MECHANISMS OF TOLERANCE AND IMMUNITY TO CENTRAL NERVOUS SYSTEM ANTIGENS

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）的炎性脱髓鞘疾病，据信具有自身免疫性病因。它是年轻人中最常见的神经系统疾病。MS的发病机制尚未完全了解，这限制了开发有效疗法的能力。实验性变态反应性脑脊髓炎（EAE）是广泛使用的MS动物模型，它为介导CNS自身免疫性疾病的髓鞘特异性CD4+ T细胞的活性提供了许多见解。然而，在MS患者中观察到的临床体征和病理学是非常异质性的，并且在经典的CD4+ T细胞介导的EAE模型中仅再现了MS患者的特征的子集。这一观察结果表明，需要新的模型来研究导致这种疾病的不同机制。本实验室基于髓鞘碱性蛋白（MBP）特异性CDS+ T细胞的活性开发了一种新的EAE模型。活化的MBP特异性T细胞的转移诱导自身免疫性疾病，其重现了在MS患者中观察到的一些临床体征和病理学，而这些临床体征和病理学在经典EAE中通常不常见。我们生成了这些CDS+ T细胞的T细胞受体转基因模型，并发现一种不寻常的耐受形式允许表达MBP的高亲和力T细胞受体的CDS+ T细胞逃避耐受并填充外周库。有趣的是，这种耐受性可以被病毒感染打破。在本申请中，我们将研究CDS+ T细胞耐受性和该模型中由于感染导致的耐受性丧失的分子机制。我们还将鉴定将MHC I类相关MBP表位呈递给CDS+ T细胞的CNS细胞以及疾病期间CDS+ T细胞和CNS细胞之间相互作用的后果。最后，我们将确定CDS+和CD4+ T细胞亚群是否利用不同的组织归巢分子浸润CNS，并将CDS+ T细胞介导的CNS损伤与髓鞘特异性CD4+ T细胞介导的病理学进行比较，后者在同一小鼠品系中诱导EAE。指导这些研究的过度假设是髓鞘特异性CDS+ T细胞在用于逃避耐受的机制、在它们对CNS中靶细胞的识别以及在CNS中抗原识别的病理后果方面不同于CD4+ T细胞。检验这一假设将确定是否存在由髓鞘特异性CDS+ T细胞介导的CNS自身免疫性疾病的独特方面，这是一种与人类疾病具有显著临床相关性的受试者。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that is believed to have an autoimmune etiology. It is the most common neurological disease in young adults. The pathogenesis of MS is not well understood and this has limited the ability to develop effective therapies. Experimental allergic encephalomyelitis (EAE), a widely used animal model for MS, has provided many insights into the activity of myelin-specific CD4+ T cells that can mediate CNS autoimmune disease. However, the clinical signs and pathology seen in MS patients is very heterogeneous and only a subset of the characteristics of MS patients is reproduced in classical CD4+ T cell-mediated EAE models. This observation suggests that new models are needed to investigate the diverse mechanisms contributing to this disease. Our laboratory developed a new EAE model based on the activity of myelin basic protein (MBP)- specific CDS+ T cells. Transfer of activated MBP-specific T cells induces autoimmune disease that recapitulates some of the clinical signs and pathology seen in MS patients that are not typically seen in classic EAE. We generated T cell receptor transgenic models of these CDS+ T cells and found that an unusual form of tolerance allows CDS+ T cells expressing a high affinity T cell receptor for MBP to escape tolerance and populate the peripheral repertoire. Interestingly, this tolerance can be broken by viral infection. In this application, we will investigate the molecular mechanisms underlying both the CDS+ T cell tolerance and the loss of tolerance due to infection in this model. We will also identify the CNS cells that present the MHC class l-associated MBP epitope to the CDS+ T cells and the consequences of interaction between the CDS+ T cells and CNS cells during disease. Finally, we will determine if the CDS+ and CD4+ T cells subsets utilize different tissue homing molecules to infiltrate the CNS and compare the CNS damage mediated by the CDS+ T cells to the pathology mediated by myelin-specific CD4+ T cells that induce EAE in the same mouse strain. The over-arching hypothesis guiding these studies is that myelin-specific CDS+ T cells differ from CD4+ T cells in the mechanisms used to escape tolerance, in their recognition of targets cells in the CNS and in the pathologic consequences of antigen recognition in the CNS. Testing this hypothesis will determine whether there are unique aspects of CNS autoimmune disease mediated by myelin-specific CDS+ T cells, a subject with significant clinical relevance to human disease.