Experimental Models of Multiple Sclerosis (eBook)

Contents 5
Dedication 9
Preface Experimental Models of Multiple Sclerosis 10
Part A EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS (EAE) (AUTOIMMUNE) 12
Chapter A1 EAE: HISTORY, CLINICAL SIGNS, AND DISEASE COURSE 13
1. INTRODUCTION 13
2. HISTORY 14
2.1 Early Studies 14
2.2 Identification of encephalitogens 15
2.3 Adoptive or passive EAE 16
2.4 Relapsing EAE 16
2.5 Transgenic models of EAE 17
3. CLINICAL SIGNS AND DISEASE COURSE 18
ACKNOWLEDGEMENTS 19
REFERENCES 19
Chapter A2 INDUCTION OF EAE 22
1. INTRODUCTION 22
2. EAE INDUCED BY IMMUNIZATION (ACTIVE EAE) OR BY ADOPTIVE T CELL TRANSFER (PASSIVE EAE, AT-EAE) 24
2.1 Overview 24
2.2 Antigenic preparations 25
2.3 Active EAE 26
2.4 Generation of PLP- or MBP-specific LNCs 27
2.6 EAE induced by adoptive T cell transfer (passive EAE, AT-EAE) 29
3. CLINICAL MANIFESTATION AND EVALUATION OF DISEASE 30
3. DISCUSSION 31
ACKNOWLEDGMENTS 32
References 32
Chapter A3 HISTOPATHOLOGY OF EAE 36
1. BASIC MICROANATOMY OF THE CENTRAL NERVOUS SYSTEM 36
2. BASIC CNS HISTOPATHOLOGY 38
2.1 Inflammation 38
2.2 Demyelination 38
3. EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 39
3.1 EAE as a model of MS 40
4. HISTOPATHOLOGY OF EAE 42
4.1 EAE in SJL/J mice 44
4.2 EAE in C57B1/6 mice 45
4.3 EAE in the NOD mouse 47
4.4 EAE in the Lewis rat 48
4.4 EAE in rhesus monkeys and marmosets 50
ACKNOWLEDGEMENTS 51
REFERENCES 51
Chapter A4 NEUROANTIGENS IN EAE 55
1. INTRODUCTION 55
2. THE CELL BIOLOGY OF MYELIN 56
3. THE BIOCHEMISTRY OF MYELIN 57
3.1 Myelin lipids and their synthetic enzymes 57
3.2 Myelin proteins 60
3.3 Myelin associated glycoprotein (MAG) 68
3.4 Oligodendrocyte specific protein (OSP aka Claudin- 11)
3.5 Myelin oligodendrocyte protein (MOG) 70
3.6 Connexin 32 (Cx32 Gap junction [~ 1)
3.7 The paranodal junction proteins (septate-like junctions) 71
3.8 Other proteins 71
4. CONCLUSIONS 72
ACKNOWLEGDMENT 72
Chapter A5 ADJUVANTS IN EAE 83
ACKNOWLEDGEMENTS 89
REFERENCES 89
Chapter A6 THE ROLE OF ASTROCYTES IN AUTOIMMUNE DISEASE OF THE CENTRAL NERVOUS SYSTEM 95
ACKNOWLEDGEMENTS 106
REFERENCES 106
Chapter A7 ROLE OF MICROGLIA AND MACROPHAGES IN EAE 119
1. MICROGLIA AND MACROPHAGES IN THE NORMAL BRAIN 120
2. CELLULAR AND MOLECULAR RESPONSE IN EAE AND MS 122
REFERENCES 132
Chapter A8 THE NEURON AND AXON IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 142
1.1 History o f axonal loss 142
2. AXONAL LOSS IN MS 143
3. AXONAL LOSS IN EAE 148
REFERENCES 154
Chapter A9 ENDOTHELIAL CELLS AND ADHESION MOLECULES IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 159
1. INTRODUCTION 159
2. INFLAMMATORY CELL MIGRATION IN EAE 160
