cells depends not only on precise recognition of the cognate antigen but also on nonantigen recognition by other cell surface markers that together help to regulate T-cell responses.

The Decade of the Mosaics, 1980–90

By 1980, it became clear that, despite many differences based on their location, all the autoimmune diseases shared a great number of fundamental properties. In my case, it meant getting together with Ian Mackay to produce the first book describing all the then recognized autoimmune diseases. The first part of the book was devoted to the common, underlying mechanisms such as genetics, cytokines, and regulation, whereas the second half described particular diseases with emphasis on applying those common mechanisms. That book, The Autoimmune Diseases, is now at its sixth edition.

The Mosaic of Autoimmunity, published in the same decade, approached the issue of the common features of autoimmune disease from a different angle. Shoenfeld took the major topics and trends in modern immunology and illustrated how they contributed to our growing mosaic picture of autoimmune disease. Like a mosaic, the full beauty of the individual pieces can best be appreciated when looked at collectively. Using both clinical features and animal models, the book gave the reader a broad view of the immune system and its many interactions both within and outside of the host, illustrating how each piece of the mosaic can contribute to autoimmunity.

The first edition of The Mosaic of Autoimmunity had enormous impact on the direction of future of future research and medical practice with respect to the autoimmune diseases. Journals and review media devoted to autoimmunity disease sprang into existence; regional, national, and international congresses on autoimmunity became regular features of the immunologic calendar. Patients with different autoimmune and related disorders have learned that their voices are much louder when they speak together to the public about the importance of supporting research on the autoimmune diseases.

Post-Mosaic Immunology 1990–2018

The years following publication of The Mosaic of Autoimmunity broadened the concept of autoimmunity and heightened its prominence in human physiology and pathology. For example, investigations of innate immunity gave rise to greater understanding of the invertebrate immune recognition system evolutionarily more primitive than the vertebrate adaptive response. These studies led to reexamination of the role of innate immunity in shaping the inflammatory response and the subtleties that inflammation played in determining the effector mechanisms of autoimmune disease. The interactions of these two immune systems, innate and adaptive, determine the pathologic or nonpathologic outcome of an autoimmune response. It has led also to a greater appreciation of the critical importance of maintaining the normal homeostasis of the host and of the microbial population, the microbiota, that inhabit the host.

Another overriding issue receiving more appropriate attention is the importance of external as well as internal factors in regulating autoimmunity. Some may operate on the epigenetic level by changing the genetic response. The historic field of infection in induction of autoimmunity found a larger place in the mainstream of immunologic research. New research on such topics as stress and pregnancy dealt with in the first edition shed new light on the darker edges of autoimmunity.

A review of contents of the current edition of The Mosaic of Autoimmunity provides an exciting prediction of where the field is likely to go before a future edition of the book. The emphasis clearly is now on translation of the half century of immunologic research to improved treatment and prevention of autoimmune disease. This goal implies earlier intervention. The appearance of antibodies well before clinical signs of disease are evident is only a starting point for understanding that development of autoimmune disease, in many instances, is a long-term process. Early detection of antigen-specific B and T cells and their cytokine products in blood can now be the goal. A part of the risk resides in the inherited traits of the individual patient and requires a personal genetic evaluation. Almost all autoimmune diseases depend on many different genes tied to the regulation of the immune response. Other than MHC, most of these genes individually contribute little to the total heightened risk. Therefore, individual genome-wide studies will have to be applied. Any intervention that can be applied before the disease has become clinically evident and irreversibly destructive requires development of the next generations of benign interventions. They are procedures that can be safely done in a healthy person, particularly a child, that is ethical and will halt the process leading to a pathogenic autoimmune outcome. The goal of early intervention must include assessing environmental factors where immunology has had its greatest successes.

The emphasis on prevention and earlier treatment must be placed on a continuing personal immunologic mosaic. These programs require assembling huge amounts of data. Methods of handling such information will require greater use of the tools of systemic biology, as this new edition of the book suggests.

As the current edition of the Mosaic book reminds us the immune system is closely integrated with the other major regulatory systems of the body, hormonal and neurologic. A complete systems biology approach is going to include the totality of the physiologic response, not just those classically identified as immunologic.

