T Cell Epitope Mimicry for Autoimmune Responses in SLE

系统性红斑狼疮(SLE)是一种复杂的自身免疫性疾病，主要影响年轻人 女性。尽管是多基因的，但总的来说，人类白细胞抗原复合体，特别是人类白细胞抗原-DR，仍然是 疾病易感性的最显性遗传危险因素。一个显著的特点是与 某些单倍型自身抗体的特异性。本提案针对的是这方面的机制。 密切联系。在这项提案中，我们将检验以下假设：在狼疮患者中，分子模仿 负责选择性地浓缩与狼疮反应的T细胞- 相关的自身抗原。根据微生物暴露的不同，人类白细胞抗原决定了交叉反应的性质。 它结合的反应性多肽和自身抗原的选择。这一过程导致了自我的激活 反应性T细胞，自身抗体的产生，表位的扩散和最终的器官损伤。使用Ro60作为 候选自身抗原和HLA-DR和-DQ转基因小鼠，提出了以下特定目标： 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。2)至 证明多次暴露于Ro60T细胞表位的多肽模拟物会影响Ro60 反应性T细胞库。3)确定抗Ro60抗体启动的自身免疫的致病潜能 转人类白细胞抗原-DR3和-DQ2基因的狼疮易感NZM2328小鼠的反应。由此得出的结论是 该提案将清楚地证明，T细胞对狼疮相关抗原的反应可以启动 系统性红斑狼疮的自身免疫反应。这将改变目前SLE主要是B细胞的模式 T和B细胞在疾病中都有其独特作用的更合理的模型 显化。这将为合理的治疗方法提供一个理论框架 精心设计的。

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 proposal addresses the mechanisms for this close association. In this proposal 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 proposal 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.