Crry（补体受体相关基因y）介导的Th1 向Th2 转化在肾纤维化中的作用及机制研究

Renal fibrosis is the common consequence of all types of renal diseases at the end stage. Infiltration and activation of CD4+ T cells could be an important early event that mediates the onset of renal fibrogenesis. Studies have shown that the switch of immune response from Th1 type to Th2 type resulting in the imbalance of Th1/Th2 is the pivotal mechanism of renal fibrosis. It is a hot topic to find the initial factors that induce the imbalance of Th1/Th2 and inhibit the switch to Th2 in renal fibrosis.Our previous study has shown that complement fragments C3b/C4b deposited on the surface of activated Th1 cells during renal fibrosis. Crry (complement receptor-related gene y), the receptor of C3b/C4b was high expressed on the surface of Th1 cells. Our study further indicated that Crry as costimulatory molecules activated Th cells resulting in the release of Th2 cytokines such as IL-13 and IL-4. Therefore, we put forward the proposal that Crry plays the pivotal role in the balance of Th1/Th2 and promotes the switch from Th1 to Th2 by binding complement fragments C3b/C4b from complement activation during renal injury, which accelerates the process of renal fibrosis. We aim to investigate the role of the switch from Th1 to Th2 mediated by Crry in renal fibrosis and explore the mechanism of the switch from Th1 to Th2 mediated by Crry. We hope to target the switch from Th1 to Th2 by Crry pathway to inhibit or reverse the process of renal fibrosis. This study will provide a new insight into the mechanism of cellualr immunity for renal fibrosis and new approach to prevent renal fibrosis.

肾纤维化是多种肾脏疾病发展至终末期的共同通路,CD4+T（Th）细胞浸润是重要的早期启动因素之一。研究表明免疫反应由Th1向Th2转化 而导致的Th1/Th2失衡是肾纤维化进展的重要机制。探寻肾纤维进展中Th1/Th2失衡的始动因素，抑制向Th2转化是肾纤维化研究的热点之一。前期实验发现肾纤维化中的Th1细胞表面补体C3b/C4b沉积，受体Crry表达上调。进一步发现Crry可作为共刺激分子促进Th细胞活化，释放Th2细胞因子。我们推测：补体激活后,补体片段C3b/C4b与 Th1表面 Crry结合，介导Th1向Th2转化,导致Th1/Th2失衡，促进肾纤维化的进展。本课题拟研究Crry介导的Th1 向Th2 转化对肾纤维化的作用及机制，并以该途径为干预靶点延缓肾纤维化进展。本研究以Crry介导的Th1向Th2转化为新视点揭示肾纤维化的细胞免疫机制，为肾纤维化的防治提供新思路。

肾纤维化是多种肾脏疾病发展至终末期的共同通路,CD4+T（Th）细胞浸润是重要的早期启动因素之一。研究表明免疫反应由Th1向Th2转化 而导致的Th1/Th2失衡是肾纤维化进展的重要机制。本课题体外实验验证了Crry可以介导的Th1 向Th2 转化；并通过建立小鼠肾纤维化UUO模型，发现体内输注Crry介导的Th2或C3b/C4b诱导的Th1向Th2 转化可促进小鼠肾纤维化，表现为a-SMA, Fibronectin和CollagenI 升高，与之相反，anti-C3b/C4b可抑制输注或体内的Th1与C3b/C4b的作用，延缓小鼠肾纤维化的进展。实验进一步显示Crry介导的Th1向Th2转化可能通过P38-MARP活化的信号转导通路。本研究以Crry介导的Th1向Th2转化为新视点揭示肾纤维化的细胞免疫机制，为肾纤维化的防治提供新思路。