B cells and autoantibodies as mediators of immunopathology in autoimmune encephalomyelitis

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The central hypothesis of this grant application states that autoantibodies are crucial to the disease pathogenesis of experimental autoimmune encephalomyelitis (EAE) induced by the MBP-PLP fusion protein MP4. To this end, we propose three specific aims: Aim 1 dissects the determinant specificity of the MP4-specific autoantibody response. In subaim 1.1, we are going to delineate the role of extra- and intracellular myelin determinants for the initiation of MP4-induced disease. Subaim 1.2 further examines the importance of these extra- and intracellular determinants for the progression of MP4-induced disease. Aim 2 deals with antibody-mediated effects of function. In subaim 2.1 we will test the hypothesis that MP4-reactive antibodies can only assert their function in the presence of a functional complement system. Subaim 2.2 investigates if MP4-specific autoantibodies trigger CNS pathology through antibody-dependent cell-mediated cytotoxicity and phagocytosis. Aim 3 finally addresses the relevance of antibody epitope spreading in MP4-induced EAE (subaim 3.1) and its impact on the autoreactive T cell response (subaim 3.2). Overall, the experiments presented here aim at improving our still imperfect understanding of how anti-myelin antibodies can mediate the immunopathology of multiple sclerosis.