The Autoimmune Diseases (Sixth Edition)

__The Autoimmune Diseases, Sixth Edition,__ emphasizes the "3 P’s" of 21^st^ Century medicine: precision, prediction and prevention. Topics cover the modern systems approach to biology that involves large amounts of personalized, ongoing physiologic data ("omics") coupled with advanced methods of analysis, new tests of genetic engineering, such as CRISPR, auto inflammatory diseases, autoimmune responses to tumor immunotherapy, and information on normal immune response and disorders. Each of the major autoimmune disorders is discussed by researchers and clinical investigators experienced in dealing with patients. Chapters emphasize the immunologic basis of the disease as well as the use of immunologic diagnostic methods and treatments. The book also covers several cross-cutting issues related to the recognition and treatment of autoimmune diseases, including chapters on the measurement of autoantibodies and T cells, the use of biomarkers as early predictors of disease, and new methods of treatment. The Autoimmune Diseases Copyright List of Contributors Acknowledgment 1 Autoimmune Disease: Reflections and Projections Foreword Personal Introduction Autoimmunity and Autoimmune Disease Clonal Balance and Regulation Genetics and Exposures Epidemiology and Prediction Acknowledgment 2 Autoimmunity: A History of the Early Struggle for Recognition The Search for Autoantibodies Horror Autotoxicus The Nature of Ehrlich’s “Contrivances” Challenges to the Ehrlich Thesis Lens Autoantibodies Paroxysmal Cold Hemoglobinuria Sympathetic Ophthalmia The Wassermann Antibody The Shift to Immunochemistry The Return of Immunobiology Concluding Remarks References 3 General Features of Autoimmune Disease Innate Immune Activation Cells of the Adaptive Immune System Defining Autoimmune Disease Prevalence of Autoimmunity Genetics and Epigenetics of Autoimmunity Monogenic Disease Polygenic Disease Shared Risk Alleles Contribution of Epigenetic Modifications and Transcriptional Regulation Hormones and Autoimmunity Autoimmunity and Central Tolerance Autoimmunity and Peripheral Tolerance Triggers of Autoimmunity Activation of the Immune System Role of Antigen as a Driver of Autoimmunity Defective Downregulation of an Immune Response Regulatory Lymphocytes The Role of the Gut Microbiota in Autoimmunity Flares and Remissions During Disease Mechanisms of Tissue Damage Therapeutic Advances Goals for the Future Concluding Remarks Acknowledgments References 4 Innate and Adaptive Systems of Immunity The Innate and Adaptive Responses Innate Responses Cellular Components Soluble Mediators Adaptive Immune Responses T-Cell Development Functional Activities of T Cells B-Cell Development and Functions Antibodies Secondary Lymphoid Tissues Resolution of the Immune Response References 5 Immunological Tolerance—T Cells Introduction T-Cell Tolerance—A Brief Historical Perspective From Fetal Tolerance to Central Tolerance From Neonatal Thymectomy to Tregs From Adjuvants to T-Cell Anergy Establishment of Self-Tolerance in the Thymus Positive Selection of Immunocompetent T Cells Negative Versus Agonist Selection of Self-Reactive T Cells Promiscuous Expression of Self-Antigens in the Thymus Induction and Maintenance of Immunological Tolerance in the Periphery Ignorance and Antigen Sequestering Dendritic Cells, the Key Inducers of Peripheral T-Cell Tolerance Intrinsic Mechanisms Suppressing Clonal Expansion and/or Reactivation Dominant Tolerance Through Treg-Mediated Immunosuppression Treg Mechanisms to Maintain Tolerance Treg Diversity and Their Role in Self-Tolerance Treg at Barrier Sites Other Tolerogenic Cells in the Periphery Concluding Remarks Acknowledgments References Further Reading 6 T Cells and Their Subsets in Autoimmunity Introduction T Helper 1 Cells T Helper 17 Cells Identification Differentiation Pathogenicity