THE MECHANISMS OF AUTOIMMUNE RESPONSE INITIATION IN MULTIPLE SCLEROSIS

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性自身免疫性脱髓鞘疾病，主要影响最具生产力年龄的年轻人，因此导致严重残疾。虽然其病因仍然难以捉摸，但大多数证据支持该疾病的自身免疫发病机制。根据这一假设，自身反应性T细胞的激活是MS自身免疫反应发展的中心事件。本研究的目的是检测MS自身免疫反应启动中涉及的分子事件。简并性和分子模拟是一种常见的现象，可能在MS中启动自身免疫反应中发挥作用。开发了偏向的组合肽文库作为表征简并T细胞的工具。由于自身抗原主要是弱TCR配体，我们提出髓鞘反应性T细胞可能在具有退化TCR的细胞中过度表达。与健康对照相比，MS患者中髓鞘碱性蛋白（MBP）特异性T细胞表现出降低的CD28共刺激需求。我们假设，共刺激途径的失调发挥作用的初始激活，延长生存期，并在MS的自身反应性细胞的扩增。共刺激独立的激活可能是特别相关的CNS内的自身抗原识别，因为局部炎症环境增强自身抗原呈递，即使在没有共刺激分子的常驻抗原呈递细胞。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库。2)定义RR MS患者和OND对照中具有柔性TCR的T细胞活化和生长特征的共刺激要求。3)确定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会产生重要的见解的生理和病理作用的自身反应性T细胞，并在结构和功能上的MS的新疗法的具体目标。

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.