Martin / Lutterotti Molecular Basis of Multiple Sclerosis

The Immune System
1. Auflage 2010
ISBN: 978-3-642-14153-9
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 51, 308 Seiten

Reihe: Results and Problems in Cell Differentiation

Despite major efforts by the scientific community over the years, our understanding of the pathogenesis or the mechanisms of injury of multiple sclerosis is still limited. Consequently, the current strategies for treatment and management of patients are limited in their efficacy. The mechanisms of tissue protection and repair are probably even less understood. One reason for these limitations is the enormous complexity of the disease and every facet of its pathogenesis, the mechanisms of tissue injury, the diagnostic procedures and finally the efficacy of treatments and their side effects. The aim of this book is to review the most recent advances made in this highly complex field.

Autoren/Hrsg.

Lutterotti, Andreas

Martin, Roland

Inhaltsverzeichnis

1;Molecular Basisof Multiple Sclerosis;2
1.1;Preface;4
1.2;Contents;5
2;Neuro-Immune Crosstalk in CNS Diseases;7
2.1;1 Introduction;7
2.2;2 Molecular Aspects of Neuro-Immune Crosstalk;8
2.2.1;2.1 Neurotrophic Factors;9
2.2.2;2.2 Cytokines;12
2.2.3;2.3 Chemokines;13
2.3;3 Functional Aspects of Neuro-Immune Crosstalk;14
2.4;4 Implications for Inflammatory CNS Disease;16
2.4.1;4.1 CNS Disease with Primary Inflammation;16
2.4.2;4.2 CNS Disease with Secondary Inflammation;18
2.5;5 Perspectives;19
2.6;References;20
3;Role of NK Cells and Invariant NKT Cells in Multiple Sclerosis;27
3.1;1 Introduction;27
3.2;2 NK Cells and MS;29
3.2.1;2.1 General Properties of NK Cells;29
3.2.2;2.2 NK Cell in MS;31
3.2.2.1;2.2.1 Protective Role of NK Cells in EAE;32
3.2.2.2;2.2.2 Ex Vivo Analysis Revealed an Alteration of NK cells in MS;33
3.3;3 iNKT Cells in MS;35
3.3.1;3.1 What Is iNKT Cell?;35
3.3.1.1;3.1.1 General Properties of Invariant NKT (iNKT) Cells;35
3.3.1.2;3.1.2 iNKT Cells and Their Ligands;36
3.3.2;3.2 Studies of iNKT Cells in MS;38
3.3.3;3.3 iNKT Cells as a Therapeutic Target in MS/EAE;39
3.4;4 MR1- Restricted Invariant T Cells in MS;41
3.5;5 Concluding Remarks;42
3.6;References;42
4;Potential Triggers of MS;48
4.1;1 Introduction;48
4.2;2 Viral Association with Demyelination;52
4.3;3 Torque Teno Virus and MS;53
4.4;4 Epstein–Barr Virus and MS;54
4.5;5 HHV-6 and MS;56
4.6;6 Basic Animal Model: Viral Persistence Within the CNS;57
4.7;7 Prime/Challenge Model: Acute Peripheral Infection;59
4.8;8 Conclusion;64
4.9;References;65
5;Prospects for Antigen-Specific Tolerance Based Therapies for the Treatment of Multiple Sclerosis;70
5.1;1 Introduction;70
5.2;2 Monoclonal Antibody Induced Tolerance;73
5.3;3 Antigen Specific Induced Tolerance Induction;74
5.3.1;3.1 Altered Peptide Ligand Induced Tolerance;74
5.3.2;3.2 Mucosal Tolerance;76
5.3.3;3.3 Soluble Peptide Tolerance;77
5.3.4;3.4 ECDI–Peptide-Coupled Cell Induced Tolerance;78
5.4;4 Conclusions;82
5.5;References;83
6;Immuno-Therapeutic Potential of Haematopoietic and Mesenchymal Stem Cell Transplantation in MS;89
6.1;1 Bone-Marrow-Derived Stem Cells;90
6.1.1;1.1 The Haematopoietic Niche;90
6.1.2;1.2 Haematopoietic Stem Cells and Their Properties;91
6.1.3;1.3 Identification of Mesenchymal Stem Cells and Their Role in Bone Marrow;92
6.2;2 Haematopoietic Stem Cell Transplantation as a Therapy for Autoimmune Disease;93
6.2.1;2.1 Autologous HSCT for MS: Clinical Results;93
6.2.2;2.2 Unraveling the Effects of Autologous HSCT on the Immune System;94
6.2.3;2.3 Immune Regeneration After HSCT;95
