Role of T Cells in Mediating Glomerulonephritis

描述（由申请人提供）：在本申请中，我们提出研究抗原特异性CD 4 + 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。然而，在现有的GN模型中，抗原特异性T细胞在很大程度上未被分析。目前尚不清楚抗原特异性T细胞是否以及如何介导肾小球损伤。根据我们在T细胞介导的自身免疫性疾病方面的经验，我们正在研究对自身抗原Col 4 α 3 NC 1（肾小球基底膜的关键成分）特异性的T细胞在大鼠GN模型中的作用。我们发现：1）Col 4 α 3 NC 1的13-mer T细胞肽诱导类似于人晚期新月体GN的致命性GN; 2）Col 4 α 3 NC 1特异性TH-1型CD 4 + T细胞在幼稚受体中转移严重GN; 3）T细胞的转移诱导单核细胞/T细胞流入肾皮质。因此，抗原特异性CD 4 + T细胞可能直接介导肾小球损伤并引起GN。 我们假设抗原特异性CD 4 + T细胞介导的肾小球损伤机制如下：1。对自身抗原Col 4alpha 3 NC 1特异性的CD 4 + T细胞通过微生物抗原的分子模拟被激活; 2.活化的T细胞识别MHC II类+肾小球细胞的亚群; 3.识别触发单核细胞/T细胞流入肾小球;启动并维持肾小球炎症。我们将利用我们基于Col 4 α 3特异性CD 4 T细胞和T细胞表位的独特模型来验证我们的假设：1）我们将基于13-mer T细胞肽的特征鉴定来自微生物抗原的模拟T细胞肽：2）我们将研究MHC II类+肾小球细胞亚群的抗原呈递能力，其可能作为CD 4 + T细胞的靶点; 3）研究T细胞移植后浸润的单核细胞和T细胞在肾小球炎症的发生和维持中的作用。

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.