Astrocytes-Innate & Adaptive Immune Response to Virus

描述（由申请人提供）： Theiler氏鼠脑脊髓炎病毒（TMEV）建立了一个持续的中枢神经系统（CNS）感染，导致自身免疫性脱髓鞘疾病的发展。由于其自身免疫性质和CD 4 + T细胞和吞噬细胞的显著浸润，TMEV诱导的脱髓鞘疾病（TMEV-IDD）被认为是多发性硬化症的高度相关的动物模型。先天免疫应答是宿主的第一道防线，并导致抗原呈递细胞（APC）功能的激活和免疫效应分子的产生。在CNS中，神经胶质细胞（小胶质细胞和星形胶质细胞）可以对感染做出强烈反应，并且是TMEV持续存在的主要细胞。这些细胞中先天免疫应答的激活可能直接导致脱髓鞘或对髓鞘抗原的免疫应答的表位扩散。初步数据显示，星形胶质细胞表达Toll样受体（TLR），其在激活先天性抗病毒应答中是重要的，并且这些受体的连接可导致星形胶质细胞的炎性细胞因子和APC功能的上调。因此，该提议将测试以下总体假设：星形胶质细胞可以通过上调先天免疫、APC和效应器功能来激活TLR来响应TMEV感染，并且这种激活在TMEV-IDD的慢性发病机制中起重要作用。

DESCRIPTION (provided by applicant): Theiler's murine encephalomyelitis virus (TMEV) establishes a persistent central nervous system (CNS) infection, leading to the development of an autoimmune demyelinating disease. Because of its autoimmune nature and the prominent infiltration of CD4+ T cells and phagocytes, TMEV-induced demyelinating disease (TMEV-IDD) is considered a highly relevant animal model for multiple sclerosis. The innate immune response is the host first line of defense and leads to activation of antigen presenting cell (APC) functions and production of immune effector molecules. In the CNS glial cells (microglia and astrocytes) can respond vigorously to infection and are the major cells in which TMEV persists. Activation of innate immune responses in these cells may contribute directly to demyelination or to epitope spreading of the immune response to myelin antigens. Preliminary data shows that astrocytes express Toll like receptors (TLRs) important in activating innate anti-viral responses and that ligation of these receptors can result in the upregulation of inflammatory cytokines and APC functions of astrocytes. This proposal will thus test the overall hypothesis that astrocytes can respond to TMEV infection through the activation of TLRs by upregulating innate immune, APC and effector functions, and that this activation plays a significant role in the chronic pathogenesis of TMEV-IDD.