THE MECHANISMS OF AUTOIMMUNE RESPONSE INITIATION IN MS

MS 自身免疫反应的启动机制

• 批准号: 7092643
• 负责人: Silva Markovic-Plese
• 金额: $ 16.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7092643
• 关键词: CD28 molecule; CHO cells; T cell receptor; antigen presenting cell; autoimmune disorder; cellular immunity; central nervous system disorders; clinical research; cross immunity; enzyme linked immunosorbent assay; experimental allergic encephalomyelitis; gene expression; helper T lymphocyte; human subject; ligands; multiple sclerosis; myelin basic proteins; myelinopathy; tissue /cell culture; transfection

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.

描述（由申请人提供）：多发性硬化症（MS）是一种慢性自身免疫性脱髓鞘疾病（中枢神经系统（CNS）），主要影响年轻人最有生产率的年龄，因此导致了严重的残疾。尽管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理。根据这一假设，自动反应性T细胞的激活是MS自身免疫反应发展的中心事件。该提案的目的是检查MS中自身免疫反应引发的分子事件。最近的研究报告说，意外高度的T细胞受体（TCR）退化和分子模仿是一种常见的现象，可能在MS中自身免疫反应的启动中起作用。 MHC DR2偏置的组合肽库是作为表征变性T细胞的工具开发的。由于自动抗原主要是弱TCR配体，因此我们认为髓磷脂反应性T细胞可能会在细胞中用退化的TCR代表过多。与健康对照组相比，MS患者的髓磷脂碱性蛋白（MBP）特异性T细胞在MS患者中表现出降低的CD28共刺激性要求。我们假设共刺激途径的失调在最初激活，长期存活以及MS中自动反应性细胞的扩展中起作用。与CNS内的自身抗原识别术相关的非共同依赖性激活可能特别相关，因为即使局部炎症环境也可以增强自身抗原的表现，即使在驻留抗原呈递细胞上没有共刺激分子。我们计划通过追求以下特定目的来实现目标：1）确定具有高度TCR灵活性的T细胞克隆型的频率和TCR曲目。 2）定义RR MS患者和OND对照中TCR的T-Cells激活和生长特性的共同刺激要求。 3）确定炎症环境诱导自动反应性T细胞激活的机制。这些研究提供的信息可能会产生对自动反应性T细胞的生理和病理作用的重要见解，并在结构和功能上表征MS新疗法的特定靶标。