Immunopathological definition of multiple sclerosis subtypes

Multiple Sclerosis is an inflammatory demyelination disease of the central nervous system. Current concepts on its pathogenesis suggest that a T-cell mediated immune response is responsible for the inflammatory component. Demyelination however apparently requires additional immune mechanisms, which may involve specific demyelinating antibodies, cytotoxic T-cells directed against oligodendrocytes or toxic immune effector molecules. In addition, metabolic disturbances of oligodendrocytes may render the cells more susceptible for immune mediated destruction. In a collaborative study with the Mayo Clinic (Rochester, USA) and the Department of Neuropathology, University Goettingen, we found preliminary evidence for a profound heterogeneity in the structural pathology and immunopathology of multiple sclerosis lesions. these findings indicate, that the immunopathogenesis of multiple sclerosis lesions in different subforms of the disease may be heterogeneous. In the present project we plan to study the structural pathology and immunopathology of multiple sclerosis lesions in a large series of biopsy and autopsy material from the active stage of the disease, collected in our institutions during the last twenty years. The plaques will be typed with stringent criteria for lesional activity, and the extent of T-cell, B-cell and macrophage infiltration will be quantitatively determined. The pathology of myeling and oligodendrocytes will be analyzed by in situ hybridization and immunocytochemistry with specific markers for myelin proteins and their respective mRNAs. Oligodendrocyte destruction will be analyzed by the in situ detection of DNA fragmentation and patterns of oligodendrocyte death by morphological criteria for apoptosis and necrosis. In addition the extent of axonal destruction and loss will be quantified and time course and patterns of acute axonal pathology determined. Finally immune effector pathways will be analyzed by determination of the deposition of ummunoglobuline and complement components (including C9-neoantigen) and the expression of toxic immune effector molecules, as for isntance perforin, granzymes, tumor necrosis factor and others. According to our preliminary data it can be expected that this type of analysis will lead to the identification of pathogenetic subtypes of multiple sclerosis lesions and/or MS cases. In a final step clinical and paraclinical (MRI and CSF) findings will be correlated with the pathological results to determine whether the immunopathological phenotype can be predicted clinically. It is expected that a clear definition of immunopathological subtypes of multiple sclerosis will have a major impact on future therapeutic strategies.