6.3;3. MSCs: Potential Role in Immunotherapy of MS;99
6.3.1;3.1 MSCs Effect on Immune cells;99
6.3.2;3.2 MSCs In vivo Effects in Preclinical Model of CNS Diseases;100
6.3.3;3.3 Clinical Applications of MSCs;101
6.4;4 Conclusions;102
6.5;References;103
7;Immune-Mediated CNS Damage;110
7.1;1 Introduction;110
7.2;2 Innate Immunity in Multiple Sclerosis;113
7.2.1;2.1 Microglia Activation;113
7.2.2;2.2 Microglial Pattern Recognition Receptors and Neurotoxicity;115
7.2.2.1;2.2.1 Toll-Like Receptors;116
7.2.2.2;2.2.2 NOD like Receptors and RNA Helicases;117
7.2.2.3;2.2.3 Triggering Receptors Expressed on Myeloid Cells;118
7.2.2.4;2.2.4 Scavenger Receptors;119
7.2.3;2.3 Macrophage Antigen Complex-1 Receptor and Other Microglial Integrin-Associated Receptor Complexes;120
7.2.4;2.4 Reactive Oxygen Species;121
7.3;3 Adaptive Immunity in Multiple Sclerosis;123
7.3.1;3.1 Antigen Presentation and Immune Cell Invasion;123
7.3.2;3.2 Cytotoxic CD8 + T Cells;125
7.4;4 Conclusion;127
7.5;References;128
8;B Cells and Antibodies in MS;134
8.1;1 Introduction;134
8.2;2 The Role of CSF B Cells in CNS Inflammation;135
8.3;3 The Role of B Cells in CNS Pathology;137
8.4;4 The Role of B Cells in MS: Therapeutic Studies;139
8.5;5 Specificity of the Antibody Response in MS;140
8.5.1;5.1 Intrathecal IgG Production and Ocbs;140
8.5.2;5.2 OCB and EBV Antigens;141
8.5.3;5.3 Anti-Myelin Antibodies;141
8.5.4;5.4 Anti-aquaporin-4 Antibody;143
8.6;6 Outlook;144
8.7;References;144
9;Immunological Basis for the Developmentof Tissue Inflammation and Organ-SpecificAutoimmunity in Animal Modelsof Multiple Sclerosis;149
9.1;1 Introduction;149
9.2;2 Experimental Autoimmune Encephalomyelitis as a Model for MS;150
9.3;3 Experimental Autoimmune Encephalomyelitis: Historical Perspective;154
9.4;4 Th1 Cells;155
9.5;5 Th17 Cells;157
9.5.1;5.1 Reciprocity between Th17 Cells and Induced T-Regs;159
9.5.1.1;5.2 How are Th17 Cells Generated In Vivo?;159
9.5.1.2;5.3 What are the Effector Functions of Th17 Cells?;161
9.5.1.3;5.4 How Does the Discovery of Th17 Cellsin Mice Translate to Humans?;162
9.6;6 Regulation of T Cell-Mediated Autoimmunity by T-Regs;163
9.7;7 Regulatory Cytokines;165
9.8;8 B Cells;165
9.9;8.1 Role of Antibodies;167
9.10;8.2 B Cells as APCs;167
9.11;9 Concluding Remarks;168
9.12;References;169
10;Cooperation of B Cells and T Cells in the Pathogenesis of Multiple Sclerosis;181
10.1;1 The Role of B Cells in Multiple Sclerosis: Effects on T Cells;181
10.1.1;1.1 B Cells as the Source for Antibody-Secreting Plasma Cells;182
10.1.2;1.2 B Cells as Antigen Presenting Cells for Activation of T Cells;183
10.1.3;1.3 B Cells as Therapeutic Target in Multiple Sclerosis: Abrogation of T Cell Activation?;185
10.1.4;1.4 B Cells with Immunomodulatory Properties;186
10.2;2 T Cells Regulate B Cell Immunity;187
10.2.1;2.1 Antigen-Specific B Cell Activation Requires T Helper Cells;187
10.2.2;2.2 Polarized T Helper Cells Facilitate Isotype Switching;188
10.2.3;2.3 T Cells Participate in the Formation of Germinal Centers;188
10.3;References;189
11;Antigen Processing and Presentation in Multiple Sclerosis;193
11.1;1 Introduction;193
11.2;2 Autoantigens;194
11.2.1;2.1 Myelin Basic Protein;195
11.2.2;2.2 Myelin Oligodendrocyte Protein;195
11.2.3;2.3 Proteolipid Protein;196
11.2.4;2.4 Posttranslational Modifications;196
11.3;3 MHC Molecules;198
11.4;4 Generation of T Cell Epitopes;199
11.4.1;4.1 Destruction Versus Creation of Epitopes by the Processing Machinery;200
11.5;5 Antigen Processing and Presentation in Multiple Sclerosis;202
11.5.1;5.1 T Cell Selection in the Thymus;202