3. ROLE OF CNS ENDOTHELIAL CELLS IN EAE 162
4. ROLE OF ADHESION MOLECULES IN EAE 166
5. CONCLUSION 179
ACKNOWLEDGMENTS 179
REFERENCES: 179
Chapter A10 GENETICS OF EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS 188
1.1 Myelin and the Major Histocompatibility complex in susceptibility to CNS autoimmunity 190
1.2 Non-MHC autosomai susceptibility loci 193
ACKNOWLEDGEMENTS 198
REFERENCES 198
Chapter A11 T LYMPHOCYTES IN EAE 209
1 EAE AS A T CELL-MEDIATED DISEASE 209
2. CYTOKINES IN EAE 214
3. NON-CD4+ T CELLS IN EAE 217
4. REGULATORY CELLS IN EAE 219
5. STUDIES ON AUTOREACTIVE T CELL DEVELOPMENT AND ACTIVATION 224
6. T CELL-DIRECTED PEPTIDE THERAPY OF EAE 230
7. CONCLUDING REMARKS 234
REFERENCES 234
Chapter A12 THE ROLE OF COMPLEMENT IN EAE 252
1. THE COMPLEMENT SYSTEM 253
2. COMPLEMENT AND BRAIN INFLAMMATION 257
3. COMPLEMENT IN EAE 258
4. THERAPEUTIC IMPLICATIONS OF COMPLEMENT INVOLVEMENT IN DEMYELINATION 267
REFERENCES 268
Chapter A13 B CELLS AND ANTIBODIES IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 275
ACKNOWLEDGEMENTS 281
REFERENCES 281
Chapter A14 CYTOKINES IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 288
ACKNOWLEDGEMENTS 304
REFERENCES 304
Chapter A15 THE ROLE OF INTERFERONS IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 317
1. INTRODUCTION 318
2. IFN- 7 IN EAE 319
3. INTERFERON- L AND -13 IN EAE 328
4. IFN-TAU IN EAE 332
ACKNOWLEDGMENTS 334
REFERENCE LIST 334
Chapter A16 THE ROLE OF GROWTH FACTORS IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 347
1. INTRODUCTION 347
2. NEUROTROPHINS 348
3. CILIARY NEUROTROPHIC FACTOR 350
4. GLIAL GROWTH FACTOR 351
5. INSULIN-LIKE GROWTH FACTOR-1 351
6. FIBROBLAST GROWTH FACTOR 354
7. NEUROPROTECTION BY ENCEPHALITOGENIC T CELLS 354
8. CONCLUSION 356
ACKNOWLEDGMENTS 356
9. REFERENCE LIST 356
Chapter A17 THE CHEMOKINE SYSTEM IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 366
CHEMOKINES AND THEIR RECEPTORS 367
CHEMOKINES IN EAE 369
CHEMOKINE RECEPTORS IN EAE 370
CHEMOKINES IN GENETICALLY MODIFIED ANIMALS WITH EAE 371
EAE IN ANIMALS WITH GENETICALLY MODIFIED CHEMOKINE SYSTEM 372
TREATMENT OF EAE STRATEGY WITH ANTICHEMOKINE 373
CHEMOKINES AND CHEMOKINE RECEPTORS IN MULTIPLE SCLEROSIS 375
CONCLUSIONS 376
REFERENCES 376
Chapter A18 FREE RADICALS AND EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 381
ONOO- vs. NO in EAE 386
ACKNOWLEDGEMENTS 390
REFERENCES 390
Chapter A19 PROTEASES AND PEPTIDASES IN EAE 393
1. INTRODUCTION 393
SUMMARY 410
REFERENCE LIST: 410
Chapter A20 THE BLOOD-BRAIN BARRIER IN EAE 416
1. INTRODUCTION 416
2. THE PHYSIOLOGICAL BLOOD-BRAIN BARRIER 417
