Epigenetics of Autoimmune Diseases (eBook)

MONCEF ZOUALI, Institut National de la Recherche et de la Santé Médicale (INSERM), France.

The Epigenetics of Autoimmune Diseases 1
Contents 7
Preface 15
Contributors 19
PART I Transcription Factors: Partners of Immune Tolerance to Self 25
1 Transcriptional regulation of T cell tolerance 27
1.1 Introduction 27
1.2 T cell anergy 28
1.3 Ca2+/calcineurin/NFAT signalling in T cell anergy 29
1.4 Transcriptional programme of T cell anergy 31
1.5 Transcriptional repression in T cell anergy: epigenetic modification of the Il2 promoter 34
1.6 Regulatory T cells 36
1.7 Transcriptional control of Treg development and function 36
References 39
2 Epigenetic regulation of Foxp3 expression in regulatory T cells 45
2.1 Introduction 45
2.2 Naturally occurring CD25+ CD4+ Tregs 46
2.3 The transcription factor FOXP3: determining Treg function and identity 49
2.4 Molecular regulation of FOXP3 50
2.5 Tregs as a stable lineage: indications of epigenetic imprinting 52
2.6 Induced Tregs: stable suppressors or transient immuno-modulators? 54
2.7 Conclusions 56
References 57
3 The role of NF-kB in central tolerance 63
3.1 Introduction 63
3.2 Canonical and alternative NF-kB pathways 64
3.3 Thymic stroma and central tolerance 67
3.4 NF-kB and regulatory T cell development 71
3.5 NF-kB and thymocyte positive and negative selection 72
3.6 Conclusions and perspectives 74
3.7 Acknowledgement 74
References 74
4 The role of Act1 in the control of autoimmunity 79
4.1 Introduction 79
4.2 Autoimmunity and autoimmune mouse models 80
4.3 Molecular mechanisms of autoimmunity 82
4.4 Act1: a modulator of autoimmunity 84
4.5 Conclusions 94
References 95
5 Regulation of T cell anergy and escape from regulatory T cell suppression by Cbl-b 99
5.1 Introduction 99
5.2 Mechanisms of T cell tolerance induction 99
5.3 Molecular establishment of T cell anergy 102
5.4 Ubiquitin E3 ligases in T cell tolerance 103
5.5 Molecular function and regulation of Cbl-b 104
5.6 Physiological relevance of Cbl-b 107
5.7 The role of Cbl-b in T cell tolerance 108
5.8 Deregulation of Cbl-b in disease 110
5.9 Therapeutic potential of Cbl-b in tumour immunity 110
5.10 Implications for autoimmune disease 112
References 112
6 Indoleamine 2,3-dioxygenase: transcriptional regulation and autoimmunity 119
6.1 Introduction 119
6.2 L-Trp degradation along the kynurenine pathway and immune functions of IDO 120
6.3 IDO immunobiology and therapeutic intervention 125
6.4 Transcriptional regulation of the IDO-encoding gene 125
6.5 Impaired IDO activity and loss of tolerance in autoimmune diseases 131
6.6 IDO-based therapies for autoimmune disease 133
6.7 Acknowledgement 134
References 135
PART II Stress Responses that Break Immune Silence 141
7 Chromatin modifications, oxidative stress and nucleosome autoantibodies 143
7.1 Introduction 143
7.2 Nucleosome and SLE 144
7.3 Epigenetics and SLE 147
7.4 Oxidative stress in SLE: definition and mechanisms 148
7.5 Oxidative stress, epigenetic alterations and nucleosome immunogenicity 151
7.6 Conclusion 153
7.7 Acknowledgements 153
References 154
8 Stress, epigenetics and thyroid autoimmunity 159
8.1 Introduction 159
8.2 The Th1/Th2 balance in immune-response regulation 160
8.3 Stress hormones and the Th1/Th2 balance 160
8.4 The Th1/Th2 balance in thyroid autoimmunity 162
8.5 Association of stress with thyroid autoimmunity 164
8.6 Stress in the clinical expression of thyroid autoimmunity: a unifying hypothesis 167
8.7 Epigenetic regulation of T cell differentiation and stress hormones 169
8.8 Conclusions 170
References 170
9 Reactive intermediates, inflammation and epigenetics in lupus 175
9.1 Introduction 175
9.2 Biology of reactive intermediates 175
9.3 RNIs in murine models of lupus 179
9.4 Genetic associations of RNI/ROI and lupus 183
9.5 Conclusions 184
