原发性膜性肾病是自身免疫性肾脏病，磷脂酶A2受体（PLA2R）是主要的靶抗原。在发病中存在B细胞抗原表位的扩展过程，且与疾病的发生发展密切相关。我们推测：该过程的初始阶段，自身免疫性T细胞和自身抗体共同识别的线性抗原表位，可能是疾病的启动因素。CD4+ T细胞识别抗原表位后，不仅能够诱导B细胞产生自身抗体，发生抗原表位扩展，导致疾病发生；还可以直接浸润到肾组织，释放细胞因子，参与肾小球的炎症损伤。因此，明确PLA2R的T细胞抗原表位是阐明该病发病机制的关键环节。我们的前期工作明确了疾病的易感HLA II类基因型及其编码的HLA分子上的关键氨基酸，并对其递呈的PLA2R的T细胞抗原表位进行了预测和初步验证。申请人拟从抗原递呈复合物入手，明确易感HLA分子递呈的PLA2R的T细胞抗原表位，确定T/B细胞共同识别的初始表位及其关键氨基酸，阐明识别各抗原表位的T细胞亚群组成及其在发病机制中的作用。

Primary membranous nephropathy is an autoimmune kidney disease, with M type phospholipase A2 receptor (PLA2R) as the major target antigen. Epitope spreading process exists in disease development and has close associations with disease severity and clinical remission. We hypothesize that the initial epitope of spreading process, which could be recognized both by autoreactive T cells and by B cells, may be the crucial player in disease mechanism. After epitope recognition, CD4+ T cells stimulate and induce antibody production by B cells, which later on undergo epitope spreading process and lead to podocyte damage, electron dense deposits, and glomerular basement membrane thickening of primary membranous nephropathy. T cell infiltration may also participate in the inflammation injury of kidney by secreting different cytokines. Thus, T cell epitope mapping is essential for the investigations on pathogenesis. Our previous studies found two risk alleles, HLA-DRB1*1501 and DRB1*0301, which were susceptible for primary membranous nephropathy by encoding arginine13 and alanine71, and lysine71 on DRβ chain of HLA molecule for antigen presentation. We further predicted the possible T cell epitopes on PLA2R which may be presented by the susceptible HLA molecules and confirmed some of them by examinations. In this project, we aim to define the PLA2R T cell epitopes presented by the susceptible HLA molecules, identify the initial epitope by mutual T/B cell recognition and the critical amino acids in it, and elucidate the autoreactive T cell profile against each epitope and their roles in disease pathogenesis.