肠道菌群代谢产物通过调控黏膜来源成浆细胞参与IgA肾病发病机制研究

IgA肾病是全球最常见的原发肾小球肾炎，但其发病的关键环节致病性IgA分子的产生来源和调控机制尚未明确。新近临床RCT证明抑制肠道黏膜免疫是有效的治疗手段。项目组前期研究发现IgA肾病患者外周血黏膜来源成浆细胞水平显著升高，体外研究发现5种与IgA肾病相关的肠道菌群差异代谢产物可调节线粒体应激等通路，可能参与成浆细胞增殖和IgA抗体分泌。据此我们提出肠道菌群代谢产物通过调控黏膜来源成浆细胞参与IgA肾病发病的研究假说。我们将利用IgA肾病患者外周血、黏膜组织和肾脏组织样本，明确成浆细胞及肠道代谢产物的组织分布和作用方式；采用反映线粒体应激和内质网应激的ATF4和CHOP荧光报告质粒转染成浆细胞，探讨肠道代谢产物对成浆细胞增殖、凋亡、分泌功能的调控机制；构建gddY小鼠验证肠道菌群代谢产物的致病性及干预靶点。研究结果为黏膜免疫参与IgA肾病发病机制提供新的理论依据，为治疗提供新靶点。

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. The formation and deposition of galactose-deficient IgA1 (Gd-IgA1)-containing immune complex has been shown to play a central role in disease pathogenesis, but the origin and regulation of Gd-IgA1 remains unclear. Recent randomized controlled trial revealed the efficiency of targeting mucosal immunity in treatment of IgAN. Previously, we found that the plasmablasts of mucosal origin is elevated in peripheral blood of patients with IgAN. In vitro, we identified 5 IgAN associated fecal metabolites which were likely to regulate proliferation and IgA secretion of plasmablasts through mitochondrial stress pathways. Thus, we proposed the pathogenetic role of intestinal metabolites in IgAN by regulating plasmablasts of mucosal origin. In this project, first using peripheral blood, intestinal biopsies and kidney biopsies of patients with IgAN and healthy controls, we were to clarify the spatial distribution of the plasmablasts and intestinal metabolites; then by transfecting the ATF4- and CHOP- fluorescence reporter plasmids into plasmablasts, we were to identify the role of intestinal metabolites in cell proliferation, apoptosis and secretion through mitochondrial stress and endoplasmic reticulum stress; finally, we were to foster grouped ddY mouse model to validate the pathogenic role of the intestinal metabolites, and to search potential interventional targets by constructing plasmablast and IgA knock out mouse. The results will provide valuable insights of mucosal mechanism and treatment targets in IgAN.