3. THE BLOOD-BRAIN BARRIER DURING EAE 427
4. RECRUITMENT OF ENCEPHALITOGENIC T CELLS ACROSS THE BBB 432
5. THE BLOOD-CEREBROSPINAL FLUID BARRIER IN EAE 439
6. OUTLOOK 439
7. ACKNOWLEDGEMENTS 440
8. REFERENCES 440
Chapter A21 IMMUNOMODULATION OF EAE: ALTERED PEPTIDE LIGANDS, TOLERANCE, AND TH1/TH2 451
Introduction 451
1. Non-specific strategies 453
2. Antigen-specific strategies 455
Acknowledgments 462
References 463
Chapter A22 THE ROLE OF COSTIMULATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 471
ACKNOWLEDGMENTS 483
REFERENCES 483
Chapter A23 EPITOPE SPREADING IN EAE 491
Introduction 491
EAE Disease Induction in Studying Epitope Spreading 492
Mouse Models for Examining Epitope Spreading 492
ACKNOWLEDGMENTS 501
REFERENCES 501
Chapter A24 APOPTOTIC CELL DEATH IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 506
1. INTRODUCTION 506
Acknowledgements 516
Chapter A25 ENVIRONMENTAL INFLUENCES IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 521
Introduction 521
Trauma 528
Solar radiation 528
Stress 532
Diet 533
Toxins 534
Effects of temperature 535
Hyperbaric oxygen 536
ACKNOWLEDGMENTS 537
Chapter A26 HORMONAL AND GENDER INFLUENCES ON EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 545
1. Glucocorticoids 546
2. Gender influences on EAE 549
3. Pregnancy 553
4. Other hormones in EAE 554
5. Conclusion 555
ACKNOWLEDGMENTS 555
REFERENCES 555
Chapter A27 EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IN PRIMATES 559
Introduction 559
1. EAE IN THE COMMON MARMOSET 560
1.1 The common marmoset 560
1.2 Myelin-induced EAE 561
1.3 MOG-induced EAE 564
2 MAGNETIC RESONANCE IMAGING 566
3. PATHOLOGY 567
4. CONCLUDING REMARKS 569
ACKNOWLEDGMENTS 569
REFERENCE LIST 570
Part B THEILER' S MURINE ENCEPHALOMYELITIS VIRUS (TMEV) - INDUCED DEMYELINATION 575
Chapter B 1 HISTOPATHOLOGY IN THE THEILER'S VIRUS MODEL OF DEMYELINATION 576
REFERENCES 585
Chapter B2 TMEV AND NEUROANTIGENS: MYELIN GENES AND PROTEINS, MOLECULAR MIMICRY, EPITOPE SPREADING, AND AUTOANTIBODY-MEDIATED REMYELINATION 589
1. INTRODUCTION 590
2. MYELIN GENES, VIRUS ENTRY, AND VIRUS PERSISTENCE 591
3. HUMORAL AUTOIMMUNE RESPONSES TO MYELIN 594
4. CELLULAR AUTOIMMUNE RESPONSES TO MYELIN 597
5. TMEV INFECTION AS MODELS TO STUDY MOLECULAR MIMICRY AND REMYELINATION 600
6. CONCLUSION 605
ACKNOWLEDGEMENTS 606
REFERENCES 606
Chapter B 3 THE ROLE OF ASTROCYTES, OLIGODENDROCYTES, MICROGLIA AND ENDOTHELIAL CELLS IN TMEV INFECTION 613
1. INTRODUCTION 613
2. THE ROLE OF CNS GLIA IN TMEV-IDD 614
Chapter B4 IMMUNOGENETICS, RESISTANCE, AND SUSCEPTIBILITY TO THEILER'S VIRUS INFECTION 625
References 634