References 184
10 Post-translational modification of HMGB1 and its role in immune activation 189
10.1 Introduction 189
10.2 Molecular biology of HMGB1 190
10.3 HMGB1 as an immune mediator 191
10.4 Mechanisms of HMGB1 modification and release 193
10.5 The role of HMGB1 as a mediator of disease and target of therapy 196
10.6 Conclusion 198
References 198
11 Idiosyncratic drug-induced liver injury: facts and perspectives 203
11.1 Introduction 203
11.2 Intrinsic drug toxicity to the liver 203
11.3 Idiosyncratic drug toxicity to the liver 204
11.4 Mechanisms of hypersensitivity reactions to drugs in the liver 206
11.5 Hypersensitivity versus tolerance 211
11.6 Hepatocyte injury as a consequence of allergic hepatitis 216
11.7 Drug-induced liver autoimmunity 218
11.8 Epigenetics of drug-induced liver injury 221
11.9 Acknowledgements 223
References 223
PART III Epigenetic Modifiers of Autoimmunity 231
12 Epigenetic modifications associated with T cell tolerance 233
12.1 Immunity versus tolerance 233
12.2 Epigenetic regulation of the physical structure of genomic DNA 233
12.3 Epigenetic control of pro-inflammatory cytokine gene transcription 235
12.4 Epigenetic silencing of cytokine genes in tolerant T cells 237
12.5 Targeting epigenetic modifications to cytokine genes in tolerant T cells 241
12.6 Common mechanisms of epigenetic silencing among distinct types of tolerant T cells? 244
References 244
13 DNA methylation alterations in systemic lupus erythematosus 253
13.1 Introduction 253
13.2 DNA methylation: an epigenetic determinant of lymphocyte function 257
13.3 DNA methylation changes in lupus 259
13.4 Epigenetic regulation as a therapeutic target 264
13.5 Future aims for epigenetic research into lupus 265
13.6 Acknowledgements 266
References 266
14 Long-range histone acetylation patterns in the development of autoimmunity 271
14.1 Introduction 271
14.2 The histone code hypothesis 271
14.3 Epigenetic defects as a mechanism of disease 273
14.4 Analysis of the histone code 274
14.5 Long-range histone acetylation patterns in Th cell differentiation 275
14.6 Long-range histone acetylation and autoimmunity 277
14.7 Perspectives 280
14.8 Acknowledgements 281
References 281
15 Roquin defects reveal a role for the microRNA machinery in regulating autoimmunity 285
15.1 Introduction 285
15.2 RNA silencing through the miRNA machinery 286
15.3 miRNAs regulate lymphoid cell development and immune responses 287
15.4 miRNAs as single drivers of immunodeficiency or inflammation 288
15.5 miRNAs regulate autoimmunity 289
15.6 Roquin regulates miRNA-mediated silencing of T cells and represses lupus 290
15.7 Concluding remarks 296
15.8 Acknowledgements 297
References 298
16 Autoimmune response to post-translationallymodified (citrullinated) proteins: prime suspect in the pathophysiology of rheumatoid arthritis 303
16.1 Introduction 303
16.2 RA is associated with B cell autoreactivity to citrullinated proteins 304
16.3 Both ACPA and citrullinated antigenic targets are present in the RA synovium 308
16.4 Autoreactivity to citrullinated proteins probably plays a role in RA synovitis 309
16.5 The way ACPA could promote joint inflammation 310
16.6 Joint-expressed citrullinated autoantigen targets possibly involved in a pro-inflammatory effect of ACPA 311
16.7 Initial triggering of the autoimmune response to citrullinated proteins 315
16.8 Goals for future research 321
16.9 Acknowledgements 322
References 322
17 Hormones: epigenetic contributors to gender-biased autoimmunity 333
17.1 Introduction 333
17.2 Oestrogen receptors 333
17.3 Oestrogen and autoimmunity 334
17.4 Foxp3 and ERs 336
17.5 ERs and histone modifications 337
17.6 The histone code 337
17.7 Co-activators 338
17.8 Pioneer factors 338
17.9 Co-repressors 339
17.10 ERs and cell proliferation 339
17.11 Epigenetic changes in disease 339
