Role of Class II MHC Antigens in Neurologic Diseases

描述（由申请人提供）：MHCII类分子表达于 中枢神经系统（CNS）在许多神经系统疾病和 脱髓鞘疾病在大多数这些疾病中，T细胞通常是 在受影响的CNS中不存在。阐明II类MHC在CNS中的重要性 疾病，我们已经描述了两种脱髓鞘模型， II小胶质细胞上MHC的高表达。这些疾病的特征 模型显示，II类MHC的缺失导致了显性免疫缺陷的减轻， 症状、神经病理学/脱髓鞘减少、小胶质细胞减少 活化/增殖和减少炎性细胞因子的产生。最 有趣的是，II类MHC的作用不受T细胞缺乏的影响， 在RAGb小鼠中，但依赖于完整的II类MHC胞质尾。这 使我们提出II类可能在体内信号传导中起作用， 转导，不同于其在抗原中的常规生物学作用， 介绍。目标是： 1.分析转基因小鼠H-2 M对铜腙的反应 治疗如果常规的抗原处理不重要， H-2 M的缺失不应影响铜腙诱导的脱髓鞘。 2.分析II类MHC和T细胞如何影响髓鞘再生过程。最近 我们实验室的研究表明， 这是最佳髓鞘再生所必需的。MHC II类抗原的存在 增强细胞因子的表达，因此及时确定 MHC在髓鞘再生过程中的作用，以及淋巴细胞是否参与了这一过程。 3.确定II类MHC介导的信号传导的新介质。我们将 确定最近发现的II类信号传导介质，细胞 活化和增殖在小胶质细胞/巨噬细胞中受到影响。 4.识别在II类MHC参与后被激活的基因。中 通过Affy筛选小胶质细胞-巨噬细胞系，并评估 这些基因在cuprizone模型中。

DESCRIPTION (provided by applicant): MHC class II molecules are expressed in the central nervous system (CNS) during a number of neurologic disorders and demyelinating disease. In a majority of these diseases, T cells are generally absent in the affected CNS. To address the importance of class II MHC in CNS disorders, we have characterized two models of demyelination that exhibit class II MHC hyper-expression on microglial cells. Characterizations of these disease models show that the deletion of class II MHC caused the alleviation of overt symptoms, reduced neuropathology/demyelination, reduced microglial activation/proliferation and reduced production of inflammatory cytokines. Most intriguingly, the role of class II MHC is unaffected by the absence of T cells in RAGb mice, but dependent on an intact class II MHC cytoplasmic tail. This caused us to propose that class II may serve an in vivo role in signal transduction, distinct from its conventional biologic role in antigen presenting. The Aims are: 1.Analyze a transgenic mouse strain, H-2M for its response to cuprizone treatment. If conventional antigen processing is not important, then the deletion of H-2M should not affect cuprizone-induced demyelination. 2.Analyze how class II MHC and T cells affect the remyelination process. Recent studies in our laboratory have demonstrated that inflammatory cytokines are necessary for optimal remyelination. The presence of MHC class II causes enhanced cytokine expression, therefore it is timely to determine the role of MHC during remyelination, and if lymphocytes are involved in this process. 3. Determine novel mediators of class II MHC-mediated signaling. We will determine if recently discovered mediators of class II signaling, cell activation and proliferation are affected in microglia/macrophages. 4. Identify genes that are activated upon class II MHC engagement. in a microglial-macrophage line by Affy metrix screening, and assess the status of these genes in the cuprizone model.