Role of Class II MHC Antigens in Neurologic Diseases

描述(申请人提供)：MHC II类分子以 中枢神经系统(CNS)在一些神经系统疾病和 脱髓鞘疾病。在大多数此类疾病中，T细胞通常是 在受影响的中枢神经系统中不存在。解决第二类MHC在中枢神经系统中的重要性 我们描述了两种脱髓鞘模型，它们展示了 II MHC高表达于小胶质细胞。这些疾病的特征 模型表明，第二类MHC的缺失导致外显性MHC的缓解 症状，神经病理/脱髓鞘减少，小胶质细胞减少 激活/增殖，减少炎性细胞因子的产生。多数 有趣的是，第二类MHC的作用不受T细胞缺失的影响 在RAGb小鼠中，但依赖于完整的II类MHC胞浆尾巴。这 导致我们提出II类可能在Signal中起体内作用 不同于其在抗原中的常规生物学作用的转导 展示。目标是： 1.分析转基因小鼠品系H-2M对铜草酮的反应 治疗。如果常规的抗原处理不重要，那么 H-2m的缺失不应影响铜试剂诱导的脱髓鞘。 2.分析II类MHC和T细胞对髓鞘再生过程的影响。近期 我们实验室的研究表明，炎性细胞因子是 对于最佳的髓鞘再生来说是必要的。MHC II类物质的存在导致 细胞因子表达增强，因此及时确定其作用 MHC在重新髓鞘形成过程中的作用，以及淋巴细胞是否参与这一过程。 3.确定新的II类MHC介导的信号转导介质。我们会 确定最近发现的II类信号的介体、细胞 小胶质细胞/巨噬细胞的激活和增殖受到影响。 4.确定在第二类MHC参与时被激活的基因。在一个 通过Affy Metrix筛选小胶质细胞-巨噬细胞系，并评估其状态 这些基因在铜试剂模型中。

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.