T Cell Epitope Mimicry for Autoimmune Responses in SLE

描述(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，但总的来说，人类白细胞抗原复合体，尤其是人类白细胞抗原-DR，仍然是疾病易感性的最主要的遗传危险因素。一个显著的特征是自身抗体的特异性与某些人类白细胞抗原单倍型有很强的相关性。本申请解决了这种紧密关联的机制。在这项应用中，我们将检验以下假设：在狼疮患者中，与微生物肽的分子模拟负责选择性地浓缩与狼疮相关的自身抗原反应的T细胞。根据微生物暴露的不同，人类白细胞抗原决定了它结合的交叉反应多肽的性质，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、表位的扩散和最终的器官损伤。本研究以Ro60作为候选自身抗原，以人类白细胞抗原-DR和-DQ转基因小鼠为研究对象，研究目的如下：1)研究Ro60上T细胞表位的分子模拟。2)证明多次暴露于Ro60 T细胞表位的多肽模拟物会影响Ro60反应性T细胞谱系。3)检测转人类白细胞抗原-DR3和-DQ2基因的狼疮易感NZM2328小鼠体内抗Ro60抗体启动的自身免疫反应的致病潜能。这项应用的发现将清楚地证明，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。这将把目前认为SLE主要是一种B细胞介导的疾病的模式转变为一种更合理的模式，在这种模式中，T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。 公共卫生相关性：目前的应用将从可能在系统性红斑狼疮中引发自身免疫反应的感染性病原体中识别蛋白质。这将确定可能是自身免疫性疾病(如狼疮)发展的诱因的感染性微生物。

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.