B cells and autoantibodies as mediators of immunopathology in autoimmune encephalomyelitis

本基金申请的中心假设是，自身抗体对MBP-PLP融合蛋白MP4诱导的实验性自身免疫性脑脊髓炎（EAE）的发病机制至关重要。为此，我们提出了三个具体目标：目的1剖析mp4特异性自身抗体反应的决定性特异性。在子目标1.1中，我们将描述细胞外和细胞内髓磷脂决定因素在mp4诱导疾病启动中的作用。Subaim 1.2进一步研究了这些细胞外和细胞内决定因素对mp4诱导疾病进展的重要性。目的2涉及抗体介导的功能效应。在子目标2.1中，我们将检验mp4反应性抗体只能在功能性补体系统存在的情况下发挥其功能的假设。Subaim 2.2研究mp4特异性自身抗体是否通过抗体依赖细胞介导的细胞毒性和吞噬作用触发中枢神经系统病理。目的3最后讨论了抗体表位扩散在mp4诱导的EAE中的相关性（详见3.1）及其对自身反应性T细胞反应的影响（详见3.2）。总的来说，这里提出的实验旨在提高我们对抗髓磷脂抗体如何介导多发性硬化症免疫病理的尚不完善的理解。

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.