Transcriptional Regulation Environmental Cues and T Helper 17 Cell Regulation in the Intestine Function T Helper 22 Cells Regulatory CD4+ T Cells Type 1 Regulatory T Cells Follicular T Helper Cells T Helper 2 Cells T Helper 9 Cells Concluding Remarks References Further Reading 7 The Role of Invariant Natural Killer T Cells in Autoimmune Diseases The Curious Case of Invariant Natural Killer T Cells The Many Names of Natural Killer T Cells The Many Faces of Invariant Natural Killer T Cells Phenotype Distribution The Many Effector Functions of Invariant Natural Killer T Cells Activation Cytokine Production Down-Stream Effects The many kinds of Invariant Natural Killer T Cells Technical Problems and the Species Divide The Species Divide The Janus-Like Character of Invariant Natural Killer T Cells in Autoimmunity Too Much of a Good Thing: Detrimental Roles of Invariant Natural Killer T Cells Atherosclerosis Asthma Inflammatory Bowel Disease/Colitis Primary Biliary Cirrhosis Rheumatoid Arthritis Skin Disorders Missed So Sadly: Beneficial Roles of Invariant Natural Killer T Cells Type 1 Diabetes Inflammatory Bowel Disease/Crohn’s Disease Multiple Sclerosis/Experimental Autoimmune Encephalomyelitis Systemic Lupus Erythematosus Good or Bad Actors? The Far End of the Question? What Activates Invariant Natural Killer T Cells During Autoimmune Responses? How Do Invariant Natural Killer T Cells Influence Autoimmune Responses? Conclusion Acknowledgments Abbreviations References 8 B-Cell Development: How to Become One of the Chosen Ones Introduction—What Has to be Generated in B-Cell Development to Make it to Maturity? Follicular B Cells Intraepithelial B Cells Two Types of Memory B Cells B Lymphopoiesis Before Ig Repertoire Generation—Development of Progenitor and Precursor Cells Development in Waves During Ontogeny and in Niches Throughout Life Cellular Environments of the First Phase of Early, Antigen-Independent B-Cell Development Early Commitments to Antigen-Independent B-Cell Development The Second, Eventually Autoantigen-Sensitive, Phase of B-Cell Development to sIgM+ Immature B Cells The First Checkpoint for the Emerging B-Cell Repertoire—Probing the Fitness for a Good BCR Expression of IgL Chains The Second Checkpoint: Sites and Mechanisms of Selection of Newly Generated sIgM+ B Cells Future Approaches to Understanding Central B-Cell Tolerance Acknowledgments References Further Reading 9 B Cell Activation and B Cell Tolerance B Cell Activation Antigen-Driven B Cell Activation Amplification and Modulation of B Cell Activation Signals Antigen Processing Following B Cell Activation Optimal B Cell Activation Requires Interaction With T Helper Cells Surface Molecules in B Cell–T Cell Interactions Cytokines Involved in B Cell–T Cell Interactions Maturation and Activation of B Cells Occur in Lymphoid Organs Location of B Cell Activation B Cell Activation and the Germinal Center Response The Germinal Center T Cell–Independent Antibody Responses B Cell Tolerance: Traditional and New Concepts Mechanisms of B Cell Central Tolerance Receptor Editing and Clonal Deletion Defective Receptor Editing and Clonal Deletion Can Promote Autoimmunity B Cell Anergy Characteristics of Anergic B Cells B Cell–Activating Factor and Tonic Signals Modulate B Cell Tolerance B Cell–Activating Factor in B Cell Development and Survival Tonic Signaling in B Cell Development and Survival B Cell–Activating Factor, Tonic Signaling, and Autoimmunity Regulatory T Cells Antibody-Independent Activity of B Cells in Tolerance Antigen Presentation by B Cells Cytokine Production by B Cells Regulatory B Cells Future Directions References Further Reading 10 Macrophages and Autoimmunity Introduction General Characteristics of Macrophages Heterogeneity of Tissue Macrophages Under Steady-State Conditions Macrophage Heterogeneity During Inflammation Opsonic and