THE MECHANISMS OF AUTOIMMUNE RESPONSE INITIATION IN MS

描述(申请人提供)：多发性硬化症(MS)是一种慢性中枢神经系统(CNS)自身免疫性脱髓鞘疾病，主要影响处于最具生产力年龄的年轻人，因此导致严重残疾。虽然其病因仍不清楚，但大多数证据支持该病的自身免疫发病机制。根据这一假说，自身反应性T细胞的激活是多发性硬化症自身免疫反应发生过程中的中心事件。本研究的目的是研究多发性硬化症自身免疫反应启动的分子事件。最近的研究报道，T细胞受体(TCR)的高度退化和分子拟态是多发性硬化症患者中一种常见的现象，可能在多发性硬化症的自身免疫反应的启动中起作用。由于自身抗原主要是弱的TCR配体，我们认为髓鞘反应性T细胞可能在退行性TCR的细胞中过度表达。与健康对照组相比，MS患者髓鞘碱性蛋白(MBP)特异性T细胞的CD28共刺激需求降低。我们推测，共刺激通路的失调在MS的初始激活、延长存活和自身反应细胞的扩张中发挥了作用。共刺激非依赖性激活可能与中枢神经系统内的自身抗原识别特别相关，因为即使在常驻抗原提呈细胞上没有共刺激分子的情况下，局部炎症环境也会增强自身抗原的提呈。我们计划通过追求以下具体目标来实现我们的目标：1)确定具有高度TCR灵活性的T细胞克隆型的频率和TCR谱系。2)明确RRMS患者和OND对照组T细胞活化和生长特性与柔性TCR的协同刺激要求。3)明确炎症环境诱导自身反应性T细胞活化的机制。这些研究提供的信息可能对自身反应性T细胞的生理和病理作用产生重要的见解，并从结构和功能上表征MS新疗法的特定靶点。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS) affecting primarily young adults in their most productive age, and therefore causing a significant disability. While its etiology remains elusive, most evidence supports the autoimmune pathogenesis of the disease. According to this hypothesis, the activation of autoreactive T-cells is a central event in the development of autoimmune response in MS. The objective of this proposal is to examine molecular events involved in the initiation of autoimmune response in MS. Recent studies have reported an unexpectedly high degree of T-cell receptor (TCR) degeneracy and molecular mimicry as a frequent phenomenon that might play a role in the initiation of autoimmune response in MS. MHC DR2-biased combinatorial peptide libraries are developed as a tool to characterize degenerate T-cells. As auto-antigens are predominantly weak TCR ligands, we propose that myelin-reactive T-cells may be over-represented among the cells with a degenerate TCR. Myelin basic protein (MBP)-specific T-cells exhibit decreased CD28 co-stimulatory requirements in MS patients when compared to healthy controls. We hypothesize that dysregulation of co-stimulatory pathways play a role in the initial activation, prolonged survival, and the expansion of autoreactive cells in MS. Co-stimulation-independent activation might be particularly relevant for the autoantigen recognition within the CNS, as local inflammatory environment enhances autoantigen presentation even in the absence of co-stimulatory molecules on the resident antigen presenting cells. We plan to achieve our objective by pursuing the following Specific Aims: 1) Determine the frequency and TCR repertoire of T-cell clonotypes with a high degree of TCR flexibility. 2) Define co-stimulation requirements for the activation and growth characteristics of T-cells with flexible TCR in RR MS patients and OND controls. 3) Identify mechanisms by which the inflammatory environment induces the autoreactive T-cell activation. The information provided by these studies may yield important insights into the physiologic and pathologic role of the autoreactive T cells, and characterize structurally and functionally the specific targets for the new therapies of MS.