Characterization of molecular alterations in normal appearing white matter of Multiple Sclerosis brain tissue and its animal model experimental autoimmune encephalomyelitis

.......................................................................................................................9 Introduction ................................................................................................................10 Multiple Sclerosis...............................................................................................................10 History of Multiple Sclerosis ....................................................................................................... 10 The Epidemiology of Multiple Sclerosis .............................................................................13 The distribution of Multiple Sclerosis .................................................................................... 13 Environmental factors ........................................................................................................... 15 Genetic factors...................................................................................................................... 16 Clinical Features of Multiple Sclerosis ....................................................................................... 17 Symptoms of MS................................................................................................................... 17 Disease course ..................................................................................................................... 17 Prognosis in MS.................................................................................................................... 19 MS variants ........................................................................................................................... 19 Pathology and Pathogenesis of Multiple Sclerosis .................................................................... 21 Immune system and the brain............................................................................................... 21 The CNS immune privilege ................................................................................................... 24 The MS lesion ....................................................................................................................... 27 Heterogeneity of active demyelinating lesions ...................................................................... 30 Cellular composition of MS lesions ....................................................................................... 32 The „normal“ white matter in MS........................................................................................... 36 Axonal pathology .................................................................................................................. 37 Grey matter pathology .......................................................................................................... 38 Origin or cause of MS ........................................................................................................... 40 Animal models for MS................................................................................................................ 43 Experimental autoimmune encephalomyelitis....................................................................... 43 Limitations and potential of EAE as a model for MS............................................................. 45 Theiler’s virus-induced encephalomyelitis............................................................................. 48 Cuprizone-induced demyelinating models ............................................................................ 48 Impacts on therapy of MS ..................................................................................................... 49 Oligodendrocytes and MS..........................................................................................50 Aim of the work ..........................................................................................................54 Results .......................................................................................................................55 Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection .....................................................................................57 Abstract...................................................................................................................................... 58..................................................................................................................................... 58 Introduction ................................................................................................................................ 59 Material and Methods ................................................................................................................ 61 Results ....................................................................................................................................... 68 Discussion.................................................................................................................................. 79 Acknowledgements.................................................................................................................... 84 Molecular changes in white matter adjacent to demyelinating lesions in early Multiple Sclerosis ............................................................................................................................85 Abstract...................................................................................................................................... 86..................................................................................................................................... 86 Introduction ................................................................................................................................ 86 Materials and Methods............................................................................................................... 87 Results ....................................................................................................................................... 88 Discussion.................................................................................................................................. 95 Acknowledgements.................................................................................................................... 97 Molecular Changes in normal appearing tissue in an animal model of MS .......................99 Lame Ducks or Fierce Creatures? The Role of Oligodendrocytes in Multiple Sclerosis ......................................................123 Abstract.................................................................................................................................... 124................................................................................................................................... 124 Introduction .............................................................................................................................. 124 Oligodendrocytes lame ducks?.............................................................................................. 125 Reactive or activated oligodendrocytes – pure defensive or even fierce creatures? ............... 130 Conclusions ............................................................................................................................. 136 RNA Profiling of MS Brain Tissues ..................................................................................137 Abstract.................................................................................................................................... 138................................................................................................................................... 138 Introduction .............................................................................................................................. 138 Microarrays in MS .................................................................................................................... 139 Summary.................................................................................................................................. 148 Acknowledgment...................................................................................................................... 148 A Chronic Relapsing Animal Model for Multiple Sclerosis ...............................................149 Abstract.................................................................................................................................... 150................................................................................................................................... 150 Introduction .............................................................................................................................. 150 Materials and Methods............................................................................................................. 152 Results and Discussion............................................................................................................ 156 Conclusions ............................................................................................................................. 161 Acknowledgments.................................................................................................................... 162 Discussion................................................................................................................163 General discussion ..........................................................................................................163 Final summary .................................................................................................................168 Outlook ............................................................................................................................169 References...............................................................................................................170 Appendix A : Main Methods .....................................................................................186 Appendix B : Curriculum Vitae .................................................................................191