链球菌激活C3a信号介导Th17细胞效应在肾脏炎症损伤中的作用

Renal inflammatory injury is always clinical exacerbation after upper respiratory tract infection. The exact pathogenesis is unknown. In our early study, we found that there is immunological imbalance of Th17/Treg in IgA Nephropathy. So we focus on the complement system being activated by respiratory infections, and suppose that hemolytic streptococcus activate C3a and interacted with the receptor C3aR in kidney, leading to the recruitment of pro-inflammatory leukocyte, which promote the differentiation and development of Th17 cells, and ultimately lead to the progression of immune-mediated kidney damages. Based on this, we are going to do the following: (1) Test C3a and Th17- related cytokines in IgA nephropathy patients, and analyse their relationships. (2) Establish an experimental model of IgA nephropathy infected by hemolytic streptococcus, and treat them with C3aR antagonist. (3) Treat the mesangial cells and lymphocyte stimulated by inactivate hemolytic streptococcus with C3aR antagonist, in order to reveal the role of complement system and the relationship between C3a and Th17 cells in kidney damage so as to find new targets to prevent the disease.

本项目从上呼吸道感染诱发或加重肾脏炎症的临床现象出发，在项目组前期研究结果“IgA肾病存在Th17/Treg免疫失衡”的基础上，以溶血性链球菌（HS）所致上呼吸道感染激活补体系统为切入点，提出链球菌感染激活补体C3a信号促进Th17细胞效应，触发肾脏炎症损伤的假说。基于此，本项目拟开展以下研究：（1）检测IgA肾病患者、HS感染IgA肾病患者外周血、尿液及肾组织C3a和Th17相关指标，分析Th17和补体与疾病的相关性；（2）建立HS感染的IgA肾病小鼠模型，应用C3aRa对其进行干预，明确链球菌感染诱发或加重IgA肾病过程中，是否通过C3a信号介导Th17细胞应答导致肾脏炎症损伤；（3）采用HS灭活菌株对人系膜细胞和淋巴细胞进行刺激，同时用C3aRa进行干预，进一步验证链球菌感染激活C3a信号介导Th17细胞应答的调控机制，为肾脏免疫炎症损伤的防治提供新的思路。

IgA肾病(IgAN)是全球最常见的原发性肾小球疾病。迄今为止，IgA肾病的发病机制尚不明确，缺乏对促进疾病进展的细胞类型和分子途径的综合分析。本项目以有或没有上呼吸道感染的IgAN患者为研究对象，检测外周血、尿液及肾组织C3a和Th17相关指标，分析了Th17和补体与疾病的相关性，同时建立HS感染的IgA肾病小鼠模型，应用C3aRa对其进行干预，探讨链球菌感染诱发或加重IgAN过程中，C3a信号介导Th17细胞应答导致肾脏炎症损伤的作用。我们发现IgAN患者Th17细胞和补体C3aR表达具有相关性，而链球菌感染诱发或加重IgAN过程中，激活了C3a/C3aR，促进Th17细胞效应参与肾脏免疫炎症损伤。同时我们采用肾组织单细胞RNA测序，揭示IgAN不同细胞基因表达特征、潜在的配体-受体作用、信号通路调控机制，为肾脏免疫炎症损伤的防治提供新的思路和治疗靶点。