The Autoimmune Diseases

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 Lesions
		Chronic Periaortitis and Retroperitoneal Fibrosis
		Nervous System
		Other Immunoglobulin G4-Related Disease Lesions
	Classification Criteria
	Treatment
		B Cell–Targeted Treatments
		Costimulatory Blockade
		CD4+ Cytotoxic T Lymphocytes
	Perspectives
	References
39 Polyendocrine Syndromes
	Historic Background
	Clinical, Pathologic, and Epidemiologic Features
		Autoimmune Polyendocrine Syndrome Type 1
		Autoimmune Polyendocrine Syndrome Type 2
	Autoimmune Features
	Genetic Features
	Environmental Features
	Animal Models
		Aire-Deficient Mouse as a Model for Autoimmune Polyendocrine Syndrome Type 1
		Spontaneous Animal Models
		Thymectomy Animal Model
	Pathogenic Mechanisms
	Immunologic Markers in Diagnosis
	Treatment and Outcome
	Concluding Remarks—Future Prospects
	Acknowledgment
	References
40 Thyroid Disease
	Autoimmune Thyroiditis
		Historic Background
		Clinical, Pathologic, and Epidemiologic Features
		Autoimmune Features
			Autoantibodies
				Thyroglobulin Antibodies
				Thyroid Peroxidase Antibodies
				Other Autoantibodies
			T-Cell Responses
				Studies of T-Cell Phenotypes
			Functional Studies
		Genetic Features
		Environmental Influences
		In Vivo Models
			Immunization-Induced Thyroiditis
			Experimental Autoimmune Thyroiditis Resulting From Immune Modulation
			Spontaneous Autoimmune Thyroiditis
		Pathologic Effector Mechanisms
			Antibody-Mediated Injury
			T-Cell Mediated Injury
		Autoantibodies as Potential Immunological Markers
		Treatment and Outcome
		Concluding Remarks—Future Prospects
	Graves’ Disease
		Historic Background
		Clinical, Pathologic, and Epidemiologic Features
		Autoimmune Features
			Autoantibodies
			T-Cell Responses
		Genetic Features
		Environmental Influences
		In Vivo Models
		Pathologic Effector Mechanisms
		Autoantibodies as Potential Immunological Markers
		Treatment and Outcome
		Thyroid-Associated Ophthalmopathy and Dermopathy
		Concluding Remarks—Future Prospects
	References
	Further Reading
41 Autoimmune (Type 1) Diabetes
	Introduction
	Epidemiology
		Asymptomatic Islet Autoimmunity
		Symptomatic Autoimmune (Type 1) Diabetes
	Diagnostic Criteria and Classification of Diabetes
	Etiology
		Genetic Etiology of Islet Autoimmunity
		Environmental Factors Associated With First Appearing Autoantibodies
	Pathogenesis
		Pathophysiology
		Genetic Factors
		Environmental Factors
		Cellular Mechanisms
		Humoral Biomarkers
		Pathology
	In Vivo and In Vitro Models
	Primary Prevention
	Secondary Prevention
	Intervention
	Conclusion and Future Directions
	References
42 Adrenalitis
	Introduction
	Anatomy and Physiology of the Adrenals
	Epidemiology of Addison’s Disease and Autoimmune Adrenalitis
	Autoimmune Addison’s Disease
		Focal Lymphocytic Adrenalitis
		Diffuse Lymphocytic Adrenalitis
		Induced Immunity in Animal Models
		Spontaneous Animal Models
		Family History of Autoimmune Addison’s Disease and Genetic Predisposition
		Cellular Immunity
		Humoral Immunity
		Identification of Autoantigens of Adrenal Cortex Autoantibodies
		Identification of Autoantigens of Steroid-Producing Cells Autoantibodies
		Techniques for Identification of Autoantibodies to 21-Hydroxylase
		Techniques for Identification of Autoantibodies to Other Steroidogenic Enzymes
		Other Autoantibodies Detected in Patients With Autoimmune Addison’s Disease
	Natural History of Autoimmune Addison’s Disease
	Diagnosis of Autoimmune Addison’s Disease
		Clinical Manifestations
		General Biochemical Indices
		Hormonal Tests
		Imaging
	Different Clinical Presentations of Autoimmune Addison’s Disease
		Association With Other Autoimmune Disorders
		Therapy
			Conventional Therapy
			New Therapies
			Regenerative Therapy
			Steroid Replacement During Surgery, Other Illness, Medical Procedures, Physical Activity, and Pregnancy
		Acute Adrenal Failure (Adrenal Crisis)
		Emergency Card
		Quality of Life
		Mortality
		Osteoporosis
	Acknowledgments
	References
43 Autoimmune Hypophysitis
	Definition and Classification
	Historical Background
	Epidemiology and Body of Literature
	Clinical Features
