PRDM1/IgG4通过浆细胞/单核细胞在炎症性肠病发病机制中的作用及机制研究

Inflammatory bowel disease (IBD) is a chronic and complex disease. Genetics studies have reported that some SNPs on 6q21 contribute to IBD susceptibility in the West. Loss of function of PRDM1 on 6q21 can lead to severe colitis in mouse. A subset of IBD patients exhibit high level of serum IgG4 and massive infiltration of IgG4+ plasma cells in lamina propria. These values can be higher than international diagnostic criteria of IgG4-RD, furthermore there are associated with clinical characters. IgG4`s receptor is mainly found on monocyte. Here we suggest an innovative hypothesis: PRDM1/IgG4 may play a role via plasma cells and monocytes in the pathogenesis of IBD. Based on this hypothesis, this project sets out to investigate whether three common SNPs on 6q21 are related to Chinese IBD, and regulate expression of their positional candidate gene PRDM1, to explore how PRDM1 regulates production of IgG4 in plasma cells. And we set out to explore how IgG4 regulates expression of pro/anti- inflammatory cytokines in monocytes in PBMC and LPMC from patients and DSS colitis mouse model. Furthermore, we continue to clinically investigate the situation of serum IgG4 and IgG4+ plasma cell infiltration in mucosa, and their correlation with clinical characters of IBD. This will be very helpful to explore IgG4-related IBD in future.

炎症性肠病（IBD）是一种慢性复杂性疾病。6q21区有SNPs与西方人群IBD易感性相关，而该区PRDM1功能缺失可导致小鼠结肠炎。部分IBD患者血清IgG4浓度和/或肠粘膜内IgG4+浆细胞浸润计数，可超过IgG4-RD国际诊断标准，且与临床特征相关。IgG4受体主要表达于单核细胞。所以我们创新性提出假说: PRDM1/IgG4可能通过浆细胞/单核细胞在IBD发病机制中起着调节作用。本研究将由此全面展开。验证在6q21区3个常见SNPs是否亦与我国IBD相关，EQTL法研究其与PRDM1表达关系。PRDM1怎样调节浆细胞的IgG4表达。在患者和动物模型的外周血和粘膜细胞中，研究IgG4怎样影响单核细胞内抗炎/促炎细胞因子的表达。另继续扩大样本研究我院IBD患者血清IgG4和肠粘膜IgG4+浆细胞浸润情况，以及与疾病特征关系。为将来深入研究IgG4相关的一亚类IBD患者奠定基础。

炎症性肠病（IBD）是一种慢性复杂性疾病。6q21区有SNPs与西方人群IBD易感性相关，而该区PRDM1功能缺失可导致小鼠结肠炎。部分IBD患者血清IgG4浓度和/或肠粘膜内IgG4+浆细胞浸润计数，可超过IgG4-RD国际诊断标准，且与临床特征相关。IgG4受体主要表达于单核细胞。所以我们创新性提出假说: PRDM1/IgG4可能通过浆细胞/单核细胞在IBD发病机制中起着调节作用, 本研究将由此全面展开。我们研究发现，既往西方报道的6Q21区域PRDM1附近与IBD相关的SNPs在我国IBD患者中缺如，提示我国与西方IB患者有一定的遗传学差异。IBD中确存在小部分患者的血清和/或肠组织IgG4的表达水平升高，且对于这部分IBD患者，UC与CD间血清及肠组织中IgG4表达水平无明显差异，但其血清IgG4/IgG比值及肠组织中IgG4+PC数目明显高于健康人群。此外，这部分IBD患者经激素等治疗后，经激素治疗的患者，随着疾病活动度降低，血清及肠组粘膜IgG4水平明显降低。进一步研究了PRDM1是如何影响浆细胞的IgG4表达，以及在患者和动物模型的外周血和粘膜细胞中，研究IgG4怎样影响单核细胞内抗炎/促炎细胞因子的表达。此研究提示IgG4可能在部分IBD患者发病机制中起着重要作用. 而且针对这部分患者，可以IgG4高表达为一个分型标记物，对其进行精准的亚型分析，通过将来进一步深入分析，有助于这部分患者的诊断治疗改善。