17.12 ERs and SLE 340
17.13 Co-activators and phosphorylation 341
17.14 Endocrine disruptors 342
17.15 Perspectives and future directions 342
17.16 Acknowledgements 344
References 345
18 Epigenetics and systemic sclerosis 351
18.1 Introduction 351
18.2 Vascular alterations in SSc 352
18.3 Tissue hypoxia, oxidative stress and SSc 353
18.4 Respiratory burst and post-translational modifications in SSc 354
18.5 The epigenome and its environmental reprogramming 355
18.6 Epigenetics and SSc 356
18.7 Conclusions 358
References 359
19 Epigenetic regulation of B lymphocyte development and repertoire selection: relevance to autoimmunity 363
19.1 Introduction 363
19.2 Initiation of B cell fate choice 364
19.3 Checkpoints of B cell tolerance to self 364
19.4 Negative regulation of immunoglobulin gene joining 366
19.5 B cell fate commitment and immunoglobulin gene accessibility 367
19.6 Changes in chromatin structure during B cell development 368
19.7 Epigenetic changes through association of different immunoglobulin loci 370
19.8 Epigenetic factors that allow full utilization of the immunoglobulin repertoire 371
19.9 Multistep regulation of B cell maturation 372
19.10 Altered B cell functions in systemic autoimmunity 373
19.11 Impaired B cell tolerance to self in systemic autoimmunity 374
19.12 Epigenetic factors underlying impaired B cell tolerance 375
19.13 Future prospects 376
19.14 Acknowledgement 377
References 377
PART IV Towards Novel Epigenetic-Based Immuno-Intervention Strategies in Autoimmune Disease 381
20 Protective effects of epigenetic modifications in experimental inflammatory bowel disease 383
20.1 Introduction 383
20.2 Mechanisms of protein acetylation and deacetylation 384
20.3 Anti-inflammatory effect of epigenetic modifications in vitro 386
20.4 Impact of HDAC inhibition in models of experimental colitis 389
20.5 Perspectives 392
References 393
21 Epigenetic regulation of autoimmune diseases through deacetylase inhibition 397
21.1 Introduction 397
21.2 Regulatory T cells 398
21.3 Epigenetic regulation of FOXP3 expression 399
21.4 FOXP3 acetylation and function 399
21.5 Protein lysine deacetylation 400
21.6 HDAC inhibitors in autoimmune disease 401
21.7 Dietary butyrate promotes lysine acetylation by inhibiting deacetylases 402
21.8 The HDAC inhibitor butyrate affects TGF-? signalling and increases Smad3 levels 402
21.9 HDAC inhibitors affect immune-cell proliferation and conversion of antigen triggered T cells into an unresponsive state 402
21.10 Conclusions 403
References 404
22 Histone deacetylases and autoimmunity 409
22.1 Introduction 409
22.2 Chromatin acetylation and deacetylation 409
22.3 Histone deacetylases and histone acetyltransferases 410
22.4 Histone acetylation, deacetylation and transcription factors in autoimmunity 413
22.5 Acetylation state and lymphocyte functions 416
22.6 HDACs and their inhibition in autoimmune disease 417
22.7 Conclusions 422
22.8 Acknowledgements 422
References 422
23 Histone deacetylase inhibitors as a therapeutic modality in multiple sclerosis 427
23.1 Introduction 427
23.2 Linking the histone code with MS 428
23.3 Neuronal traits are modulated by HDAC transcription-factor complexes 429
23.4 Motor neurone genes modulated by HDACs 430
23.5 The transcription factor E2F1, HDACs and neuronal survival mechanisms 430
23.6 HDACs play important roles in stem cell neuronal differentiation 431
23.7 HDIs lead to acetylation of the Sp1 transcription factor 431
23.8 Immune-system effects of HDIs 432
23.9 HDACs and pro-inflammatory and stress-related pathways in immune settings 435
23.10 HATs, HDACs and the NF-kB pathway 435
23.11 HATs, HDACs and ER stress 438
23.12 Clinical trials and caveats of HDIs 439
23.13 Do HDIs target genes or help chaperone activity as their primary response? 441
23.14 Future directions 442
References 443
Index 457