	Pathological Features
	Autoimmune Features
	Genetic and Environmental Influences
	Animal Models
	Diagnosis
	Treatment
	Outcome
	Hypophysitis Secondary to Cytotoxic T Lymphocyte Antigen 4 Blockade
	Concluding Remarks—Future Perspectives
	Acknowledgments
	References
44 Autoimmune Gastritis and Pernicious Anemia
	Clinical, Pathologic, and Epidemiologic Features
	Autoimmune Features
		Autoantibodies
		T-Cell Immunity
	Genetic Features
	In Vivo and In Vitro Models
	Pathogenesis and Complications of Autoimmune Gastritis
		Pathologic Effector Mechanisms
	Autoantibodies as Potential Immunologic Markers
	Laboratory Diagnosis
	Concluding Remarks—Future Prospects
	References
	Further Reading
45 Celiac Disease
	General Introduction
	Historical Aspects
	Epidemiology
	Clinical Features and Disease Associations
	Pathological Features
	Autoimmune Features
		Autoantibodies
		Autoreactive Intraepithelial Lymphocytes
	Genetics
		HLA Genes
		Non-HLA Genes
	Environmental Factors
		Gluten Proteins
		Other Environmental Factors
	In Vivo and In Vitro Disease Models
		Animal Models
		Organ Culture Assays
	Pathogenic Mechanisms
		Gluten-Specific CD4+ T Cells
		Transglutaminase 2
		Gluten Antigen Presentation by Disease Associated HLA-DQ Molecules
		Macrophages and Dendritic Cells
		Plasma Cells
		Effector Mechanisms Leading to Mucosal Alterations
	Autoantibodies as Immunologic Markers
		Serology
		Staining of Immune Complexes
	Treatment and Outcome
		Current Treatment
		Novel Treatments
	Perspectives
	Acknowledgments
	References
46 Inflammatory Bowel Disease
	General Introduction
	Historical Aspects
	Epidemiology
	Clinical Features and Disease Associations (Table 46.1)
		Crohn’s Disease
		Ulcerative Colitis
		Extraintestinal Manifestations Common to Ulcerative Colitis and Crohn’s Disease (Brown and Coviello, 2015; Vavricka et al.,...
			Skin
			Joints
			Eyes
			Mouth
			Hepatobiliary
			Kidney Disease
		Other Diseases With a Link to Inflammatory Bowel Disease
		Cancer
	Pathological Features
	Etiology Including Autoimmune Features
		Microbiota
		Intestinal Epithelium and Barrier Function
		Innate and Adoptive Immunity
	Genetics
	Animal Models
	Diagnostic Procedures
		Serologic Markers
		Stool Markers
		Imaging
	Treatment
		Medical (Table 46.2)
		Aminosalicylates
			Glucocorticoids
			Thiopurines
			Methotrexate
			Cyclosporine
			Anti-TNF Therapies
			Anti-IL12/13 Therapies
			Inhibitors of Leukocyte Infiltration
			Janus Kinase Inhibitors and Some Other Medications on the Horizon
			Nutritional Support
		Surgical
	Future Prospects
	Acknowledgment
	Abbreviations
	References
47 Autoimmune Hemolytic Anemia
	Historical Background
	Classification of Autoimmune Hemolytic Anemia
	Animal Models of Autoimmune Hemolytic Anemia
	Mechanisms of Red Blood Cells Destruction in Autoimmune Hemolytic Anemia
		Cold Reactive Antibodies
		Warm Reactive Antibodies
		Pathogenicity of Warm Reactive IgG Antibodies
		Additional Mechanisms of Hemolysis by Warm Antibodies
		Red Blood Cell Autoantigens
	Clinical Signs of Autoimmune Hemolytic Anemia
	Laboratory Diagnosis of Autoimmune Hemolytic Anemia
	Treatment of Autoimmune Hemolytic Anemia
	Etiology of Autoimmune Hemolytic Anemia and Predisposing Factors
		Genetic Predisposition
		Gender and Age
		Infectious Agents
		Drugs
		Neoplasia
	Immune Mechanisms Underlying Loss of Self Tolerance in Warm Autoimmune Hemolytic Anemia
		B Cells and Tolerance
		T-Helper Cells and Tolerance
	Concluding Remarks
	References
48 Immune Thrombocytopenia: A Complex Autoimmune Disease
	Introduction
	Epidemiology
	Diagnosis
	Pathogenesis
	Platelet Autoantibodies
	T-Cell Involvement
	Megakaryopoiesis
	Treatment
	First-Line Therapies
	Second-Line Therapies
	Splenectomy
	Rituximab
	Thrombopoietin Receptor Agonists
	Conclusion
	References
49 Acquired Aplastic Anemia
	Historic Background
	Genetic Features
	Clinical, Pathologic, and Epidemiologic Features
	Autoimmune Features and Pathogenic Mechanisms
	Environmental Features
	Animal Models
	Therapy for Aplastic Anemia
		Bone Marrow Transplantation
		Bone Marrow Transplantation From Unrelated Donors
	Immunosuppressive Therapy
	Eltrombopag