Nonopsonic Receptors in Macrophages Fc Receptors Pattern Recognition Receptors Toll-Like Receptors Scavenger Receptors Lectin Receptors Cytosolic Pattern Recognition Receptors The Phagocytic Process Clearance of Apoptotic Cells by Macrophages Concluding Remarks; Macrophages and Autoimmunity References 11 Dendritic Cells in Autoimmune Disease Introduction Antigen Uptake, Processing, and Presentation by Dendritic Cells Migration Pattern Recognition Receptors and Dendritic Cell Activation Alignment of Mouse and Human Dendritic Cell Subsets by Function and Development Development of Dendritic Cell Subsets Dendritic Cell Subset Phenotypes Conventional Dendritic Cell 1 Conventional Dendritic Cell 2 Plasmacytoid Dendritic Cells Tissue-Specific Dendritic Cells Dendritic Cell Subsets and Tolerance Dendritic Cells and Autoimmune Disease Systemic Lupus Erythematosus Inflammatory Bowel Disease—Crohn’s Disease and Ulcerative Colitis Psoriasis and Psoriatic Arthritis Type 1 Diabetes Targeting of Dendritic Cells in Autoimmune Disease Conclusion and Future Prospects Acknowledgments References 12 Natural Killer Cells Introduction to Natural Killer Cells Natural Killer Cell Development and Differentiation Phenotype and Tissue Localization Functional Responses by Natural Killer Cells Natural Killer Cell Receptor Signaling and Effector Functions Natural Killer Cell Contact and Adhesion to Target Cells Natural Killer Cell Lytic Granule Polarization and Maturation Natural Killer Cell Cytolytic Granule Exocytosis Natural Killer Cell Chemokine and Cytokine Production Natural Killer Cells and Human Autoimmunity Defective Control of other Immune Cells Links Natural Killer Cells to Autoimmune Diseases Genetic Association Studies Revealing Links Between Natural Killer Cells and Autoimmune Diseases Conclusions References 13 Granulocytes: Neutrophils, Basophils, Eosinophils Neutrophils Basic Biological Principles and Role in Immunity Neutrophils and Neutrophil Extracellular Traps Neutrophils in Systemic Autoimmune Diseases: Pathogenic Role Systemic Lupus Erythematosus Dysregulated Neutrophil Phenotype and Function and Proinflammatory Role of Neutrophil Proteases in Systemic Lupus Erythematosus Systemic Lupus Erythematosus and NETosis Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitides Neutrophil-Induced Vasculitic Organ Damage Neutrophil Extracellular Traps and Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitides Rheumatoid Arthritis Proinflammatory Effects of Neutrophil Proteases and Reactive Oxygen Species in Rheumatoid Arthritis Neutrophil Extracellular Traps and NETosis in Rheumatoid Arthritis Primary Sjögren Syndrome Systemic Sclerosis Antiphospholipid Antibody Syndrome Polymyositis and Dermatomyositis Neutrophils in Systemic Autoimmune Diseases: Therapeutic Implications Basophils Basic Biological Principles and Role in Immunity Basophils and IgE Antibodies in Autoimmune Diseases: Pathogenic Role Basophils and IgE Antibodies in Systemic Lupus Erythematosus Basophils and IgE Antibodies in Bullous Pemphigoid IgE Antibodies in Other Autoimmune Disorders Basophils and IgE Antibodies in Autoimmune Diseases: Therapeutic Implications Eosinophils Basic Biological Principles and Role in Immunity Eosinophils in Autoimmune Diseases: Pathogenic Role Eosinophils in Eosinophilic Granulomatosis With Polyangiitis Eosinophils in Other Vasculitis Eosinophils in Eosinophilic Granulomatosis With Polyangiitis: Therapeutic Implications Conclusions References 14 The Roles and Contributions of the Complement System in the Pathophysiology of Autoimmune Diseases The Complement System and Complement Activation Pathways The Classical Pathway The Lectin Pathway The Alternative Pathway The Membrane Attack Complex Control of Complement Activation Fluid Phase Regulators Membrane-Bound Regulators The Biological Effects of Complement Activation Complement