Role of T Cells in Mediating Glomerulonephritis

描述(申请人提供)：在这项申请中，我们建议调查抗原特异性的CD4+T细胞如何介导肾小球损伤，这是导致肾小球肾炎(GN)的第一个关键步骤。T细胞机制已成为GN中潜在的最重要的介质。然而，在现有的GN模型中，抗原特异性T细胞在很大程度上没有被分析。目前尚不清楚抗原特异性T细胞是否以及如何在GN中介导肾小球损伤。根据我们在T细胞介导的自身免疫性疾病方面的经验，我们正在研究自身抗原Col4alpha3NC1的特异性T细胞在大鼠肾小球肾炎模型中的作用。我们发现：1)COL4Alpha3NC113聚体T细胞多肽诱导的致死性GN类似于人类晚期新月体GN；2Col4Alpha3NC1TH-1型特异性CD4+T细胞在幼稚受者中转移严重GN；3T细胞转移诱导单核细胞/T细胞进入肾皮质。因此，抗原特异性的CD4+T细胞可能直接介导肾小球损伤并导致肾小球肾炎。 抗原特异性的CD4+T细胞介导的肾小球损伤的假设机制如下：1.自身抗原Col4alpha3NC1特异性的CD4+T细胞通过微生物抗原的分子模拟而被激活；2.活化的T细胞识别MHC II+亚群的肾小球细胞；3.识别触发单核细胞/T细胞进入肾小球；肾小球炎症被启动和维持。通过我们基于Col4alpha3特异性CD4T细胞和T细胞表位的独特模型，我们将检验我们的假设：1)我们将基于13-聚T细胞肽的特性从微生物抗原中鉴定出一个模拟的T细胞肽；2)我们将研究MHC II+肾小球细胞亚群的抗原提呈能力，这可能是CD4+T细胞的靶标；3)我们将研究T细胞转移后浸润性单核细胞和T细胞在肾小球炎症启动和维持中的作用。

DESCRIPTION (provided by applicant): In this application, we propose to investigate how antigen specific CD4+ T cells mediate glomerular injury, the first key step leading to glomerulonephritis (GN).T cell mechanisms have emerged as potentially the most important mediators in GN. However, antigen specific T cells are largely unanalyzed in existing GN models. It is unknown whether and how antigen specific T cells mediate glomerular injury in GN. Guided by our experience in T cell mediated autoimmune disease we are investigating the roles of T cells specific to autoantigen Col4alpha3NC1, a critical component of glomerular basement membrane, in a rat GN model. We discovered: 1) a 13-mer T cell peptide of Col4alpha3NC1 induced fatal GN similar to human late stage cresentic GN; 2) Col4alpha3NC1 specific CD4+ T cells of TH-1 type transferred severe GN in the naive recipients; 3) transfer of the T cells induced influx of monocytes/T cells into renal cortex. Thus, antigen specific CD4+ T cells may directly mediate glomerular injury and cause GN. Our hypothetical mechanism of glomerular injury mediated by antigen specific CD4+ T cells is as follows: 1. CD4+ T cells specific to autoantigen Col4alpha3NC1 are activated through molecular mimicry by microbial antigens; 2. activated T cells recognize a subpopulation of MHC class II+ glomerular cells; 3. recognition triggers monocytes/T cells influx into glomeruli; glomerular inflammation is initiated and maintained. With our unique model based on Col4alpha3 specific CD4 T cells and the T cell epitope, we will test our hypotheses: 1) We will identify a mimicking T cell peptide from microbial antigens based on the characterization of the 13-mer T cell peptide; 2) We will investigate the antigen presenting capacity of the MHC class II+ glomerular cell subpopulation, which may serve as the target for CD4+ T cells; 3) We will investigate the roles of infiltrating monocytes and T cells in the initiation and maintenance of glomerular inflammation after T cell transfer.