	High-Dose Cyclophosphamide Without Bone Marrow Transplantation
	Human Leukocyte Antigen Haploidentical Bone Marrow Transplant With Posttransplant Cyclophosphamide
	Aplastic Anemia and Clonality
	Concluding Remarks—Future Prospects
	References
50 Autoimmune Clotting Dysfunction
	Prothrombotic Disorders
	Autoimmune Inhibitors to a Disintegrin and Metalloproteinase With a Thrombospondin Type 1 Motif 13
	Anticoagulant Disorders
	Autoimmune Inhibitors to Fibrinogen (Factor I) and Fibrin
	Autoimmune Inhibitors to Prothrombin (Factor II) and Thrombin
	Autoimmune Inhibitors to Factor V
	Autoimmune Inhibitors to Factor VII
	Autoimmune Inhibitors to Factor VIII
	Autoimmune Inhibitors to Factor IX
	Autoimmune Inhibitors to Factor X
	Autoimmune Inhibitors to Factor XI
	Autoimmune Inhibitors to Factor XII
	Autoimmune Inhibitors to Factor XIII
	Autoimmune Inhibitors to Von Willebrand Factor
	Autoimmune Inhibitors to Further Proteins
	Conclusion and Future Aspects
	Acknowledgments
	References
51 Multiple Sclerosis
	Historical Background
	Clinical Features
		Radiologically Isolated Syndrome
		Clinically Isolated Syndrome
		Relapsing-Remitting Multiple Sclerosis
		Progressive Multiple Sclerosis
	Diagnostic Criteria
	Imaging
	Immunological Markers in Diagnosis
	Pathology
	Epidemiology of MS
		Genetic Factors
		Environmental Factors
	Immune Pathogenesis
		T-Cell Pathogenesis
		Immune Dysregulation
		Autoantigens
		The Role of B Cells
	Treatment
		Infusion-Based Therapies
			Natalizumab (Tysabri)
			Alemtuzumab (Lemtrada)
			Ocrelizumab (Ocrevus)
			Mitoxantrone (Novantrone)
		Oral Therapies
			Fingolimod (Gilenya)
			Teriflunomide (Aubagio)
			Dimethyl Fumarate, BG-12 (Tecfidera)
		Injection-Based Therapies
			Interferons
			Glatiramer Acetate (Copaxone)
	Concluding Remarks
	References
	Further Reading
52 Peripheral Neuropathies
	Introduction
	Acute Neuropathies: The Guillain–Barré Syndrome
		Historical Background
		Epidemiology
		Clinical Features and Subtypes of Guillain–Barré Syndrome
			Acute Inflammatory Demyelinating Polyradiculoneuropathy
			Acute Motor Axonal Neuropathy
			Acute Motor and Sensory Neuropathy
			Miller Fisher Syndrome
		Autoimmune Features
			Molecular Mimicry
			Antiganglioside Antibodies in Guillain–Barré Syndrome Variants
			Gangliosides in Peripheral Nerve
			Functional Effects of Antibodies
		Environmental Effects
		Animal Models of Disease
		Cellular Mechanisms
		Cellular and Humoral Immune Elements Are Synergistic
		Genetic Aspects of Guillain–Barré Syndrome
		Treatment and Outcomes
	Chronic Neuropathies: Chronic Inflammatory Demyelinating Polyradiculoneuropathy
		History
		Epidemiology and Clinical Features
			Multifocal Motor Neuropathy With Conduction Block
			Multifocal-Acquired Demyelinating Sensory and Motor Neuropathy
			Multifocal-Acquired Sensory and Motor Neuropathy
			Paraproteinemic Demyelinating Peripheral Neuropathy
		Autoimmune Features
		Immunogenetic Features
		Environmental Influences
		Animal Models
		Pathogenic Mechanisms
		Treatment and Outcome
	Concluding Remarks and Future Prospects
	Acknowledgments
	References
	Further Reading
53 Myasthenia Gravis and Related Disorders
	Introduction
		The Neuromuscular Junction
		Neuromuscular Transmission
		Acetylcholine Receptor and Muscle-Specific Kinase, the Main Antigenic Targets
	Myasthenia Gravis
		Epidemiology
		Etiology of Myasthenia
		General Clinical Aspects
	Clinical Heterogeneity of Myasthenia
		Different Forms Related to Antibodies and Thymic Pathology
		Early-Onset Acetylcholine Receptor-Antibody Positive Myasthenia Gravis
		Late-Onset Acetylcholine Receptor-Antibody Myasthenia Gravis
		Thymoma Associated Myasthenia Gravis
		Muscle-Specific Kinase Antibody Positive Myasthenia Gravis
		Neonatal Myasthenia Gravis
	Antibodies in Myasthenia
		Evidence for Pathogenicity of Acetylcholine Receptor and Muscle-Specific Kinase Antibodies
		Acetylcholine Receptor Antibodies
		Characteristics and Mechanisms
		Muscle-Specific Kinase Antibodies
		The Role of Muscle-Specific Kinase in Neuromuscular Junction Development and Maintenance
		LRP4 Antibodies
		Novel Targets
	The Thymus and Cellular Immunity in Myasthenia Gravis