Involvement in the Pathophysiology of Diverse Autoimmune Diseases References 15 Cytokines, Their Receptors and Signals Historical Perspective Cytokines and Immunity Cytokine Receptor Subsets The Common γc Chain Subset The βc Utilizing Subset The gp130 Utilizing Subset (Interleukin-6 Family) Cytokines Sharing Either a p35 or p40 Ligand Chain Th17 Cytokines and Receptors Class II Cytokine Receptor Family Type I Interferons α and β Type II Interferon Gamma Type III Interferon Lambda Noninterferon Members Tumor Necrosis Factor Receptor Family The Interleukin-1/Toll-Like Receptor Family of Receptors Immunosuppressive Cytokines/Growth Factors Chemokines Alarmins Conclusion Acknowledgments References 16 Cell Death and Autoimmune Disease Apoptosis Apoptosis in Autoimmunity Defective Apoptosis Excessive Apoptosis and Apoptotic Cells as Sources of Autoantigen Apotopes NETosis Necrosis Necroptosis in Autoimmunity Parthanatos in Autoimmunity Clearance of Dead Cells Find-Me Signals Eat-Me Signals and Their Receptors Receptors for Necrotic Cells Antiinflammatory Effects of Apoptotic Cells Immunostimulatory Effects of Necrotic Cells A Glimpse Into the Future References 17 Autophagy in Autoimmunity Autophagy Pathways Molecular Autophagy-Related Proteins Machinery of Macroautophagy Noncanonical Autophagy Pathways Autophagy in T- and B-Cell Development and Activation Autophagy in Innate Immunity Autophagy Pathways During Antigen Presentation Autophagy in Tolerance and Autoimmunity References Further Reading 18 Effector Mechanisms in Autoimmunity Introduction Autoantibodies Direct Antibody-Mediated Disease Immune Complex Disease Complement Cascades Macrophages Neutrophils Mast Cells Natural Killer Cells and Cytotoxic T Cells Effector T-Helper Cell–Mediated Autoimmune Disease Innate Lymphoid Cells Effector Cytokines and Their Targets Conclusions References 19 Diet, the Gut Microbiome, and Autoimmune Diseases Introduction Evidence That Diet and the Gut Microbiome Associate With Human Autoimmune Diseases Diet and the Gut Microbiota Major Products of the Gut Microbiome—Short-Chain Fatty Acids, Mediate Gut Homeostasis, and Immune Tolerance Sites Other Than the Gut Where Dietary or Bacterial Metabolites May Influence the Immune Response Mechanisms for Microbiome-Mediated Gut and Immune Homeostasis Metabolite-Sensing G-Protein Coupled Receptors Transcriptional and Epigenetic Effects Other Important Metabolites: Tryptophan Catabolites, ω-3 Fatty Acids Concluding Remarks References 20 Noninfectious Environmental Agents and Autoimmunity Introduction Evidence Supporting the Role of Environmental Agents in Autoimmune Disease Identifying and Defining Environmentally Associated Autoimmune Diseases Noninfectious Agents Associated With Autoimmune Diseases Drugs Occupational Exposures Others Foods Vitamin D Tobacco Smoke Heavy Metals Microchimerism Vaccines Implants Stress Air Pollution Exercise Microbiome Possible Mechanisms by Which Environmental Agents May Induce Autoimmune Diseases Overview and Future Directions Acknowledgments References 21 Microbial Infection as a Trigger of T-Cell Autoimmunity Introduction Infectious Triggering of Autoreactive T Cells Proposed Mechanisms Underlying Autoimmunity Molecular Mimicry Bystander Activation of Autoreactive Cells and Epitope Spreading Emerging Mechanisms of Infection-Induced Autoimmune Disease Reciprocal Relationships of Pathogen-Derived Mechanisms of Autoimmunity How Do These Mechanisms Lead to Autoimmune Disease? Autoimmunity Can Occur at a Site Distal to the Initiating Infection Conclusions Acknowledgments References 22 Autoimmune Diseases: The Role for Vaccines Introduction Concerns for Autoimmune Diseases in the Context of Vaccination Crossfire and Coincidence Example of an Animal Model Developed to Understand Acute Disseminated Encephalomyelitis Observed With Older Rabies Vaccine—... Practical