Chapter B5 THE ROLE OF T CELLS AND THE INNATE IMMUNE SYSTEM IN THE PATHOGENESIS OF THEILER'S VIRUS DEMYELIATING DISEASE 641
1. Introduction 642
2. Role of virus-specific T cell responses in disease resistance/ susceptibility 642
3. Role of myelin-specific T cell responses in TMEV-IDD 645
4. TMEV-IDD Model of Molecular Mimicry 646
5. Innate Immune Response Induced by TMEV Infection 648
6. Conclusions 649
7. References 649
Chapter B6 CYTOKINES, CHEMOKINES AND ADHESION MOLECULES IN TMEV-IDD 654
1. CYTOKINES 655
2. CHEMOKINES 659
3. ADHESION MOLECULES 660
4. ROLE IN PATHOGENESIS OF DISEASE 661
Chapter B7 MOLECULAR DETERMINANTS OF TMEV PATHOGENESIS 667
INTRODUCTION 667
RECOMBINANT AND MUTANT VIRUS STUDIES 669
THE ROLE OF L* IN TO SUBGROUP STRAIN DISEASE 672
Cell-Type Specific Regulation of L* Synthesis 675
CONCLUSION 675
ACKNOWLEDGMENTS 676
REFERENCES 676
Chapter B8 NITRIC OXIDE IN TMEV 678
1. INTRODUCTION 679
ACKNOWLEDGEMENTS 686
REFERENCES 686
Chapter B9 THEILER'S MURINE ENCEPHALOMYELITIS VIRUS (TMEV)-INDUCED DEMYELINATION 690
DEFINITION OF APOPTOSIS 690
Pathways to Cell Death 691
Intrinsic Pathway 692
Extrinsic Pathway 692
TMEV-INDUCED APOPTOSIS 693
PICORNAVIRUS ANTI-APOPTOTIC MECHANISMS 696
ROLE OF APOPTOSIS IN TMEV-INDUCED DEMYELINATING DISEASE 697
Part C CORONA VIRUS-INDUCED DEMYELINATION 702
Chapter C1 HISTOPATHOLOGY IN CORONAVIRUS- INDUCED DEMYELINATION 703
INTRODUCTION 703
MHV INDUCD ACUTE ENCEPHALITIS 704
ACKNOLEDGEMENTS 706
REFERENCES 706
Chapter C2 THE ROLE OF ASTROCYTES, MICROGLIA, AND ENDOTHELIAL CELLS IN CORONAVIRUS- INDUCED DEMYELINATION 709
1. INTRODUCTION 709
2. Animal models of coronavirus induced demyelination 713
3. The role of astrocytes, microglia, and endothelial cells in MHV-induced CNS demyelination 713
4. CONCLUSIONS 721
References 721
Chapter C3 AXONS AND NEURONS IN CORONAVIRUS- INDUCED DEMYELINATION 728
1. INTRODUCTION 728
2. TEMPOROSPATIAL PROFILE OF AXONAL DAMAGE IN MHV INFECTION 729
2.1 The relationship between demyelination and axonal damage in MHV-induced disease 730
2.2 Contribution of CD4 and CD8 cells to axonal damage 733
3. FUTURE DIRECTIONS 733
REFERENCES 734
Chapter C4 THE ROLE OF T CELLS IN CORONA-VIRUS- INDUCED DEMYELINATION 737
INTRODUCTION 737
CONCERTED ANTI-VIRAL EFFORTS OF T CELLS 738
T Cell Priming, CNS Recruitment, and Effector Function 739
Distinct Anti-Viral Functions of IFN- T and Perforin 740
Auxilliary and Direct Anti-Viral Functions of CD4 T Cells 741
T CELL FUNCTION DURING PERSISTENCE 742
T CELLS AS CORRELATES OF DEMYELINATION 743
CONCLUSIONS 744
REFERENCES 745
Chapter C5 THE ROLE OF HUMORAL IMMUNITY IN MOUSE HEPATITIS VIRUS INDUCED DEMYELINATION 748
HUMORAL IMMUNITY AND MULTIPLE SCLEROSIS 748