		Role of T Lymphocytes in Myasthenia Gravis
		Advances in the Cellular Immunology of Acetylcholine Receptor Myasthenia Gravis
		The Thymus in Myasthenia Gravis
		Thymoma
	Treatments in Myasthenia Gravis
		General Approach
		Biologics
	Lambert–Eaton Myasthenic Syndrome
		Introduction
		Epidemiology and Etiology
		Clinical Features
		Investigation and Treatment
		Pathophysiology
	Conclusions and Future Prospects
	References
54 Ocular Disease
	Historical Background
	Clinical Features
	Pathologic Features
	Epidemiologic Features
	Genetic Factors
	The Unique Immune System of the Eye
	Animal Models
	Autoimmune Features
	Pathogenic Mechanisms
	Immunological Markers
	Treatment and Outcomes
		Concluding Remarks and Future Projects
	References
55 Immune-Mediated Inner Ear Disease
	Introduction
	Clinical Features
		Immune-Mediated Inner Ear Disease Associated With Systemic Autoimmune Diseases
		Immune-Mediated Inner Ear Disease Associated With Primary Vasculitides
			Cogan’s Syndrome
	Evidence of Autoimmunity
	Genetic Susceptibility
	Animal Models
	Treatment
	Concluding Remarks and Future Perspectives
	Acknowledgment
	References
	Further Reading
56 Autoimmune and Autoantibody-Associated Encephalomyelopathies
	Introduction
	Systemic Immunopathic Disorders With Encephalitis and Myelitis
		Systemic Vasculitides
			Definition and Classification
			Neurological Manifestation
			Central Nervous System Imaging
			Biopsy
		Large Vessel Vasculitides
			Giant Cell Arteritis
		Medium Vessel Vasculitides
			Classical Polyarteritis Nodosa
		Small Vessel—Antineutrophil Antibodies Positive Vasculitides
			Granulomatosis With Polyangiitis (Formerly Wegener’s Granulomatosis)
			Microscopic Polyangiitis
			Eosinophilic Granulomatosis With Polyangiitis (Formerly Churg–Strauss Syndrome)
		Small Vessel—Antineutrophil Antibodies Negative Vasculitides
			Rheumatoid Arthritis
				Neurological Manifestations
			Systemic Lupus Erythematosus
			Sjögren’s Syndrome
		Behçet’s Disease
		Sarcoidosis
	Antibody-Associated Diseases of the Central Nervous System
		General Considerations
			Antibodies Targeting Intracellular and Cell Surface Antigens
			Antibodies Nomenclature
			Diagnostical Considerations: Detection of Antibodies
			Principles of Treatment
				Tumor Detection and Management
				Principles of Immunotherapy
		Antibody-Associated Clinical Syndromes
			Autoimmune Encephalomyelitis and Limbic Encephalitis
				Anti-N-Methyl-d-Aspartate Receptor Encephalitis
					Epidemiology and Clinical Characteristics
					Pathophysiology
					Treatment
					Relapses
				Antivoltage-Gated Potassium Channels Antibody Encephalitis (Voltage-Gated Potassium Channels Encephalitis)
					Leucine-Rich Glioma Inactivated-1 Encephalitis
					Contactin-Associated Protein-Like-2 Encephalitis
					Treatment of Leucine-Rich Glioma Inactivated-1- and Contactin-Associated Protein-Like-2-Encephalitis
			Encephalitis Associated With Antibodies to Other Neuronal Surface Proteins
				Dipeptidyl-Peptidase-Like Protein 6 Encephalitis
				α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor Encephalitis
				GABA-b Receptor Encephalitis
				γ-Aminobutyric Acid Type-a Receptor Encephalitis
				Ophelia Syndrome or Metabotropic Glutamate Receptor 5 Encephalitis
				IgLON5 Encephalitis
				Dopamine-2 Receptor (Basal Ganglia) Encephalitis
			Subacute Cerebellar Degeneration
			Stiff-Person Spectrum Disorder
			Opsoclonus–Myoclonus Syndrome
			Isolated Myelopathies and Visual Loss, Associated With Antineuronal Antibodies
			Neuromyelitis Optica and Further Disorders Associated With Antiglial Antibodies
				Neuromyelitis Optical Spectrum Disease
					Epidemiology and Clinical Characteristics
					Pathophysiology
					Therapy
				Neurological Syndromes Associated With Myelin-Oligodendrocyte Glycoprotein-Antibodies
				Neurological Syndromes Associated With Glial Fibrillary Acidic Protein-Antibodies
		Target Antigens: Main Functions and Role in the Central Nervous System Autoimmunity
			Neuronal Cell Surface Antigens
				Excitatory Receptors
					N-Methyl-d-Aspartate Receptor
					α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor
					Metabotropic Glutamate Receptors 1 and 5
				Inhibitory Receptors
					Glycine Receptor
					Gamma-Aminobutyric Acid Type-a Receptors
					Gamma-Aminobutyric Acid Type b Receptors
				Other Neuronal Cell Surface Antigens
					Leucine-Rich Glioma Inactivated-1
					Contactin-Associated Protein Like 2
					Dipeptidyl-peptidase-like protein 6
					Dopamine-2 Receptor
					IgLON5 Receptors
					Amphiphysin
					Delta/Notch-Like Epidermal Growth Factor-Related Receptor (Tr)
			Intracellular Neuronal Antigens
				Antineuronal Nuclear Antibodies
					Hu (Antineuronal Nuclear Antibodies 1)
					Ri (Antineuronal Nuclear Antibodies 2)
					Antineuronal Nuclear Antibodies 3
					Ma (Paraneoplastic Ma Antigens)
				Cytoplasmatic Antigens
					Yo (Purkinje Cell Antigen-1)
					Microtubule-Associated Protein 1B (Purkinje Cell Antigen-2)
					Collapsing Response Mediator Protein 5 (CV2)
					Glutamic Acid Decarboxylase 65
			Glial antigens
				Aquaporin-4
				Myelin Oligodendrocyte Glycoprotein
				Glial Fibrillary Acidic Protein
	References
57 Hepatitis
	General Introduction
	Historical Aspects
	Epidemiology
	Clinical Features, Diagnostic Procedures, and Disease Associations
	Pathological Features
	Autoimmune Features
	Genetics
	Pathogenic Mechanisms
	Animal Models
	Treatment
		Standard Treatment
		Alternative Treatments
		Duration of Treatment
		Liver Transplantation
		Future Treatment Approaches
	Perspectives
	References
58 Primary Biliary Cholangitis
	Introduction
	Changing Nomenclature for Primary Biliary Cholangitis—From “Cirrhosis” to “Cholangitis”
	Epidemiology
	Etiology
		Antimitochondrial Autoantibody Epitopes
		CD4+ and CD8+ T-Cell Epitopes
		Why Biliary Epithelial Cells?—The “ABC” of Primary Biliary Cholangitis
		Genetic Predisposition
		Environmental Triggering Factors
	Animal Models of Primary Biliary Cholangitis
		Spontaneous Murine Models
		Xenobiotics-Triggered Murine Models
		Adenylate Uridine-Rich Element Del−/− Mice as a Novel Primary Biliary Cholangitis Model
	Diagnosis
		Serum Biochemistry and Imaging Studies
		Serological Testing
		Histopathology
	Treatment
		Ursodeoxycholic Acid
		Obeticholic Acid
		Fibrates
		Ileal Bile Acid Transporter Inhibitors
	Management of Symptoms and Extrahepatic Manifestations
		Fatigue
		Pruritus
	Disorders Associated With Primary Biliary Cholangitis
		Primary Biliary Cholangitis With Features With Autoimmune Hepatitis
		Sicca Syndrome
		Osteopenia and Osteoporosis
		Hyperlipidemia and Metabolic Syndrome
		Hepatocellular Carcinoma
	Stratification of the Risk for Progression
		Stratification at Baseline
		Stratification During Treatment
	Perspectives
	References
59 Autoimmune Pancreatitis and Immunoglobulin G4–Related Disease
	General Introduction
		Gateway From Autoimmune Pancreatitis to Immunoglobulin G4–Related Disease
	Historical Progression From Autoimmune Pancreatitis to Immunoglobulin G4–Related Disease
	Epidemiology
	Clinical Features and Disease Associations
		Autoimmune Pancreatitis
			Immunoglobulin G4–Related Pituitary and Stalk Lesions
			Immunoglobulin G4–Related Hypertrophic Pachymeningitis
			Immunoglobulin G4–Related Lacrimal and Salivary Gland Lesions
			Immunoglobulin G4–Related Ophthalmic Disease
			Immunoglobulin G4–Related Thyroid Disease
			Immunoglobulin G4–Related Lung Disease
			Immunoglobulin G4–Related Sclerosing Cholangitis
			Immunoglobulin G4–Related Liver Disease
			Immunoglobulin G4–Related Kidney Disease
			Immunoglobulin G4–Related Retroperitoneal Fibrosis
			Immunoglobulin G4–Related Periaortitis/Periarteritis
			Immunoglobulin G4–Related Prostate Disease
	Pathological Features
	Autoimmune Features
		Complement Activation System
		Innate Immunity
		Adaptive Immunity
			Autoantibodies
			Immunoglobulin G4
			Cellular Immunity
	Genetics
		Association Studies Using Polymorphic Markers in Candidate Genes
		Association Studies Using Genome-Wide Polymorphic Markers
	Animal Models
	Diagnostic Procedures
	Treatment
	Perspectives
	References
60 Autoimmune Bullous Skin Diseases: Pemphigus and Pemphigoid
	Introduction
	Pemphigus Vulgaris
		Clinical, Pathologic, and Epidemiologic Features
		Autoimmune Features
