Molecular Basis of Multiple Sclerosis (eBook)

Molecular Basisof Multiple Sclerosis 2
Preface 4
Contents 5
Neuro-Immune Crosstalk in CNS Diseases 7
1 Introduction 7
2 Molecular Aspects of Neuro-Immune Crosstalk 8
2.1 Neurotrophic Factors 9
2.2 Cytokines 12
2.3 Chemokines 13
3 Functional Aspects of Neuro-Immune Crosstalk 14
4 Implications for Inflammatory CNS Disease 16
4.1 CNS Disease with Primary Inflammation 16
4.2 CNS Disease with Secondary Inflammation 18
5 Perspectives 19
References 20
Role of NK Cells and Invariant NKT Cells in Multiple Sclerosis 27
1 Introduction 27
2 NK Cells and MS 29
2.1 General Properties of NK Cells 29
2.2 NK Cell in MS 31
2.2.1 Protective Role of NK Cells in EAE 32
2.2.2 Ex Vivo Analysis Revealed an Alteration of NK cells in MS 33
3 iNKT Cells in MS 35
3.1 What Is iNKT Cell? 35
3.1.1 General Properties of Invariant NKT (iNKT) Cells 35
3.1.2 iNKT Cells and Their Ligands 36
3.2 Studies of iNKT Cells in MS 38
3.3 iNKT Cells as a Therapeutic Target in MS/EAE 39
4 MR1- Restricted Invariant T Cells in MS 41
5 Concluding Remarks 42
References 42
Potential Triggers of MS 48
1 Introduction 48
2 Viral Association with Demyelination 52
3 Torque Teno Virus and MS 53
4 Epstein–Barr Virus and MS 54
5 HHV-6 and MS 56
6 Basic Animal Model: Viral Persistence Within the CNS 57
7 Prime/Challenge Model: Acute Peripheral Infection 59
8 Conclusion 64
References 65
Prospects for Antigen-Specific Tolerance Based Therapies for the Treatment of Multiple Sclerosis 70
1 Introduction 70
2 Monoclonal Antibody Induced Tolerance 73
3 Antigen Specific Induced Tolerance Induction 74
3.1 Altered Peptide Ligand Induced Tolerance 74
3.2 Mucosal Tolerance 76
3.3 Soluble Peptide Tolerance 77
3.4 ECDI–Peptide-Coupled Cell Induced Tolerance 78
4 Conclusions 82
References 83
Immuno-Therapeutic Potential of Haematopoietic and Mesenchymal Stem Cell Transplantation in MS 89
1 Bone-Marrow-Derived Stem Cells 90
1.1 The Haematopoietic Niche 90
1.2 Haematopoietic Stem Cells and Their Properties 91
1.3 Identification of Mesenchymal Stem Cells and Their Role in Bone Marrow 92
2 Haematopoietic Stem Cell Transplantation as a Therapy for Autoimmune Disease 93
2.1 Autologous HSCT for MS: Clinical Results 93
2.2 Unraveling the Effects of Autologous HSCT on the Immune System 94
2.3 Immune Regeneration After HSCT 95
3. MSCs: Potential Role in Immunotherapy of MS 99
3.1 MSCs Effect on Immune cells 99
3.2 MSCs In vivo Effects in Preclinical Model of CNS Diseases 100
3.3 Clinical Applications of MSCs 101
4 Conclusions 102
References 103
Immune-Mediated CNS Damage 110
1 Introduction 110
2 Innate Immunity in Multiple Sclerosis 113
2.1 Microglia Activation 113
2.2 Microglial Pattern Recognition Receptors and Neurotoxicity 115
2.2.1 Toll-Like Receptors 116
2.2.2 NOD like Receptors and RNA Helicases 117
2.2.3 Triggering Receptors Expressed on Myeloid Cells 118
2.2.4 Scavenger Receptors 119
2.3 Macrophage Antigen Complex-1 Receptor and Other Microglial Integrin-Associated Receptor Complexes 120
2.4 Reactive Oxygen Species 121
3 Adaptive Immunity in Multiple Sclerosis 123
3.1 Antigen Presentation and Immune Cell Invasion 123
3.2 Cytotoxic CD8 + T Cells 125
4 Conclusion 127
References 128
B Cells and Antibodies in MS 134
1 Introduction 134
2 The Role of CSF B Cells in CNS Inflammation 135
3 The Role of B Cells in CNS Pathology 137
4 The Role of B Cells in MS: Therapeutic Studies 139
5 Specificity of the Antibody Response in MS 140
5.1 Intrathecal IgG Production and Ocbs 140
5.2 OCB and EBV Antigens 141
5.3 Anti-Myelin Antibodies 141
5.4 Anti-aquaporin-4 Antibody 143
6 Outlook 144
References 144
Immunological Basis for the Developmentof Tissue Inflammation and Organ-SpecificAutoimmunity in Animal Modelsof Multiple Sclerosis 149
1 Introduction 149
2 Experimental Autoimmune Encephalomyelitis as a Model for MS 150
3 Experimental Autoimmune Encephalomyelitis: Historical Perspective 154
4 Th1 Cells 155
5 Th17 Cells 157
5.1 Reciprocity between Th17 Cells and Induced T-Regs 159
5.2 How are Th17 Cells Generated In Vivo? 159
5.3 What are the Effector Functions of Th17 Cells? 161
5.4 How Does the Discovery of Th17 Cellsin Mice Translate to Humans? 162
6 Regulation of T Cell-Mediated Autoimmunity by T-Regs 163
7 Regulatory Cytokines 165