A topic of increasing interest is the tracking of regulatory pathways now needed in cancer immunotherapy. The goal of the oncologist is to mobilize the immune system, whereas the auto-immunologist is engaged in reducing it. Manipulation of the immune system is best targeted as selectively as possible, an area where the body of immunologic research may contribute.

A final word comes from an omission in the current edition of the Mosaic book. Too many patients are ill-served by our predominantly organ-based medical system because so many autoimmune diseases involve multiple organs. Diagnosis and treatment, therefore, become increasingly difficult as patients move from specialist to specialist. Our medical system must find a way to better serve patients with multiple autoimmune problems. Yehuda Shoenfeld has led the way. His clinic is one of the few in the world where patients with complicated, immune-mediated disorders can be seen by a team of specialists who pool their talents and arrive at a cohesive plan of treatment. Maybe The Autoimmune Disease Clinic will be a chapter in the next edition of The Mosaic of Autoimmunity.

Chapter 2

The Novel Aspects on the Mosaic of Autoimmunity

Carlo Perricone ¹ , and Yehuda Shoenfeld ² , ³       ¹ Rheumatology, Department of Internal Medicine, Sapienza University of Rome, Rome, Italy      ² Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel      ³ Laboratory of the Mosaics of Autoimmunity, Saint-Petersburg University, Saint-Petersburg, Russian Federation

Abstract

Almost 30 years ago, the concept of Mosaic of Autoimmunity was introduced to the scientific community, and since then it has continuously evolved adding new tiles to the puzzle. We are looking now at an era in which the players of autoimmunity have changed names and roles.

In this book, these novel players from genetic, epigenetic to cellular mechanisms and environmental factors have been discussed at the light of the scientific progresses of these years.

Keywords

AIDs; Familial autoimmunity; Major histocompatibility complex; Natural killer cells; Neuroimmunology; Postvaccination phenomena; Systemic lupus erythematosus

Almost 30   years ago, the concept of Mosaic of Autoimmunity [1] was introduced to the scientific community, and since then it has continuously evolved adding new tiles to the puzzle [2]. We are looking now at an era in which the players of autoimmunity have changed names and roles.

One of the mainstays of the mosaic concept is that autoimmune diseases (AIDs) occur in genetically predisposed individuals [3]. This concept is now expanded by the evidence of familial autoimmunity: not only a single AID shows familial aggregation [4,5] but also a familial aggregation of diverse AIDs exists. This was brought to light by the evidences from a systematic review and metaanalysis performed by Cárdenas-Roldán et al. [6]. Physicians should be aware that familial autoimmunity is a frequent event especially in specific disorders, such as autoimmune thyroid disease and systemic lupus erythematosus (SLE), suggesting a stronger shared genetic influence in their development.

To strengthen the theory of a genetic basis, there is the evidence that AIDs occur more often in young people [7]. On the other hand, AIDs were thought to be rare in older persons. Nowadays, this assumption was found to be not always valid, and a tendency to have more severe autoimmunity in older has been noted [8]. The possible explanation of such paradox comes from another branch of the mosaic: the presence of an abnormal immune response. Vadasz et al. [9] indeed suggested that expansion of many protective regulatory mechanisms and especially of peripheral CD4+CD25highFoxP3+ T-regulatory cells is highly characteristic in the elderly. It is possible that during aging, an imbalance between thymic and peripheral T-regulatory cell output occurs with a ratio favoring the peripheral component, possibly allowing a proinflammatory response increasing the susceptibility to autoimmunity. Furthermore, besides adaptive immunity, it has been elucidated that the disruption of the autoimmune response also occurs at the innate immunity system [10].

In this book on the revised concepts of the mosaic of autoimmunity, we will show the main multiple actors that are now on the scene.

If only we consider the cellular and molecular mechanisms, the old and well-known cells—B cells, T cells, and so on—have been better characterized and found to play pleiotropic roles in autoimmunity. We will see that B cells are antigen-presenting cells and can have a proinflammatory role [11], and in some instance may produce IL-6 rather than IL-10, generating different immune responses which more likely to associate them to specific autoimmune patterns [12]. B-regulatory cells have been recently described, producing IL-10, but also independently via IL-35 secretion [13].

