足细胞高表达磷脂酶A2受体在膜性肾病中的机制研究

原发性膜性肾病是抗磷脂酶A2受体（PLA2R）抗体介导的自身免疫病。申请人的前期工作明确了该病的易感HLA II类分子及其递呈的PLA2R的T细胞抗原表位，发现正常人对PLA2R的免疫稳态主要通过外周免疫耐受实现，足细胞高表达PLA2R可能是打破免疫耐受、发生自身免疫反应的主要原因。PLA2R通过降解sPLA2负调控炎症反应，并引起细胞凋亡。我们推测：某些炎症介质可能刺激足细胞高表达PLA2R，一方面打破免疫耐受，产生自身抗体，一方面直接导致足细胞损伤，发生病理改变。本课题围绕足细胞高表达PLA2R，拟从诱发原因、细胞效应和干预途径三方面，明确足细胞高表达PLA2R的原因；阐明高表达的PLA2R诱导自身免疫反应和导致足细胞损伤的机制；寻找抑制足细胞表达PLA2R的化合物。为阐明膜性肾病的发病机制及开发新的治疗手段提供线索。

Primary membranous nephropathy is an autoimmune disease mediated by anti-phospholipase A2 receptor (PLA2R) antibodies. The over-expression of PLA2R on podocyte membrane has been observed precedes the production of circulating antibodies and persists after the antibody clearance and clinical remission. Our previous studies have identified the risk HLA class II genotypes and their encoding molecules, and detected the T cell epitopes of PLA2R presented these HLA molecules. We found that the immune homeostasis to PLA2R was mainly achieved by peripheral immune tolerance in healthy individuals, and the over-expression of PLA2R in podocytes might break the immune tolerance and initiate autoimmune disorder. PLA2R can negatively regulate inflammatory response through the degradation of sPLA2 and induce cell apoptosis. We hypothesis that some inflammatory mediators may stimulate the over-expression of PLA2R in podocytes, on the one hand, to break the immune tolerance and produce autoantibodies, on the other hand, to directly induce podocyte injury and apoptosis. This project focuses on the over-expression of PLA2R in podocytes, we aim to identify the stimulating factors, to clarify the cellular effects, and potential intervention chemical molecules. We aim to provide clues for elucidating the pathogenesis of membranous nephropathy and developing novel therapeutic agents.