T Cell Epitope Mimicry for Autoimmune Responses in SLE

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，主要影响年轻女性。尽管是多基因的，HLA复合物，特别是HLA- dr，仍然是疾病易感性的最主要遗传风险因素。一个显著的特征是自身抗体特异性与某些HLA单倍型的强烈关联。这个应用程序解决了这种紧密关联的机制。在这个应用中，我们将测试狼疮患者的假设，微生物肽的分子模拟负责选择性富集与狼疮相关自身抗原反应的T细胞。根据微生物暴露，HLA决定了它所结合的交叉反应肽的性质，从而决定了自身抗原的选择。这一过程导致自身反应性T细胞的激活、自身抗体的产生、表位扩散和终末器官损伤。利用Ro60作为候选自身抗原和HLA-DR和-DQ转基因小鼠，提出以下具体目的：为我们的假设寻找证据1)鉴定Ro60上T细胞表位的分子模拟物。2)证明多次暴露于Ro60 T细胞表位的肽模拟物会影响Ro60反应性T细胞库。3)检测HLA-DR3和-DQ2转基因狼疮易感小鼠抗ro60启动自身免疫反应的致病潜力。这项应用的结果将清楚地表明，T细胞对狼疮相关抗原的反应可以在SLE中启动自身免疫反应。这将改变目前SLE主要是B细胞介导的疾病的范式，使其转变为更合理的模型，其中T细胞和B细胞在疾病表现中都有其独特的作用。这将为设计合理的治疗方法提供一个理论框架。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a complex, autoimmune disorder predominantly affecting young females. Despite being multigenic, the HLA complex in general and HLA-DR in particular remains the most dominant genetic risk factor for disease susceptibility. A striking feature is the strong association of autoantibody specificities with some HLA haplotypes. This application addresses the mechanisms for this close association. In this application we will test the hypotheses that in lupus patients, molecular mimicry with microbial peptides is responsible for the selective enrichment of T cells reactive with lupus- associated autoantigens. Depending on microbial exposure, the HLA dictates the nature of cross- reactive peptides it binds and thereby the autoantigen selection. This process leads to activation of self- reactive T cells, autoantibody production, epitope spreading and end organ damage. Using Ro60 as the candidate autoantigen and HLA-DR and -DQ transgenic mice, following specific aims are proposed: to seek evidence for our hypothesis 1) To identify the molecular mimics of T cell epitopes on Ro60. 2) To demonstrate that multiple exposures to peptide mimics of Ro60 T cell epitopes influences the Ro60 reactive T cell repertoire. 3) To determine the pathogenic potential of anti-Ro60 initiated autoimmune responses in lupus-prone NZM2328 mice transgenic for HLA-DR3 and -DQ2. The findings from this application will clearly demonstrate that T cell responses to lupus-associated antigens can initiate autoimmune responses in SLE. This will shift the current paradigm that SLE is predominantly a B cell mediated disease to a more rational model in which both T and B cells have their unique roles in disease manifestation. This will provide a theoretical framework from which rational therapeutic approach can be devised. PUBLIC HEALTH RELEVANCE: The current application will identify proteins from infectious agents that might initiate an autoimmune response in systemic lupus erythematosus. This will identify infectious microorganisms that can be predisposing factors for the development of an autoimmune disorder such as lupus.