The counterpart of B cells, T cells have been widely explored and from the CD8 and Th1/Th2 paradigm we are now in an era in which double-negative T cells, Th17   cells, Th9 cells, γδ T cells, T follicular helper (Tfh) cells, and T-regulatory cells have their role in autoimmunity. The imbalance toward any of these population may disrupt the tolerance, leading to the development of an autoimmune disorder, and unveiling such complex pathways will help finding novel targets and biomarkers and, also, develop tools toward personalized medicine [14].

Nevertheless, autoimmunity is not only humoral immunity but innate immunity seems to have a major role. Several studies showed that the number of circulating natural killer cells can be frequently altered, for instance, in multiple sclerosis (MS), rheumatoid arthritis (RA), type 1 diabetes mellitus, Sjögren’s syndrome, and miastenia gravis [15], and it was showed that they are detrimental in recurrent spontaneous abortion even when associated with antiphospholipid syndrome (APS) [16].

Dendritic cells are essential in the initiation and perpetuation of inflammation and secrete cytokines that polarize the cooperative immune response toward Th1 and Th17 that have been shown to be important in multiple AIDs, for instance, in SLE [17]. Even neutrophils take a place in mechanisms leading to autoimmunity: the discovery of the neutrophil extracellular traps (NETs), structures made of chromatin and histones that interact with integrins and toll-like receptors and whose insufficient removal or increased production may be implicated in the pathogenesis of several AIDs including SLE and RA [18].

The old complement is a vintage player in autoimmunity: still fundamental in everyday practice, especially in SLE, seems to be a promising therapeutic target in APS, and is implicated in most of the other autoimmune conditions [19].

We have observed in the past decade to an explosion of autoantibodies [20]: over 180 only in SLE and the knowledge that such antibodies often precede the disease of years if not decades. At the same extent, the diagnostic methods to assess such antibodies have improved: besides classical techniques, ELISA and automated tests have improved toward standardization of these tests [21]. When considering the diagnosis of AIDs, the technologic progress has given novel tool to physicians in particular in the assessment of inflammatory arthritides including magnetic resonance and musculoskeletal ultrasonography that permit earlier and more accurate depiction of the inflammatory status as well as of the bone damage in these conditions [22].

Everything is based on the genetic predisposition of the individual: genetic that drives the phenotype, genetic that has evolved in the techniques so that now we have the next generation sequencing allowing to study the whole genome of an individual [23]. Nonetheless, it was shown that epigenetic modifications are detrimental, dramatically changing genetic expression via DNA methylation/demethylation, histone modification, and noncoding RNAs, and thereby play a key role in various biological processes and pathogenesis of disease [24]. In this view, the role of hormones seems now much more an interaction resulting with genetic and epigenetic modifications rather than being detrimental per se [25]. For instance, posttranslational modifications are now part of the mosaic of autoimmunity, citrullination has been discovered, and recently a role for carbamylation has been described, introducing novel classes of autoantibodies frequently linked with the exposure to environmental agents [26]. The families of cytokines and chemokines have enormously increased, the role in each disease better depicted, and several have been identified as therapeutic targets in common clinical practice as well as in future trials [27]. Lysosomal degradation occurring in eukaryotic organisms, namely autophagy, has a crucial role in cell homeostasis by controlling organelles and proteins turnover and sustaining survival in cellular stress conditions such as nutrients deprivation. Dysfunction of this mechanism has been implicated in several autoimmune disorders including SLE, RA, and MS [28]. And another player is microbiota that is the set of microorganisms that cohabit a multicellular organism. Dysbiosis is an event occurring in several autoimmune conditions: specific species seem to become pathogenic by driving the immune response toward an imbalanced status, for instance, toward a Th17 response for segmented filamentous bacteria that proliferate in animal models of arthritis [29]. The counterplayers are infections that are well known to be associated with AID flares and increased disease susceptibility [30]. More recently, parasitic infections have been either associated with or found being protective to certain AIDs, suggesting a possible therapeutic strategy [31].

It is also well known that genetic factors do not explain all of the susceptibility to AIDs, just because of these interactions with epigenetic factors and the environment. The study of the geo-epidemiological factors on big data will allow to identify such data and clarify the pathogenic mechanisms of AIDs [32].

