MBL2基因突变调控T细胞分化在IgA肾病进展中的作用及分子机制研究

作为最常见的原发性肾小球肾炎，IgA肾病(IgAN)也是我国终末期肾衰最常见原因之一。辅助性T2细胞（Th2）异常增殖在IgAN肾损伤中起重要作用。有研究表明，补体甘露糖结合凝集素(MBL)通过其胶原样区(CLR)结合并抑制T细胞增殖，且MBL血清水平低表达与IgAN疾病进展相关，但机制不明。前期研究中，我们在多中心IgAN队列中进行MBL基因检测发现：与非突变者相比，携带G54D突变者的血清MBL表达水平更低，肾脏存活时间更短，Th2细胞百分比更高；进一步研究发现，G54D突变位于CLR区，且点突变后T细胞呈现Th2细胞转化趋势。因此，我们推测G54D突变后，MBL结合并抑制Th2细胞增殖的作用减弱，从而加重肾损。本课题立足于前期研究基础，通过已制备的G54D点突变鼠品系及T细胞，应用免疫共沉淀、蛋白质谱等技术，在整体-细胞-分子层次证明假说，为临床防治提供新靶点及思路。

As the most commonly occurring primary glomerulonephritis worldwide, IgA nephropathy (IgAN) is also one of the major causes of end-stage renal failure in China. Studies have confirmed that abnormities of helper T cell differentiation-especially abnormal proliferation of Th2 cell plays an important role in renal injury of IgAN. Complement mannose-binding lectin (MBL) binds to T cells through its collagen-like region (CLR) and inhibits cell proliferation. Low expression of MBL is associated with disease progression of IgAN, but the specific regulatory mechanisms remain unclear. Our preliminary study has confirmed that serum MBL levels in IgAN patients carrying MBL-G54D mutations are significantly reduced, kidney survival time is significantly shortened, and the percentage of Th2 cells is increased. The further experiments presented that the G54D mutation is located in the CLR region, and the T cells with G54D mutation had a tendency to transform into Th2 cells. Therefore, we speculate that the G54D mutation impaired the binding ability of MBL to Th2 cells, consequently the inhibitory effect is weakened, thereby aggravating renal damage. Based on our previous research, the aim of this study is to prove our hypothesis through the whole-cell-molecule levels by constructed mouse model with G54D mutation and T cell model, applied ChIP, protein mass spectrum and other techniques, thus providing new immunotherapy targets and ideas for clinical prevention and treatment.