			Autoantibodies
			T-Cell Activation
		Genetic Features
		In Vivo and In Vitro Models
			In Vitro Models
			Autoantibody Passive Transfer Model
			Murine Models of Pemphigus Vulgaris
		Pathologic Effector Mechanisms
			Pathogenic Role of Autoantibodies
		Autoantibodies as Potential Immunologic Markers
	Pemphigus Foliaceus
		Clinical, Pathologic, and Epidemiologic features
		Autoimmune Features
			Autoantibodies
			T-Cell Activation
		Genetic Features
		In Vivo and In Vitro Models
		Pathologic Effector Mechanisms
		Autoantibodies as Potential Immunologic Markers
		Environmental Factors Involved in Fogo Selvagem
	Other Types of Pemphigus
		Paraneoplastic Pemphigus
		Drug-Induced Pemphigus
		IgA Pemphigus
	Bullous Pemphigoid
		Clinical, Pathologic, and Epidemiologic features
		Autoimmune Features
			Autoantibodies
			T-Cell Activation
		Genetic Features
		In Vivo and In Vitro Models
		Pathologic Effector Mechanisms
		Autoantibodies as Potential Immunologic Markers
	Other Subepidermal Bullous Diseases
		Herpes Gestationis (Pemphigoid Gestationis)
		Cicatricial Pemphigoid
		Linear IgA disease
		Epidermolysis Bullosa Acquisita
		Dermatitis Herpetiformis
	Treatment of Autoimmune Bullous Diseases
	Concluding Remarks
	References
61 Nonbullous Skin Diseases: Alopecia Areata, Vitiligo, Psoriasis, and Urticaria
	Alopecia Areata
		Clinical, Pathologic, and Epidemiologic Features
		Autoimmune Features
		Genetic Features
		In Vivo and In Vitro Models
		Pathologic Effector Mechanisms
		Autoantibodies as Potential Immunologic Markers
		Concluding Remarks—Future Prospects
	Vitiligo
		Clinical, Pathologic, and Epidemiologic Features
		Autoimmune Features
		Genetic Features
		In Vivo and In Vitro Models
		Pathogenetic Mechanism
		Autoantibodies as Potential Immunologic Markers
		Concluding Remarks—Future Prospects
	Psoriasis
		Clinical, Pathologic, and Epidemiologic Features
		Autoimmune Features
		Genetic Features
		In Vivo and In Vitro Models
			In Vivo Models
				Spontaneous Mouse Models
				Constructed Mouse Models
				Acute Models
				Genetically Engineered Mouse Models
				Xenograft Models (Nestle et al., 2009; Gudjonsson et al., 2007)
			In Vitro Models
			Pathogenic Mechanism
			Autoantibodies as Potential Immunologic Markers
		Concluding Remarks—Future Prospects
	Chronic Urticaria
		Clinical, Pathologic, and Epidemiologic Features
		Autoimmune Features
			Genetic Features
		In Vivo and In Vitro Models
		Pathologic Effector Mechanisms
		Autoantibodies as Potential Immunologic Markers
		Concluding Remarks—Future Prospects
	References
	Further Reading
62 Autoimmune Orchitis and Autoimmune Oophoritis
	Introduction
	Autoimmune Disease of the Testis
		Tolerance Mechanism for Testis Autoantigens
			The Landscape of Testicular Autoantigen Expression
			Systemic Tolerance to the Exposed Meiotic Germ-Cell Antigens
			Local Regulation in the Testis (Immune Privilege)
		Experimental Autoimmune Disease of the Testis
			Classical Experimental Autoimmune Orchitis Induced by Immunization with Testis Antigen in Adjuvant
			Autoimmune Orchitis in the Dark Mink
			Autoimmune Orchitis in Rats Expressing Transgenic Human HLA B27 and Human β2 Microglobulin
			Testis Antigen–Specific Tolerance Occurs in Vasectomized Mice and Concomitant Treg Depletion is Required for Postvasectomy ...
			Autoimmune Orchitis Associated With Bacterial and Viral Infections
		Clinical Autoimmune Disease of the Testis
			Idiopathic Male Infertility
			Infertility and Antisperm Antibodies Coexist With Other Autoimmune Diseases
			Antibody Response in Vasectomy and Cystic Fibrosis
			Orchitis Associated With Bacterial and Virus Infections
	Autoimmune Oophoritis
		Tolerance Mechanism for Ovary Autoantigens
		Experimental Autoimmune Ovarian Disease
			Spontaneous Autoimmune Ovarian Disease in the AIRE Null Mice
			Autoimmune Ovarian Disease in Day 3 Thymectomized (d3tx) Mice
			Autoimmune Ovarian Disease in Adult Mice Immunization with Zp3 Peptide (pZP3) with T- and B-Cell Epitopes in Adjuvant
			Neonatal AOD Induction Involves Innate and/or Adaptive Immune Responses Requiring the Neonatal NK Cell with Unique Pathogen...
