肠道菌群调节肠粘膜ILC3细胞分化、归巢的机制及其与过敏性紫癜性肾炎相关性的研究

Henoch-Schönlein purpura nephritis is one of the common causes of chronic renal failure in children. Many studies have demonstrated that abnormalities of the mucosal immune system could be a key element in the pathogenesis of HSPN. But until now, the regulation of mucosal immune response and the mechanisms of how abnormal mucosal immune contributes to increased susceptibility to HSPN remain unclear. Our preliminary results have shown that there are increased G+ bacteria and decreased G- bacteria (such as bifidobacterium, lactobacillus, enterobacterium etc) in the intestinal tract of HSPN children. Interestingly, some commensal microbes which can stimulate production of IgA are significantly increased, such as prevotella. Innate lymphoid cells (ILCs), as the first defense line of immune system, play an important role in the interactions between mucosal immune system and gut flora, especially type 3 innate lymphoid cells (ILC3). So, in this study, we will investigate the regulatory mechanism of the differentiation and homing of ILC3, especially the role of gut flora in this process. Furthermore, we will focus on studying whether activated ILC3-mediated immune response contributes to the pathogenesis of HSPN. This study is helpful to understand the development, differentiation and homing of ILC3, and more importantly, will contribute to clarify the mechanisms of how disturbance of intestinal flora affects the progression of HSPN by regulating mucosal immune response, and possibly provides new clues and targets for the therapy of HSPN.

过敏性紫癜性肾炎（HSPN）是儿童慢性肾衰竭的主要病因之一。“粘膜—肾脏轴”为其关键的发病机制之一，但迄今为止，粘膜免疫应答的调控及其如何影响肾脏病变的机制还不清楚。我们的初步研究发现HSPN患儿肠道G+菌增多G-菌减少，且促IgA产生的细菌明显增多，如Prevotella。固有淋巴细胞（ILC）作为第一道防线，在微生物与粘膜免疫的对话中发挥着重要作用，其中ILC3亚群与肠道粘膜免疫的关系最为密切。本研究将利用基因工程鼠和粪菌移植鼠研究肠道菌群调节肠粘膜ILC3分化、归巢的机制，并进一步探讨肠道ILC3介导的免疫应答与HSPN发生、发展的相关性。该研究不仅有助于深入认识ILC3的发育分化过程，更有助于阐明肠道菌群通过调节粘膜免疫应答影响HSPN发生发展的机制，从而临床阻断该病的发生发展提供新思路。

过敏性紫癜性肾炎（HSPN）是儿童慢性肾衰竭的主要病因之一。“粘膜—肾脏轴”为其关键的发病机制之一，但迄今为止，粘膜免疫应答的调控及其如何影响肾脏病变的机制还不清楚。前期本课题组已发现HSPN患儿肠道G+菌增多而G-菌减少，存在显著的菌群差异。固有淋巴细胞（ILC）作为第一道防线，在微生物与粘膜免疫的对话中发挥着重要作用，其中ILC3亚群与肠道粘膜免疫的关系最为密切。本项目以HSPN患儿肠道菌群紊乱及其对粘膜免疫应答的影响为切入点，通过临床样本分析和构建小鼠粪菌移植模型，采用16s测序、功能磁共振、多重标记流式细胞术、基因芯片、qRT-PCR、共聚焦显微镜等技术，阐明了，HSPN患儿肠道菌群丰度下降，且存在显著的肠道菌群构成差异，拟杆菌属减少，Parabacteroides属增加；BOLD-MRI和IVIM-DWI是一种可行的无创评估HSPN患儿肾功能的方法；肠道粘膜固有层的ILC3参与介导HSPN模型鼠肾脏病变的发生；通过粪菌移植重塑肠道菌群可以减少ILCs介导的肠道粘膜免疫应答，促使Breg—效应B的平衡向Breg倾斜，从而减少IgA沉积于肾小球，最终改善HSPN模型鼠的肾脏病变。从而为深入认识HSPN发病机理和阻断该病的发生发展提供理论依据。