Current Concepts in Autoimmunity and Chronic Inflammation (eBook)

Preface 5
List of Contents 7
List of Contributors 9
B Cell Tolerance—How to Make It and How to Break It 10
1 Introduction 11
2 Repertoire Selections by the pre-B Cell Receptor 15
3 Generation of Immature, sIgM+ B Cells 16
4 Negative and Positive Selection, and Ignorance of the Developing Immature B Cell Repertoires 18
5 Negative Selection and Editing 19
6 Ignorance 21
7 Positive Selection 22
8 Peripheral B CellsWithout sIg Expression 23
9 Rescue of Autoreactive B Cells by T Cell-Independent Antigens of Type I, TLR– Ligand– Antigen- Complexes 24
10 Autoreaction Rescued by Ignorance 25
11 Breaking the Tolerance ofMature, Peripheral B Cell Repertoires 26
12 Consequences of Breaking B Cell Tolerance—Autoimmune Diseases 28
References 29
Breaking Ignorance: The Case of the Brain 34
1 Introduction 35
2 Brain Autoantigens in the Immune System 36
3 B Cell Ignorance? 39
4 Activation of Ignorant Autoreactive T Cells— The Transition from Autoreactive to Autoaggressive 41
5 Regulatory Suppression of Autoimmune T Cells— But How Do Suppressor T Cells Know? 47
6 Conclusion 53
References 54
Naturally Arising Foxp3-Expressing CD25+ CD4+ Regulatory T Cells in Self- Tolerance and Autoimmune Disease 60
1 Introduction 61
2 Self-Tolerance Maintained by Thymus-Produced Natural Treg: Induction of Autoimmune Disease by Their Manipulation at the Cellular and Molecular Level 62
3 IPEX as an Example of Human Autoimmune Disease Due to a Genetic Defect of Naturally Arising CD25+ CD4+ Treg: Its Implications for Immunologic Self- Tolerance and Autoimmune Disease in Humans 66
4 Contribution of Impaired Immunoregulation and Host Genetic Factors to the Development of Autoimmune Disease: A Possible Mechanism of Autoimmune Disease 67
5 Conclusion and Perspective 71
References 71
Sex Hormones and SLE: Influencing the Fate of Autoreactive B Cells 76
1 Introduction 77
2 Estrogen, Prolactin, and B Cell Fate in the R4A Model 83
3 Clinical Relevance 88
4 Conclusion 89
References 90
Innate (Over)immunity and Adaptive Autoimmune Disease 98
1 Introduction 98
2 Autoimmunity and/or Infection 99
3 Innate Regulators of Autoreactive T Cell Priming 102
4 Regulatory T Cells and Their Relation to Toll-Like Receptor Signals 104
5 Lack of (Auto)immunity After Innate Overactivation: A Role for Interferons and the Nervous System 105
6 Autoreactivity and Conversion to Autoimmune Disease 106
7 Conclusion 108
References 109
Can Unresolved Infection Precipitate Autoimmune Disease? 114
1 Introduction 115
2 Crohn’s Disease 116
3 Ankylosing Spondylitis and the Other Spondyloarthritides 121
4 Regulatory Mechanisms in Autoimmunity 124
References 127
The Systemic Autoinflammatory Diseases: Inborn Errors of the Innate Immune System 136
1 Introduction 137
2 Familial Mediterranean Fever 139
3 Syndrome of Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne 142
4 The Cryopyrinopathies: Familial Cold Autoinflammatory Syndrome, Muckle- Wells Syndrome, and Neonatal- Onset Multisystem Inflammatory Disease 144
5 Blau Syndrome 148
6 TNF Receptor-Associated Periodic Syndrome 150
7 Hyperimmunoglobulinemia D with Periodic Fever Syndrome 154
8 Concluding Remarks 157
References 158
Inefficient Clearance of Dying Cells and Autoreactivity 170
1 The Comeback of Dying Cells 171
2 Various Molecules Are Involved in the Clearance of Dying Cells 172
3 C-Reactive Protein and Dying Cells 173
4 Complement and DNase I Act as Back-up Molecules in the Clearance Process 174
5 Phosphatidylserine Exposure as One Early Membrane Change of Apoptotic Cells 174
6 Changes in the Glycoprotein Composition of Membranes of Apoptotic Cells 175
7 Impaired Clearance Functions and Autoimmunity 177
8 Heterogeneous and Intrinsic Clearance Defects in Some SLE Patients 179
9 Conclusion 180
References 180
The Importance of T Cell Interactions with Macrophages in Rheumatoid Cytokine Production 186
1 Introduction 187
2 Cognate-Dependent Interactions 189
3 Macrophage Lineage 193
4 Concluding Remarks 195
References 195
T Cell Activation as Starter and Motor of Rheumatic Inflammation 204
1 T Cell Development and T Cell Subsets 205
2 CD4 T Cells in Rheumatic Inflammation 208
3 The Th1/Th2 Dichotomy 209
4 Rheumatic Inflammation Is Driven by Activated Th1 Cells 211
5 T Cell-Directed Therapies 213
6 Conclusion 216
References 217
Signalling Pathways in B Cells: Implications for Autoimmunity 222
1 Introduction 223
2 Disturbed Homeostasis of Peripheral B Cells in Autoimmune Diseases 225
3 B Cellular Signal Transduction Pathways and Their Implications for Autoimmunity 227
4 Inhibitory Receptor Pathways and Autoimmunity 237
5 Activated B Cells May Bridge the Innate and Adaptive Immune System 239
6 Rationales of B Cell-Targeted Therapy in Autoimmune Diseases 240
References 243
Immunological Memory Stabilizing Autoreactivity 250
1 Mechanisms Contributing to Autoimmune Diseases 251
2 Immunological Memory and Chronic Autoimmune Diseases 252
3 Autoreactive Memory and Chronic Inflammation 258
References 260
Genetics of Autoimmune Diseases: AMultistep Process 268
1 Introduction 269
2 Definition of Autoimmune Disease: Physiology Versus Pathology 269
3 From Genes to Disease: The Basic Science Approach 271
4 FromDisease to Genes: The Monogenic Success and the Polygenic Failure 271
5 The Use of Animal Models in a Disease-to-Gene Approach 273
6 Positional Cloning of Ncf1, a Genetic Polymorphism Explaining aMajor Quantitative Trait Locus Controlling Chronic Inflammation 274
7 The Ncf1 Protein and the NADPH Complex 276
8 Pathway Analysis 277
9 Therapeutic Possibilities Can Be Immediately Explored 279
10 Analyses of a QTL Containing Interacting Genes 279
11 Conclusions 282
References 282
Subject Index 286