			Clinical Autoimmune Disease of the Ovary
	Concluding Remarks
	Acknowledgments
	References
63 Rheumatic Fever and Rheumatic Heart Disease
	Clinical, Pathological, and Epidemiologic Features
	Autoimmune Features
	Genetic Features
		Innate Immune Response
			MBL2 Gene
			TLR-2 Gene
			Ficolin Gene
			FcγRIIA Gene
			Masp2 Gene
			MIF Gene
		Adaptive Immune Response
		Major Histocompatibility Complex: DRB1, DRB3, DQB1, DQA1 Genes
			CTLA4 Gene
		Both Innate and Adaptive Immune Response
	In Vivo and In Vitro Models
		In Vivo Model of Myocarditis and Valvulitis
		In Vitro Model of Rheumatic Heart Disease Autoimmune Reactions
	Pathologic Effector Mechanisms
	Autoantibodies as Potential Immunologic Markers
	Concluding Remarks—Future Prospects
	References
64 Myocarditis and Dilated Cardiomyopathy
	Historical Background
	Myocarditis—Clinical, Pathologic, and Epidemiologic Features
	Treatment
	Dilated Cardiomyopathy—Clinical, Pathologic, and Epidemiologic Features
	Treatment
	Autoimmune Features
	Genetic Features
	Animal Models
	Perspectives
	Acknowledgments
	References
	Further Reading
65 Necrotizing Arteritis and Small-Vessel Vasculitis
	Historical Background
		Necrotizing Arteritis
		Purpura and Small-Vessel Vasculitis
	Polyarteritis Nodosa
		Definition
		Epidemiology
		Clinical Features and Disease Association
		Pathological Features
		Pathogenesis
		Autoimmune Features
		Environmental Influences and Genetic Features
		Animal Models
		Diagnostic Procedures
		Treatment
	Kawasaki’s Disease
		Definition
		Epidemiology
		Clinical Features and Disease Associations
		Pathological Features
		Pathogenesis
		Autoimmune Features
		Genetic Features and Environmental Influences
		Animal Models
		Diagnostic Procedures
		Treatment
	Antineutrophil Cytoplasmic Autoantibody Vasculitis
		Definition
		Epidemiology
		Clinical Features and Disease Associations
		Pathological Features
		Pathogenesis
		Autoimmune Features
		Genetic Features and Environmental Influences
		Animal Models
		Diagnostic Procedures
		Treatment
	Cryoglobulinemic Vasculitis
		Definition
		Epidemiology
		Clinical Features and Disease Associations
		Pathological Features
		Pathogenesis
		Autoimmune Features
		Genetic Features and Environmental Influences
		Animal Models
		Diagnostic Procedures
		Treatment
	IgA Vasculitis (Henoch–Schönlein Purpura)
		Definition
		Epidemiology
		Clinical Features and Disease Associations
		Pathological Features
		Pathogenesis
		Autoimmune Features
		Genetic Features and Environmental Influences
		Animal Models
		Diagnostic Procedures
		Treatment
	Concluding Remarks—Future Prospects
	References
66 Large and Medium-Vessel Vasculitides
	Vasculitides of Large and Medium-Sized Blood Vessels
	Giant Cell Arteritis
		Historic Background
		Clinical, Pathologic, and Epidemiologic Features
		The Vascular Lesion
		Epidemiology
		Genetic Features
		Pathogenic Mechanisms
	T Cells and Antigen-Presenting Cells in Giant Cell Arteritis
	Macrophages in Giant Cell Arteritis
	Neoangiogenesis of Microvascular Networks and Intimal Hyperplasia
	Immuno-stromal Interactions in Vasculitis
	Extravascular Giant Cell Arteritis
		Treatment, Monitoring, and Outcome
	Takayasu’s Arteritis
		Historic Background
		Clinical, Pathologic, and Epidemiologic Features
		Genetic Features
		Pathogenic Mechanisms
		Treatment and Outcome
	Concluding Remarks—Future Perspectives
	Acknowledgment
	References
67 Idiopathic and Autoimmune Interstitial Lung Disease
	Introduction
	History
		Cryptogenic Organizing Pneumonia
		Idiopathic Pulmonary Fibrosis
	Clinical, Pathological and Epidemiological Features
		Cryptogenic Organizing Pneumonia
		Idiopathic Pulmonary Fibrosis
	Autoimmune Features
		Cryptogenic Organizing Pneumonia
		Idiopathic Pulmonary Fibrosis
	Genetic Features
		Cryptogenic Organizing Pneumonia
		Idiopathic Pulmonary Fibrosis
	In Vivo and In Vitro Models
		Cryptogenic Organizing Pneumonia
		Idiopathic Pulmonary Fibrosis