MHV PATHOGENESIS 750
HUMORAL IMMUNITY AND ACUTE INFECTION 750
HUMORAL IMMUNITY AND VIRAL PERSISTENCE 752
ANTIBODY AND DEMYELINATION 755
CONCLUSIONS 756
REFERENCES: 756
Chapter C6 THE ROLE OF T CELL EPITOPES IN CORONAVIRUS INFECTION 759
1. INTRODUCTION 759
2. CELL-MEDIATED IMMUNITY DURING MHV INFECTION OF RODENTS 760
3. CTL ESCAPE IN MHV-INFECTED MICE 761
4. BIOLOGICAL SIGNIFICANCE OF CTL ESCAPE VARIANTS IN MHV-INFECTED MICE 765
5. CONCLUDING REMARKS 765
REFERENCES. 765
Chapter C7 CORONAVIRUSES AND NEUROANTIGENS: 768
1. INTRODUCTION 768
2. NEUROANTIGENS 769
3. MS AND CORONAVIRUSES 770
4. T CELL CROSS-REACTIVITY TO CORONAVIRUS AND MYELIN PROTEINS 770
5. CLONAL T-CELL CROSS-REACTIVITY 772
6. MS SPECIFICITY OF T-CELL CROSS-REACTIVITY 773
7. CONCLUSIONS 774
ACKNOWLEDGEMENTS 775
REFERENCES 776
Chapter C8 CORONAVIRUS-INDUCED DEMYELINATION AND SPONTANEOUS REMYELINATION 779
1. INTRODUCTION 779
2. DISEASE SEVERITY IN THE MHV-A59 MODEL 780
3. MHV-A59 DISEASE SEVERITY RELATIVE TO GENDER AND ESTROUS CYCLE 783
4. GROWTH FACTOR EXPRESSION FOLLOWING DEMYELINATION 784
5. CONCLUSION 787
ACKNOWLEDGEMENTS 787
REFERENCES 787
Chapter C9 CHEMOKINES IN CORONAVIRUS-INDUCED DEMYELINATION 790
1. INTRODUCTION 790
ACKNOWLEDGEMENTS 802
REFERENCES 802
Chapter C10 CORONAVIRUS RECEPTORS 806
1. INTRODUCTION 806
2. RECEPTORS FOR MHV 807
3. INTERACTION OF CEACAM1 AND MHV S PROTEIN 811
4. MHV RECEPTOR AND ITS IMPLICATIONS FOR MOUSE SUSCEPTIBILITY TO MHV 812
5. REFERENCES 813
Chapter C11 APOPTOSIS IN MHV-INDUCED DEMYELINATION 817
INTRODUCTION 817
APOPTOSIS IN MHV-INDUCED DISEASE 818
DISCUSSION 819
ACKNOWLEDGMENTS 820
REFERENCES 820
Chapter C 12 THE ROLE OF METALLOPROTEINASES IN CORONA VIRUS INFECTION 822
INTRODUCTION 822
BACKGROUND 823
MMP AND TIMP EXPRESSION CORONAVIRUS INFECTION DURING 824
ROLE OF MMPS IN DEMYELINATION 826
CONCLUSIONS 827
REFERENCES 828
Chapter C 13 MOLECULAR DETERMINANTS OF CORONAVIRUS MHV- INDUCED DEMYELINATION 832
THE MHV GENOME 832
STRUCTURAL-FUNCTIONAL RELATIONSHIP OF MHV 833
THE SPIKE GLYCOPROTEIN (S) 835
SUMMARY. 837
REFERENCES 838
Part D DEMYELINATION INDUCED BY OTHER VIRUSES 842
Chapter D1 SEMLIKI FOREST VIRUS INDUCED DEMYELINATION 843
1. VIRUS STRAINS 843
2. AGE-RELATED VIRULENCE AND RESTRICTED REPLICATION 844
3. ENTRY INTO AND SPREAD WITHIN THE BRAIN 845
4. BLOOD-BRAIN BARRIER CHANGES 846
5. ANTIBODY RESPONSES 847
6. INFLAMMATORY RESPONSES 848
7. NEUROPATHOLOGY 848
ACKNOWLEDGEMENTS 849
REFERENCES 849
Chapter D2 THE PATHOGENESIS OF CANINE DISTEMPER VIRUS INDUCED DEMYELINATION 853
1. INTRODUCTION 854
2. DEMYELINATING DISTEMPER ENCEPHALITIS 857
3. CONCLUSIONS 862
ACKNOWLEDGEMENTS 862
REFERENCES 862
INDEX 870