Approach to Vaccination in Patients With Autoimmune Disease The Reality Facing Clinicians Currently Certainty About Vaccines, Uncertainty About Compatibility of Administration in Certain Settings Search and You Will Find Conclusion References Further Reading 23 Genetic Predisposition, Humans Introduction Diseases of Interest Type 1 Diabetes Multiple Sclerosis Systemic Lupus Erythematosus Human Leukocyte Antigen and Other Candidate Genes Association of Type 1 Diabetes with Human Leukocyte Antigen and Other Candidate Genes INS PTPN22 Association of Multiple Sclerosis with Human Leukocyte Antigen and Other Candidate Genes Association of Systemic Lupus Erythematosus with Human Leukocyte Antigen and Other Candidate Genes Tumor Necrosis Factor (TNF) TNFSF4 C4A, C4B C2 C1Q FCGR2A, FCGR3A, FCGR3B IRF5 Mechanisms of Complement and Fc Associations with Autoimmunity Mechanisms of Human Leukocyte Antigen Association with Autoimmunity Genetic Linkage Studies of Autoimmunity Linkage Studies of Type 1 Diabetes CTLA4 GAD2 IL2RA Other Loci Linkage Analyses of Combined Datasets and the Limits of Linkage Analyses UBASH3A Linkage Studies in Multiple Sclerosis Linkage Studies in Systemic Lupus Erythematosus TNFR1, TNFR2, LTBR Signal Transducer and Activator of Transcription 4 Racial Heterogeneity in Systemic Lupus Erythematosus Genome-Wide Association Studies of Autoimmunity Genome-Wide Association Studies of Type 1 Diabetes IFIH1 SH2B3 ERBB3 CLEC16A PTPN2 BACH2 IL2 IL10 CD69 Genome-Wide Association Studies of Multiple Sclerosis IL7R IL2RA CD58 CYP27B1 CD40 TNFRSF1A IRF8 CD6 CD86 EOMES IL12B CD5 Signal Transducer and Activator of Transcription 3 Signal Transducer and Activator of Transcription 4 C-C Motif Chemokine Receptor 4 Genome-Wide Association Studies of Systemic Lupus Erythematosus Integrin Alpha M Plant Homeodomain (PHD) and Ring Finger Domains 1/ Interferon Regulatory Factor 7 B-Cell Scaffold Protein with Ankyrin Repeats 1 B-Lymphoid Tyrosine Kinase TNF Alpha-Induced Protein 3 TNF Alpha-Induced Protein 3 Interacting Protein 1 PRDM1 IL10 NCF2 IRF8 UBE2L3 IL12A Concluding Comments Acknowledgments References 24 Sexual Dimorphism in the Immune System Introduction Overview of Sexual Dimorphism Sexual Dimorphism in the Immune System Effects of Hormones on the Immune System Estrogens Progesterone Androgens Role of the Sex Chromosomes in Immunity X Chromosome Y Chromosome Environmental Effects on Sex Differences in Immunity Consequences for Autoimmunity of Sexual Dimorphism in the Immune System References 25 Epigenetics of Autoimmune Diseases Epigenetic Modifications DNA Methylation Histone Posttranslational Modifications Histone Acetylation and Deacetylation Histone Methylation Arginine Methylation Ubiquitination Writers, Readers, and Erasers of Histone Modifications Noncoding RNAs Cross Talk Between Epigenetic Regulations Epigenetic Stability Rheumatoid Arthritis Acetylation Marks in Rheumatoid Arthritis Immune Cells Histone Modifications in Rheumatoid Arthritis Synovial Fibroblasts DNA Methylation in Rheumatoid Arthritis Immune Cells Genomic DNA Hypomethylation and the Activated Phenotype of Rheumatoid Arthritis Synovial Fibroblasts Aberrant SUMOylation miRNA and the Destructive Potential of Rheumatoid Arthritis Synovial Fibroblasts Autoimmune Thyroid Diseases DNA Methylation in Autoimmune Thyroid Diseases Histone Tail Modifications in Autoimmune Thyroid Diseases Noncoding RNAs in Autoimmune Thyroid Diseases Type-1 Diabetes DNA Methylation Profiling in Type-1 Diabetes Chromatin Remodeling and Histone Acetylation in Type-1 Diabetes Histone Deacetylase Inhibitors in Type-1 Diabetes Preclinical Studies Multiple Sclerosis DNA Methylation and Multiple Sclerosis Histone Modifications in Multiple Sclerosis Generation of Neo-Epitopes MicroRNAs in Multiple Sclerosis Systemic Lupus Erythematosus DNA Methylation in Systemic Lupus