	Pathologic Effector Mechanisms
		Cryptogenic Organizing Pneumonia
		Idiopathic Pulmonary Fibrosis
	Treatment and Outcome
		Cryptogenic Organizing Pneumonia
		Idiopathic Pulmonary Fibrosis
			Corticosteroids
			Cytotoxic Agents
		Antifibrotic Agents
	Conclusions
	References
68 Autoimmune Diseases in the Kidney
	Introduction
	History
	Epidemiology
	Genetics
	Autoimmune Features
	Animal Models
	Pathological Features
	Autoimmune Responses (Allograft Rejection) in Kidney Transplantation
	Clinical Features and Disease Associations
	Summary
	References
69 Autoantibody Assays: Performance, Interpretation, and Standardization
	Introduction
	Spectrum of Autoantibodies
	Approaches to and Standardizing Autoantibody Testing
	Clinical Interpretation and Application of Autoantibody Testing
	Clinical Practice Guidelines
	Laboratory Reports, Electronic Medical Records, and Cost Analysis
	Standardization and Quality Assurance
	Summary
	References
70 Prevention of Autoimmune Disease: The Type 1 Diabetes Paradigm
	Overview of Type 1 Diabetes
		Autoimmune Pathology
		Nature and Nurture
	Prevention of Type 1 Diabetes
	Primary Prevention
		Diet and Gut Microbiome Modification
		Virus Vaccination
		Antigen-Specific Immunotherapy
	Secondary Prevention
		Mucosa-Mediated Antigen-Specific Tolerance
		Trials of Islet Autoantigen-Specific Vaccination in Humans
	Epilogue
	Acknowledgments
	References
	Further Reading
71 Treatment of Autoimmune Disease: Established Therapies
	Principles of Immune Suppression
	General Considerations
	Nonspecific Antiinflammatory Drugs
		Nonsteroidal Antiinflammatory Drugs
		Glucocorticoids
	Established Treatments of Rheumatic Diseases
		Antimalarials
		Sulfasalazine
		Leflunomide
		Methotrexate
		Cyclophosphamide
		Mycophenolate Mofetil (Cellcept)
		Azathioprine (Imuran)
		Calcineurin Inhibitors: Cyclosporin A, Tacrolimus, and Voclosporin
	Biologic Agents
		Cytokine-Targeted Therapies
		Tumor Necrosis Factor Inhibitors
		Tocilizumab (Anti-IL6R: Actemra)
		IL-1 Antagonists
		Secukinumab (Anti-IL17A: Cosentyx)
		Ustekinumab (Anti-p40 for IL-12 and IL-23 Signaling: Stelara)
		B-Cell-Targeted Therapies
		Rituximab (Rituxan)
		Belimumab (Anti-BLyS: Benlysta)
		T-Cell-Targeted Therapies
			Abatacept (CTLA4-Ig Blocks Second Signals: Orencia)
	Other Treatment Options
		Apremilast (Otezla)
		Tofacitinib (Inhibitor of Janus Kinase Activation Pathway: Xeljanz)
	Intravenous Immunoglobulin
	Comment Regarding Costs of Therapies: Biosimilars
	Moving Toward More Biological and Molecular Therapies
	References
72 Emerging Biological and Molecular Therapies in Autoimmune Disease
	Introduction
	Monoclonal Antibodies Used Clinically: Ways to Make Them More Efficient
		Engineering Fc Regions of Monoclonal Antibodies to Avoid Side Effects and Prolong Half-Life
		Engineering Variable Regions of Monoclonal Antibodies to Increase Affinity
		Engineering Variable Regions of Monoclonal Antibodies to Decrease Immunogenicity
	The Adequation of the Antibody Specificity to the Target Disease: From Immunosuppression to Immune Tolerance
		The Breakthrough in Rheumatoid Arthritis
		The Breakthrough in Multiple Sclerosis
		The Breakthrough in Autoimmune Diabetes
			CD3 Monoclonal Antibodies and Autoimmune Diabetes
		The Surprises and the Expectations of B Lymphocyte Targeting
	Bone-Marrow Transplantation
	Soluble Autoantigens
	Cell Therapy and Antigen Receptor Gene–Modified T Cells
		Cell Therapy Using Regulatory T Cells
		Cell Therapy Using Antigen Receptor Gene–Modified T Cells
	Perspectives and Conclusions
	References
73 Cameos: Candidates and Curiosities
	Introduction
	Autonomic Neuropathy
	Birdshot Retinopathy
	Cystitis, Interstitial
		Endometriosis
		Epilepsy
		Fatigue Syndrome
		Folate Deficiency
		Lichen Sclerosus
		Lymphocytic Mastitis
		Metabolic-Genetic Storage Diseases
		Movement Disorders
		Narcolepsy
		Osteoarthritis
		Parathyroid Disease
		Polychondritis, Relapsing
		Prostatitis
		Sarcoidosis
	References
Index