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，但HLA复合体，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单倍型的强相关性。本申请解决了这种密切关联的机制。在本申请中，我们将测试以下假设：在狼疮患者中，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决定其结合的交叉反应性肽的性质，从而决定自身抗原选择。该过程导致自身反应性T细胞的活化、自身抗体的产生、表位扩散和终末器官损伤。以Ro 60为候选自身抗原，以HLA-DR和-DQ转基因小鼠为研究对象，本研究的具体目的是：1）鉴定Ro 60上T细胞表位的分子模拟物。2)证明多次暴露于Ro 60 T细胞表位的肽模拟物影响Ro 60反应性T细胞库。3)确定HLA-DR 3和-DQ 2转基因狼疮易感NZM 2328小鼠中抗Ro 60启动自身免疫应答的致病潜力。本申请的发现将清楚地证明T细胞对狼疮相关抗原的应答可以启动SLE的自身免疫应答。这将把SLE主要是B细胞介导的疾病的当前范例转变为T和B细胞在疾病表现中具有其独特作用的更合理的模型。这将提供一个理论框架，从中可以设计出合理的治疗方法。 公共卫生相关性：目前的应用将确定蛋白质的感染性病原体，可能会引发系统性红斑狼疮的自身免疫反应。这将确定感染性微生物，可以是诱发因素的发展，自身免疫性疾病，如狼疮。

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.