Erythematosus Histone Modifications in Systemic Lupus Erythematosus MicroRNA in Systemic Lupus Erythematosus Sjögren’s Syndrome DNA Methylation in Sjögren’s Syndrome miRNAs in Sjögren’s Syndrome Systemic Sclerosis DNA Methylation in Scleroderma Histone Modifications in Scleroderma MicroRNAs in Scleroderma Antineutrophil Cytoplasmic Autoantibodies–Associated Vasculitis Epigenetics of Immune Tolerance to Self Dysruption of B Cell Tolerance to Self Epigenetic Regulators of Tolerant T Cells DNA Methylation in Treg Development and Function Impacts of Histone Acetylation on Development and Function of Regulatory T Cells Epigenetic Modulation of Regulatory T-Cell Stability Genetic and Epigenetic Interactions in Autoimmune Diseases Epigenetics Changes Associated With Environment Triggers in Autoimmunity Exposures to Ultraviolet Light Drugs Toxic Chemicals Microbiome Epigenetics Dietary Components and Nutri-Epigenomics Translational Applications of Epigenetics Potential Disease Biomarkers Epigenetic Therapy Targeting DNA Methylation Histone Deacetylase Inhibitors MicroRNAs-Targeting Therapeutics Epigenetic Generation of Regulatory T Cells Conclusions and Future Prospects References 26 Genetic Predisposition to Autoimmune Diseases Conferred by the Major Histocompatibility Complex: Utility of Animal Models Major Histocompatibility Complex Major Histocompatibility Complex and Autoimmunity The Mystery of Human Leukocyte Antigen-B27 and Spondyloarthropathies Human Leukocyte Antigen-B27 Transgenic Mice Human Leukocyte Antigen-B27 and Autophagy Human Leukocyte Antigen-B27 and AIDS Human Leukocyte Antigen-B27 and Peptide Binding Human Leukocyte Antigen-B27 and Natura Killer Cells Human Leukocyte Antigen-B27 and Evolution Human Leukocyte Antigen Class II Association With Autoimmune Diseases Predisposition Onset Environmental Factors Infectious Agent Smoking and Autoimmunity Porphyromonas gingivalis and Rheumatoid Arthritis Genetic Factors, Gut Microbiome in Autoimmune Diseases Human Leukocyte Antigen, Microbiome, and Rheumatoid Arthritis Vitamin D in Autoimmune Diseases Posttranslational Modifications in Autoimmunity Deimination Deamidation Humanized Animal Models of Autoimmunity Collagen-Induced Arthritis Nonrheumatoid Arthritis-Associated Human Leukocyte Antigen Alleles Can Predispose to Autoimmunity Human Leukocyte Antigen–DR Transgenic Mice With Experimental Autoimmune Encephalomyelitis as an Animal Model of Multiple Sc... Role of DQ Molecule in Predisposition to Multiple Sclerosis Animal Model of Celiac Disease Animal Model for Type 1 Diabetes Human Leukocyte Antigen Class II Molecule Regulate Infection Through Modulation of Cytokine Networks Human Leukocyte Antigen Class II Molecules Regulate Autoimmunity by Antigen-Specific T Regulatory Cells Concluding Remarks References 27 Animal Models of Organ-Specific Autoimmune Disease What Can Animal Models Teach Us About Organ-Specific Autoimmunity? Animal Models in Basic Science: Understanding the Complexity of Organ-Specific Autoimmunity Animal Models in Drug Development: Picking the Winners Summary of Advantages and Disadvantages of Animal Models A Survey of Animal Models for Organ-Specific Autoimmune Diseases Hashimoto’s Thyroiditis and Graves’ Disease Type 1 Diabetes Addison’s Disease Celiac Disease Pernicious Anemia Ulcerative Colitis and Crohn’s Disease Autoimmune Hepatitis Primary Biliary Cirrhosis Vitiligo Alopecia Arreata Dermatitis Herpetiformis Multiple Sclerosis Narcolepsy Immune Thrombocytopenic Purpura Giant Cell Arteritis Conclusions References 28 Autoimmunity in Primary Immunodeficiency Disorders Introduction Immunodeficiencies Affecting Cellular and Humoral Immunity Severe Combined Immunodeficiency Combined Immune Deficiencies Combined Immunodeficiencies With Syndromic Features Predominantly Antibody Deficiencies Disorders of Immune Dysregulation: T-Cell Tolerance