Thus, here we come to the novel factors that have been associated with several autoimmune conditions. Some associations with seasonality have been demonstrated, probably linked with the effects of melatonin [33]. Ultraviolet radiation in some cases can be used as a therapy, for instance, in patients with psoriasis, whereas it is harmful in patients with SLE because of its proapoptotic capacities [34]. Vitamin D has been found to be an immunomodulator by improving the number of T-regulatory cells, and vitamin D supplementation has been suggested as a valid supportive strategy in several conditions besides the treatment of osteoporosis [35]. It has been found that patients with autoimmune disorders have impaired sense of smell, linking the olfactory gene cluster to the major histocompatibility complex located on chromosome 6 [36]. Even breastfeeding (or not breastfeeding) seems to have an influence on future development of autoimmunity [37]. Likewise, prolactin is implicated in a number of autoimmune conditions such as SLE [38].

Vaccination is fundamental in patients with AID because it prevents the onset of infections that trigger disease flares and worsen disease prognosis. It has been found that sporadically, in predisposed individuals, vaccines may trigger autoimmune response and should be avoided in patients with active disease. The role of adjuvants in the vaccines may at least partly explain this effect and rise a question on personalized medicine, notwithstanding that nowadays, vaccine’s benefits largely overwhelm the risks, and that vaccines are recommended in patients with AIDs following current recommendations [39]. Chronic silicone stimulation has been for long suspected to trigger autoimmune phenomena [40]. Thus, in 2011, Shoenfeld and Agmon-Levin described five medical conditions with similar complex of symptoms and signs and a common pathogenesis, namely siliconosis, the Gulf War syndrome, the macrophagic myofasciitis syndrome, postvaccination phenomena, and the sick building syndrome, linked with previous exposure to an adjuvant substance. The authors proposed to gather these five entities under a common syndrome denominated Autoimmune/inflammatory Syndrome Induced by Adjuvants and suggested a set of diagnostic criteria for this new entity [41].

As we saw that the microbiota can influence the onset of an autoimmune reaction, it is likely that we are what we eat. Some substances contained in spicy foods, specifically capsaicin, fatty acids, and some beverages such as tea or coffee, can modify our immune system in an anti- or proinflammatory way [42]. Gluten is an important component in wheat whose consumption has dramatically increased over time and that seems to have a proinflammatory effect in predisposed individuals on microbiome and on increasing intestinal permeability, by changing the intestinal tight junctions [43]. It should be not surprising that a proinflammatory state, in which there is an abundance of Th17, such as obesity, is associated with autoimmunity [44]. We have already mentioned smoke, especially cigarette smoke, which has multiple detrimental effects including increase of reactive oxygen species, increased NETosis, increased citrullination especially in the lungs, increased periodontitis, and association with the pathogen Porphyromonas gingivalis thus resulting in a destructive arm for predisposed subjects and patients with AIDs [45]. Cannabis has been shown to have immunomodulatory and pain relief effects when the endocannabinoids are modulated [46]. Psychological stress and physical activity seem two faces of the same medal leading or rather protecting toward the development of autoimmunity [47]. Living in a polluted environment has been also now recognized as a risk factor for the development of autoimmunity. For instance, it has been shown that diesel exhaust particles induce autophagy and citrullination in normal human bronchial epithelial cells [48]. Another pollutant is bisphenol A, molecule frequently used in the manufacturing of epoxy resins and plastics, which seems to act on estrogens thus driving autoimmunity [49].

Thus, given these premises, it is quite evident that the definitions, management, and treatment of AIDs have changed over the years. There is much more knowledge among the relationships between autoimmunity and cancer: from one side the events linking the development of specific malignant conditions in autoimmune patients, either or not associated with the disease per se rather than with the treatment. On the other side, the novel compounds used treat some neoplasia, the so-called immune checkpoints inhibitors, have been found to have as potential adverse events the development of autoimmune phenomena [50]. In addition, the relationships between allergy and autoimmunity have been better depicted, and some medications are now in development to be effective in both circumstances [51]. A branch, which is neuroimmunology, has been studied and implemented [52], as well as atherosclerosis and autoimmunity have been found to have lots in common starting from a proinflammatory milieu.

Novel classification criteria have been developed for SLE, RA, APS, vasculitis, psoriatic arthritis, and Sjögren’s syndrome, and