| Preface | 6 |
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| Contents | 7 |
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| Contributors | 9 |
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| Series Editor Introduction | 11 |
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| Color Plates | 12 |
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| Neuromuscular Junction Physiology and Pathophysiology | 13 |
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| 1.1 INTRODUCTION | 13 |
| 1.2 MOTOR NERVE PROPERTIES | 13 |
| 1.2.1 Distal Motor Nerve Properties | 13 |
| 1.2.2 The Nerve Terminal | 14 |
| 1.2.2.1 Role of Ca2+ Channels in Transmitter Release | 14 |
| 1.2.2.2 Synaptic Vesicle Fusion | 15 |
| 1.3 THE SYNAPTIC CLEFT | 16 |
| 1.3.1 Synatpic Cleft Acetylcholine Esterase | 17 |
| 1.3.2 Alteration of AChE in Neuromuscular Diseases | 17 |
| 1.3.3 Extracellular Matrix in the Synaptic Cleft | 17 |
| 1.3.4 ACh-Binding Protein | 18 |
| 1.4 POSTSYNAPTIC MEMBRANE SPECIALIZATION | 18 |
| 1.4.1 How the NMJ Accommodates to Muscle Contraction | 19 |
| 1.4.2 Postsynaptic Na+and AChR Channels | 19 |
| 1.5 SAFETY FACTOR FOR NEUROMUSCULAR TRANSMISSION | 20 |
| REFERENCES | 20 |
| Acetylcholine Receptor Structure | 25 |
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| 2.1 INTRODUCTION | 25 |
| 2.2 SIZE AND SHAPE OF ACHRS | 26 |
| 2.3 STRUCTURES OF ACHR SUBUNITS | 27 |
| 2.4 ORGANIZATION OF SUBUNITS IN ACHR SUBTYPES | 31 |
| 2.5 ACETYLCHOLINE-BINDING SITES | 33 |
| 2.6 CATION CHANNEL AND ITS GATE | 35 |
| 2.7 ANTIGENIC STRUCTURE AND THE MAIN IMMUNOGENIC REGION (MIR) | 35 |
| 2.8 INDUCTION OF THE AUTOIMMUNE RESPONSE TO ACHRS IN MG | 38 |
| 2.9 AUTOIMMUNE MECHANISMS WHICH IMPAIR NEUROMUSCULAR TRANSMISSION IN MG AND EAMG | 39 |
| 2.10 EFFECTS OF ACHR MUTATIONS IN CONGENITAL MYASTHENIC SYNDROMES | 40 |
| 2.11 NEURONAL ACHR SUBTYPES AND FUNCTIONAL ROLES | 42 |
| 2.12 AUTOIMMUNE IMPAIRMENT OF NEURONAL ACHRS | 43 |
| 2.13 EFFECTS OF HUMAN NEURONAL ACHR MUTATIONS | 44 |
| REFERENCES | 45 |
| Immunopathogenesis of Myasthenia Gravis | 54 |
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| 3.1 INTRODUCTION | 54 |
| 3.2 ANTI-ACHR Ab IN MG AND IN EXPERIMENTAL AUTOIMMUNE MG (EAMG) | 54 |
| 3.3 EPITOPES RECOGNIZED BY ANTI-ACHR Ab IN MG AND EAMG | 56 |
| 3.3.1 The MIR | 56 |
| 3.3.2 The Cholinergic Site | 56 |
| 3.3.3 Non-AChR Antigens | 57 |
| 3.4 ANTI-ACHR CD4+ T-HELPER CELLS IN MG | 58 |
| 3.4.1 Epitope Repertoire of Anti-AChR CD4+ T Cells in MG | 59 |
| 3.4.2 CD4+ T Cells of MG Patients Recognize ‘‘Universal’’, Immunodominant AChR Epitopes | 61 |
| 3.4.3 Unstable Recognition of AChR Epitopes by CD4+ T Cells of Ocular MG Patients | 61 |
| 3.5 TCR Vbeta AND Valpha USAGE BY ANTI-ACHR CD4+ T CELLS OF MG PATIENTS | 62 |
| 3.6 ROLES IN MG AND EAMG OF CYTOKINES SECRETED BY DIFFERENT CD4+ SUBSETS | 64 |
| 3.7 CD8+ CELLS IN MG AND EAMG | 67 |
| 3.8 THE THYMUS IN MG | 68 |
| 3.8.1 AChR-Like Proteins Are Expressed in the Thymus | 68 |
| 3.8.2 Thymus Cells That Express AChR Proteins | 69 |
| 3.9 PATHOGENIC MECHANISMS OF MG | 70 |
| REFERENCES | 72 |
| Epidemiology and Genetics of Myasthenia Gravis | 82 |
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| 4.1 INTRODUCTION | 82 |
| 4.2 EPIDEMIOLOGICAL ISSUES AND MYASTHENIA GRAVIS | 82 |
| 4.2.1 Definition of Terms | 82 |
| 4.2.2 Epidemiological Studies of Myasthenia Gravis | 83 |
| 4.2.3 Current Trends in the Epidemiology of Myasthenia Gravis | 83 |
| 4.2.4 Seronegative and Muscle-Specific Kinase Antibody-Related Myasthenia Gravis | 85 |
| 4.2.5 Genetics of MG | 86 |
| 4.2.6 Proof of Inheritance | 86 |
| 4.3 CANDIDATE GENES | 87 |
| 4.3.1 HLA Complex | 87 |
| 4.3.2 AChR as a Self-Antigen and Other HLA Genes | 87 |
| 4.3.3 Other Candidate Genes | 88 |
| REFERENCES | 88 |
| Clinical Presentation and Epidemiology of Myasthenia Gravis | 90 |
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| 5.1 DEFINITION AND CLASSIFICATION | 90 |
| 5.2 CLINICAL MANIFESTATIONS | 90 |
| 5.2.1 Ocular | 90 |
| 5.2.2 Bulbar | 91 |
| 5.2.3 Limb, Trunk and Respiratory | 94 |
| 5.2.4 Muscle Atrophy | 95 |
| 5.2.5 Clinical Classifications and Quantitative Tests | 97 |
| 5.2.6 Cognitive Involvement | 97 |
| 5.2.7 The Course of the Disease | 98 |
| 5.2.8 Exacerbating Factors | 99 |
| 5.3 EPIDEMIOLOGY | 100 |
| 5.3.1 Incidence and Prevalence | 100 |
| 5.3.2 Age, Gender and Classification | 100 |
| 5.3.3 Acquired Infantile MG | 101 |
| 5.3.4 Myasthenia Gravis in the Elderly
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