Monogenic Defects Affecting T-Cell Selection and Homeostasis Disorders of Regulatory T Cells Gain-of-Function Disorders of Cytokine Signaling Innate Immune Defects Conclusion References 29 Animal Models: Systemic Autoimmune Diseases Introduction Spontaneous Models of Systemic Autoimmunity Overview of Spontaneous Autoimmune Disease Models and Autoimmune-Susceptibility Loci New Zealand Mixed Mice MRL/lpr and gld Mice BXSB Mice Palmerston North Mice Ank/ank Mice K/BxN Mice SKG Mice Genetically Manipulated Models of Systemic Autoimmunity Lymphocyte Activation Molecules Ubiquitination-Related Enzymes Cytokines and Their Receptors Complement and Complement Receptor Proteins Clearance of Dead Cells Innate Immune Cell Signaling Induced Models of Systemic Autoimmunity Pristane-Induced Lupus Model Graft-Versus-Host Reaction–Induced Autoimmunity Collagen-Induced Arthritis Model Proteoglycan-Induced Arthritis Model Collagen Antibody–Induced Arthritis Model Conclusion References Further Reading 30 Systemic Lupus Erythematosus Introduction Epidemiology Pathogenesis of Disease Genetic and Associated Studies Transcriptional Analysis in Systemic Lupus Erythematosus Autoantibodies in Systemic Lupus Erythematosus Cellular Players in Systemic Lupus Erythematosus Adaptive Immunity B Cells T Cells Innate Immunity Dendritic Cells Neutrophils and Extracellular Traps Animal Models of Systemic Lupus Erythematosus Disease Features Cutaneous and Mucosal Disease Musculoskeletal Manifestations Cardiac Vascular Pulmonary Renal Neuropsychiatric Hematologic Therapeutics in Systemic Lupus Erythematosus Measurement of Disease Activity Management of Comorbidities Disease Modifying Drugs Hydroxychloroquine Azathioprine Mycophenolate Calcineurin Inhibitors Intravenous Steroids and Cyclophosphamide Biologic Agents and Small Molecule Inhibitors in Systemic Lupus Erythematosus Rituximab Belimumab Atacicept Other Agents and Treatment Options Future Perspectives References 31 Systemic Sclerosis (Scleroderma) Definition and Classification Epidemiology Pathogenesis Genetics Preclinical Disease Models Microvascular Disease in Systemic Sclerosis Inflammation and Autoimmunity Cellular Immunity Humoral Autoimmunity Fibrosis Pathology Skin Lungs Gastrointestinal Tract Kidneys Heart Pathology in Other Organs Clinical Features Overview Initial Clinical Presentation Organ Involvement Raynaud’s Phenomenon Skin Features Pulmonary Features Interstitial Lung Disease Pulmonary Arterial Hypertension Gastrointestinal Involvement Upper Gastrointestinal Tract Involvement Lower Gastrointestinal Tract and Anorectal Involvement Renal Involvement: Scleroderma Renal Crisis Cardiac Involvement Musculoskeletal Complications Less Recognized Disease Manifestations Cancer Biomarkers and Autoantibodies in Systemic Sclerosis Screening and Follow-Up Evaluation Natural History and Prognosis References 32 Antiphospholipid Syndrome General Introduction and Historical Aspects Epidemiology Clinical Features and Disease Associations Obstetric Antiphospholipid Syndrome Thrombotic Antiphospholipid Syndrome Noncriteria Antiphospholipid Syndrome Manifestations Neurological Antiphospholipid Syndrome Hematologic Antiphospholipid Syndrome Dermatologic Antiphospholipid Syndrome Cardiac Antiphospholipid Syndrome Pulmonary Antiphospholipid Syndrome Renal Antiphospholipid Syndrome Catastrophic Antiphospholipid Syndrome The Antiphospholipid Antibodies Criteria-Relevant Antiphospholipid Antibodies Lupus Anticoagulant Anticardiolipin Anti-b2-Glycoprotein-I Antibody Noncriteria Antiphospholipid Antibodies Antiphospholipid Antibodies of the IgA Isotype Low Level Antiphospholipid Antibodies Autoantibodies to Domain 1 of b2-Glycoprotein-I Antibody Antiphosphatidylethanolamine Antibodies Antiphosphatidylserine Antibodies Antiprothrombin Antibodies Antiphosphatidylserine/Prothrombin Antibodies Antiannexin A5 