补体系统活化在抗肾小球基底膜病肾脏损伤中的机制研究

补体系统的活化途径及其介导的炎症效应是抗GBM病肾脏损伤的重要环节。我们的前期工作发现在抗GBM病患者中，补体系统是充分激活的，活化部位主要集中在肾脏局部，活化的最终作用是导致肾脏的损伤，在疾病的发生发展中起促进作用，其中旁路途径的活化过程与肾脏的新月体形成和肾功能损害有密切联系。我们推测，在人类抗GBM病中，补体系统主要通过旁路途径活化，并直接参与肾脏炎症损伤的形成机制。本课题拟检测患者体内补体活化的三条途径中的启动因子、关键因子和促炎症因子，明确补体活化的途径；同时根据补体成分与肾脏损伤程度以及预后之间的关系，明确补体活化的关键环节以及导致肾脏损伤的发生机制。进一步针对已确定的关键分子，利用基因敲除的小鼠抗GBM肾炎模型，证实补体的活化途径及肾脏损伤机制；同时，寻找该途径中的重要调控分子及其作用方式。共同阐明补体系统活化在人类抗GBM病的肾脏损伤中的机制，并探索有针对性的治疗靶点。

The complement system activation pathways and their inflammatory effects are of key roles in the kidney injury of anti-GBM disease. Our previous studies have identified that in patients with anti-GBM disease, the complement system is activated thoroughly, with the activation location mainly restricted in the kidney. The pathogenic role of complement activation was also proven in our patients. Among the three activation pathways, we found that the level of factor B, the key component of the alternative pathway, showed closely positive correlation with the crescent formation in glomeruli and the severity of renal function damage. Thus, we hypothesized that in human anti-GBM disease, the complement system is activated mainly through the alternative pathway and plays a direct pathogenic role in the kidney injury. In this study, we planned to investigate the complement components in the plasma, urine and kidney tissues from our patients, including the promoters, the key factors and the pro-inflammatory effectors, in order to clarify the pathway of complement activation in human anti-GBM disease. Then we will analyze the relationship between the complement components and the severity of kidney injury, especially the renal outcomes during follow-up. It will help us to demonstrate the key factors in the activation pathway of complement and the inflammatory mechanisms leading to the kidney damage. Furthermore, we will set up the anti-GBM nephritis model using the Rag-1 knock-out mice and provide more evidence for the complement activation pathway and their pathogenic mechanism in the kidney. Finally, we will explore the regulatory factors in the pathway and their action pattern. This study will clarify the pathway of complement activation in human anti-GBM disease and their inflammatory mechanism leading to the kidney injury, and then explore the potentially therapeutic target based on the key factors.