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HLA复合物一般和HLA-DR特别地仍然是多基因的。 疾病易感性的最主要遗传风险因素。一个显著的特点是， 自身抗体特异性与一些HLA单倍型。本提案涉及这方面的机制 密切的联系。在这项提案中，我们将测试的假设，在狼疮患者，分子模拟， 与微生物肽的作用是选择性富集与狼疮反应的T细胞， 相关自身抗原根据微生物的暴露，HLA决定了交叉的性质。 它结合的反应性肽，从而选择自身抗原。这一过程导致了自我的激活， 反应性T细胞、自身抗体产生、表位扩散和终末器官损伤。使用Ro 60作为 候选自身抗原和HLA-DR和-DQ转基因小鼠，提出以下具体目标： 为我们的假设寻找证据1）鉴定Ro 60上T细胞表位的分子模拟物。2)到 表明多次暴露于Ro 60 T细胞表位的肽模拟物影响Ro 60 T细胞表位的表达。 反应性T细胞库。3)为了确定抗Ro 60启动的自身免疫的致病潜力， HLA-DR 3和-DQ 2转基因狼疮易感NZM 2328小鼠的免疫应答。这一发现 该提案将清楚地表明，T细胞对狼疮相关抗原的应答可以启动 SLE的自身免疫反应这将改变目前SLE主要是B细胞的模式 T细胞和B细胞在疾病中都有其独特的作用 表现。这将为合理的治疗方法提供一个理论框架， 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.