Antibodies Metaanalysis: Prevalence of Different Noncriteria Antiphospholipid Antibodies Seronegative Antiphospholipid Syndrome Risk Assessment in Antiphospholipid Syndrome Genetics Classification Criteria Versus Diagnostic Criteria Diagnostic Procedures The Mechanisms of Antiphospholipid Antibodies-Mediated Disease Expressions: Clinical Trials and Animal Models Thrombotic Manifestations Antiphospholipid Antibodies and the Coagulation Cascade Antiphospholipid Antibodies Cellular Interactions Obstetric Manifestations The Complement System in Antiphospholipid Syndrome Mortality in the Antiphospholipid Syndrome Treatment of Antiphospholipid Syndrome Conclusions and Future Aspects References Further Reading 33 Sjogren’s Syndrome General Introduction Historical Aspects Epidemiology Clinical Features and Disease Associations Eyes Oral Cavity Lungs Kidney Gastrointestinal Tract Nervous System Genitourinary Vascular System Musculoskeletal and Constitutional Symptoms Lymphoma and Other Hematological Manifestations Pathological Features Autoimmune Features Genetics Animal Models Including Relevance Diagnostic Procedures Treatment Perspectives References 34 Rheumatoid Arthritis Introduction Clinical, Pathologic, and Epidemiologic Features Autoimmune Features Genetic Characteristics In Vivo Models Pathologic Effector Mechanisms Autoantibodies as Potential Immunologic Markers Concluding Remarks—Future Prospects References 35 Juvenile Idiopathic Arthritis Epidemiology Clinical Features Systemic Arthritis Rheumatoid Factor–Positive Polyarthritis Enthesitis-Related Arthritis Oligoarthritis Rheumatoid Factor Negative Polyarthritits Psoriatic Arthritis Undifferentiated Arthritis Perspectives Etiology and Pathogenesis Systemic Juvenile Idiopathic Arthritis Genetics Proinflammatory Mediators Interleukin-6 Interleukin-1 Interleukin-18 Macrophage Activation Syndrome Oligoarticular Juvenile Idiopathic Arthritis Treatment References 36 Spondyloarthritides General Introduction Historical Aspects Epidemiology Clinical Features and Disease Associations Pathological Features Autoimmune Features Genetics The Role of HLA-B27 in the Pathogenesis of Spondyloarthritis The Role of Non-MHC Genes in Spondyloarthritis Animal Models With Possible Relevance for the Pathogenesis of Spondyloarthritis Treatment References Further Reading 37 The Autoimmune Myopathies Defining Autoimmune Myopathies Clinical and Pathological Descriptions of Different Phenotypes, Including Immune-Mediated Necrotizing Myopathy Characteristic Pathology, but Significant Overlap Between Phenotypes Epidemiological Clues Into Mechanism Specific Autoantibodies Are Strongly Associated With Phenotype, Making Them Useful Probes of Disease Mechanism Myositis-Specific Autoantibodies 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Autoantibodies in Statin-Associated Immune-Mediated Necrotizing Myopathy Mechanisms of Disease The Association of Malignancy With Autoimmunity: Insights Into Disease Initiation Enhanced Expression of Myositis Autoantigens in Regenerating Muscle Cells to Focus Propagation on Muscle Modification of Autoantigen Expression or Structure by Immune Effector Pathways to Generate a Self-Sustaining Phenotype Therapeutic Insights Concluding Remarks References 38 Immunoglobulin G4-Related Disease General Introduction Historical Aspects Epidemiology Pathology Histological Features Immunostaining Pathophysiology B Cells T Cells Serum Immunoglobulin G4 Concentrations Autoimmune Features Does the Immunoglobulin G4 Molecule Participate in Autoimmunity? Evidence for Autoimmunity in Immunoglobulin G4-Related Disease Galectin-3 Genetics An Animal Model Clinical Features and Disease Associations Lymphadenopathy Lacrimal and Salivary Glands Orbits Ear/Nose/Throat Pancreas Immunoglobulin G4-Related Sclerosing Cholangitis and Cholecystitis Lung Kidney Thoracic Aorta and Coronary L