8 B Cells 165
8.1 Role of Antibodies 167
8.2 B Cells as APCs 167
9 Concluding Remarks 168
References 169
Cooperation of B Cells and T Cells in the Pathogenesis of Multiple Sclerosis 181
1 The Role of B Cells in Multiple Sclerosis: Effects on T Cells 181
1.1 B Cells as the Source for Antibody-Secreting Plasma Cells 182
1.2 B Cells as Antigen Presenting Cells for Activation of T Cells 183
1.3 B Cells as Therapeutic Target in Multiple Sclerosis: Abrogation of T Cell Activation? 185
1.4 B Cells with Immunomodulatory Properties 186
2 T Cells Regulate B Cell Immunity 187
2.1 Antigen-Specific B Cell Activation Requires T Helper Cells 187
2.2 Polarized T Helper Cells Facilitate Isotype Switching 188
2.3 T Cells Participate in the Formation of Germinal Centers 188
References 189
Antigen Processing and Presentation in Multiple Sclerosis 193
1 Introduction 193
2 Autoantigens 194
2.1 Myelin Basic Protein 195
2.2 Myelin Oligodendrocyte Protein 195
2.3 Proteolipid Protein 196
2.4 Posttranslational Modifications 196
3 MHC Molecules 198
4 Generation of T Cell Epitopes 199
4.1 Destruction Versus Creation of Epitopes by the Processing Machinery 200
5 Antigen Processing and Presentation in Multiple Sclerosis 202
5.1 T Cell Selection in the Thymus 202
5.2 MBP Processing and Presentation in the Periphery 204
5.2.1 Dendritic Cells 206
5.2.2 B Cells 206
5.3 Processing and Presentation in the Brain 207
5.3.1 Macrophages/Microglia 207
5.3.2 Dendritic Cells 208
6 Future Trends and Therapies 208
7 Conclusion 209
References 209
Examination of the Role of MRI in Multiple Sclerosis: A Problem Orientated Approach 217
1 Measuring Acute Disease Using MRI 217
2 Evidence for Lesion Heterogeneity 219
3 Involvement of NAWM 221
4 Involvement of Gray Matter 222
5 Use of MRI to Monitor Clinical Trials 223
5.1 Phase I Studies 224
5.2 Phase IIa Studies (Proof-of-Principle) 224
5.3 Phase III Studies 226
6 Use of Imaging in the Diagnosis of MS 226
7 Use of Imaging for Patient Management 227
8 Conclusions 228
References 229
Multiple Sclerosis Therapies: Molecular Mechanisms and Future 232
1 Introduction 232
1.1 Multiple Sclerosis as an Immune-Mediated Disease 232
1.2 Molecular Mechanisms of MS Immunopathogenesis 233
1.3 Emerging Molecular Targets for MS Therapeutics 236
2 Promising Molecular Target-Based MS Therapies 238
2.1 Oral Therapies 238
2.1.1 FTY720 238
2.2 Teriflunomide 240
2.2.1 BG-12 241
2.2.2 Laquinimod 242
2.2.3 Cladribine 244
2.3 Monoclonal Antibodies 246
2.3.1 Rituximab 246
2.3.2 Daclizumab 247
2.3.3 Alemtuzumab 248
3 Antigen-Specific Therapies 250
3.1 MBP8298 250
3.1.1 BHT-3009 251
4 Conclusions 252
References 253
T-Cells in Multiple Sclerosis 259
1 Background 259
2 Immunopathophysiology of MS 260
3 Autoreactive T-Cells in MS 262
4 Costimulation 262
4.1 The B7/CD28/CTLA-4 Axis 263
4.2 Other Costimulatory Pathways 264
4.3 Costimulation as a Therapeutic Target 264
5 T-Cell Polarization 265
5.1 Th1/Th2/Th17 Cells 265
5.2 Characterization of Th17 Cells 266
5.3 Th1 Cells in MS 267
5.4 IL-17 and Th17 Cells in Multiple Sclerosis 267
5.5 Th1 Versus Th17 267
5.6 Th1 Versus Th17 in EAE 268
5.7 Th1 Versus Th17 in MS 268
6 FoxP3+ Regulatory T-Cells 269
6.1 Cell Surface Characterization of Human Tregs 269
6.2 Strength of Signal and Human Treg Suppression 270
6.3 Treg Frequency in Patients with MS 271
6.4 Impaired Treg Function in Patients with MS 271
6.5 CD62L Expression on CD4+CD25hi Regulatory T-Cells 272
7 Tr1 Regulatory T-Cells 272
7.1 Tr1 Cells in MS 273
8 Regulatory T-Cells and Th17 Cells 274
9 T-Cell–CNS Interactions 275
9.1 Intrinsic Inflammatory Cells of the CNS 275
9.2 A Model of Reciprocal T-Cell-CNS Interactions: TIM-3 275
10 Conclusion 276
References 276
The Genetics of Multiple Sclerosis 283
1 Genetic Epidemiology 284
2 MS as a Homogeneous Entity 284
3 A Short History of MS Genetics (Including Methodology Outline) 285
4 HLA Complex Genes in MS 286
4.1 HLA on Disease Characteristics 290
5 The Candidate Gene and Linkage Screen Approaches in MS Genetics 291
6 The Interleukin Receptor Gene (IL7R) 292
7 The New MS Genes: Identification Through Genome Wide Association Screen 292
7.1 Genetic Control of Disease Characteristics in MS 295
7.2 Coinheritance with Other Autoimmune Diseases 296
7.3 Discussion 296
References 297
Index 302