肠道IgA大量分泌的分子机制及其在炎症性肠病中的应用

Inflammatory bowel disease (IBD) is an incurable chronic intestinal disease. Mucosal IgA plays a critical role in maintaining diverse and balanced bacteria and suppressing intestinal inflammation. This project focuses on the endoplasmic reticulum-localized protein MZB1, which we recently discovered to mediate IgA-J chain binding and promote IgA secretion into the gut. By using the latest technologies including single-cell RNA sequencing, two-photon fluorescence microscopy, CRISPR/Cas9-mediated genome editing and native mass spectrometry, combined with routine immunological experiments, animal disease models and analysis of clinical samples, we aim to elucidate the molecular mechanism of MZB1-mediated mucosal IgA secretion and the effect of oral IgA administration on the prevention and treatment of gut inflammatory diseases and colorectal cancer. The results of this project should deepen our understanding of the pathogenesis of IBD and provide new insights and strategies for the clinical application of IgA and IgM.

炎症性肠病（IBD）是难以治愈的慢性肠道疾病。肠道分泌的IgA是维持肠道菌群平衡和多样性、抑制炎症性肠病的重要因子。本项目围绕中国人高发的IBD及IBD诱发的结直肠癌，聚焦自主发现的介导IgA-J链结合、促进IgA肠道分泌的内质网蛋白MZB1的功能，运用单细胞测序、双光子荧光显微成像、CRISPR/Cas9基因编辑、非变性质谱分析等最新技术，结合常规免疫实验，动物疾病模型以及临床样本分析，阐明MZB1介导的肠道IgA大量分泌的分子机制，以及口服IgA对预防和治疗炎症性肠病及结直肠癌的作用和机制。本项目的结果将加深对IBD的发病机制的理解，并为IgA及IgM应用于临床治疗提供充分的理论基础。

炎症性肠病（IBD）是难以治愈的慢性肠道疾病。肠道分泌的IgA是维持肠道菌群平衡和多样性、抑制炎症性肠病的重要因子。本项目围绕中国人高发的IBD及IBD诱发的结直肠癌，聚焦自主发现的浆细胞特异性分子伴侣MZB1，阐明MZB1介导肠道IgA大量分泌的细胞和分子机制，以及口服IgA对预防和治疗炎症性肠病及结直肠癌的作用和机制。我们发现，1）MZB1促进IgA二聚体和单体的分泌，而J链只介导IgA二聚体的形成，不影响IgA单体的分泌；2）在稳态状态下，肠道IgA和IgM都来源于B-1细胞；3）MZB1缺陷导致DSS诱导性肠道炎症加剧，结直肠癌发生率上升；口服IgA能够有效缓解肠道炎症；4）跟健康人相比，溃疡性结肠炎患者的血清IgA2水平显著上升。本项目的结果进一步阐明了IgA的质和量的调控机制，加深了对IBD的发病机制的理解，并为IgA的临床应用打下了基础。