11.5.2;5.2 MBP Processing and Presentation in the Periphery;204
11.5.2.1;5.2.1 Dendritic Cells;206
11.5.2.2;5.2.2 B Cells;206
11.5.3;5.3 Processing and Presentation in the Brain;207
11.5.3.1;5.3.1 Macrophages/Microglia;207
11.5.3.2;5.3.2 Dendritic Cells;208
11.6;6 Future Trends and Therapies;208
11.7;7 Conclusion;209
11.8;References;209
12;Examination of the Role of MRI in Multiple Sclerosis: A Problem Orientated Approach;217
12.1;1 Measuring Acute Disease Using MRI;217
12.2;2 Evidence for Lesion Heterogeneity;219
12.3;3 Involvement of NAWM;221
12.4;4 Involvement of Gray Matter;222
12.5;5 Use of MRI to Monitor Clinical Trials;223
12.5.1;5.1 Phase I Studies;224
12.5.2;5.2 Phase IIa Studies (Proof-of-Principle);224
12.5.3;5.3 Phase III Studies;226
12.6;6 Use of Imaging in the Diagnosis of MS;226
12.7;7 Use of Imaging for Patient Management;227
12.8;8 Conclusions;228
12.9;References;229
13;Multiple Sclerosis Therapies: Molecular Mechanisms and Future;232
13.1;1 Introduction;232
13.1.1;1.1 Multiple Sclerosis as an Immune-Mediated Disease;232
13.1.2;1.2 Molecular Mechanisms of MS Immunopathogenesis;233
13.1.3;1.3 Emerging Molecular Targets for MS Therapeutics;236
13.2;2 Promising Molecular Target-Based MS Therapies;238
13.2.1;2.1 Oral Therapies;238
13.2.1.1;2.1.1 FTY720;238
13.2.2;2.2 Teriflunomide;240
13.2.2.1;2.2.1 BG-12;241
13.2.2.2;2.2.2 Laquinimod;242
13.2.2.3;2.2.3 Cladribine;244
13.2.3;2.3 Monoclonal Antibodies;246
13.2.3.1;2.3.1 Rituximab;246
13.2.3.2;2.3.2 Daclizumab;247
13.2.3.3;2.3.3 Alemtuzumab;248
13.3;3 Antigen-Specific Therapies;250
13.3.1;3.1 MBP8298;250
13.3.1.1;3.1.1 BHT-3009;251
13.4;4 Conclusions;252
13.5;References;253
14;T-Cells in Multiple Sclerosis;259
14.1;1 Background;259
14.2;2 Immunopathophysiology of MS;260
14.3;3 Autoreactive T-Cells in MS;262
14.4;4 Costimulation;262
14.4.1;4.1 The B7/CD28/CTLA-4 Axis;263
14.4.2;4.2 Other Costimulatory Pathways;264
14.4.3;4.3 Costimulation as a Therapeutic Target;264
14.5;5 T-Cell Polarization;265
14.5.1;5.1 Th1/Th2/Th17 Cells;265
14.5.2;5.2 Characterization of Th17 Cells;266
14.5.3;5.3 Th1 Cells in MS;267
14.5.4;5.4 IL-17 and Th17 Cells in Multiple Sclerosis;267
14.5.5;5.5 Th1 Versus Th17;267
14.5.6;5.6 Th1 Versus Th17 in EAE;268
14.5.7;5.7 Th1 Versus Th17 in MS;268
14.6;6 FoxP3+ Regulatory T-Cells;269
14.6.1;6.1 Cell Surface Characterization of Human Tregs;269
14.6.2;6.2 Strength of Signal and Human Treg Suppression;270
14.6.3;6.3 Treg Frequency in Patients with MS;271
14.6.4;6.4 Impaired Treg Function in Patients with MS;271
14.6.5;6.5 CD62L Expression on CD4+CD25hi Regulatory T-Cells;272
14.7;7 Tr1 Regulatory T-Cells;272
14.7.1;7.1 Tr1 Cells in MS;273
14.8;8 Regulatory T-Cells and Th17 Cells;274
14.9;9 T-Cell–CNS Interactions;275
14.9.1;9.1 Intrinsic Inflammatory Cells of the CNS;275
14.9.2;9.2 A Model of Reciprocal T-Cell-CNS Interactions: TIM-3;275
14.10;10 Conclusion;276
14.11;References;276
15;The Genetics of Multiple Sclerosis;283
15.1;1 Genetic Epidemiology;284
15.2;2 MS as a Homogeneous Entity;284
15.3;3 A Short History of MS Genetics (Including Methodology Outline);285
15.4;4 HLA Complex Genes in MS;286
15.4.1;4.1 HLA on Disease Characteristics;290
15.5;5 The Candidate Gene and Linkage Screen Approaches in MS Genetics;291
15.6;6 The Interleukin Receptor Gene (IL7R);292
15.7;7 The New MS Genes: Identification Through Genome Wide Association Screen;292
15.7.1;7.1 Genetic Control of Disease Characteristics in MS;295
15.7.2;7.2 Coinheritance with Other Autoimmune Diseases;296
15.7.3;7.3 Discussion;296
15.8;References;297
16;Index;302