Th9细胞对原发性胆汁性肝硬化胆管免疫微环境和胆管上皮细胞损伤的作用

Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by nonsuppurative inflammation of intrahepatic bile duct and damage of biliary epithelia. Recently described Th9 cell subset, which preferentially produces interleukin (IL)-9, was demonstrated to be involved in the pathogenesis of a wide spectrum of autoimmunities. Our previous study found that the level of IL-9 secreted by Th9 cells in peripheral blood in patients with PBC was significantly elevated compared with healthy subjects. The expression of IL-9 in liver tissue was significantly increased in PBC patients and positively correlated with PBC pathologic stages. Based on the facts, we hypothesize that Th9 cells may play a role in the regulation of immune microenviroment around bile ducts in PBC and directly promote intrahepatic biliary epithelial cells damage. Our study intends to answer the following scientific questions: 1. what effect does Th9 cell exert on the immune microenviroment around bile ducts? 2. Will Th9 cells make a difference on the expression of apoptosis-related genes，tight junction associated proteins or chemokine CX3CR1? Our results will be helpful in illustrating the pathogenesis of PBC and searching for potential therapeutic targets.

原发性胆汁性肝硬化（PBC）是以肝内小胆管非化脓性炎症和胆管上皮细胞损伤为特征的自身免疫性肝病。Th9细胞是一群新鉴定的T淋巴细胞亚群，它分泌的IL-9在多种自身免疫疾病中发挥重要免疫调节作用。我们前期研究发现，PBC患者外周血中由Th9细胞分泌的IL-9水平明显升高。PBC肝汇管区内IL-9阳性细胞聚集，其频率与PBC胆管损伤程度相关。据此，我们创新性提出 Th9 细胞参与了PBC胆管免疫微环境的调控，通过分泌IL-9直接影响胆管上皮细胞生物学行为和功能，进而促进胆管损伤。本研究拟回答以下科学问题：①Th9细胞对PBC胆管免疫微环境（Th1/Th17/B细胞/肥大细胞）有何影响？②Th9细胞对胆管上皮细胞的凋亡基因、紧密连接蛋白（Claudins）、趋化因子（CX3CR1）的表达有何作用？本研究有利于阐明PBC胆管损伤的免疫调节机制，提供潜在药物治疗靶点。

原发性胆汁性肝硬化(PBC)是以肝内胆汁淤积和胆管上皮细胞损伤为特征的自身免疫性肝病。Th9细胞是一群新鉴定的T淋巴细胞亚群，它分泌的IL-9在多种自身免疫疾病中发挥重要免疫调节作用。我们前期研究发现，PBC患者外周血IL-9水平明显升高，肝脏内IL-9阳性细胞聚集，其频率与PBC胆管损伤程度相关。据此，我们提出假设Th9细胞可能参与了PBC胆管免疫微环境的调控，促进了胆管损伤。本研究通过在IL-9敲除小鼠中构建DDC喂养诱导的慢性胆汁淤积模型，发现IL-9促进了T淋巴细胞、肥大细胞的增殖和聚集，介导了肝内Th1信号轴向Th17信号轴偏移的免疫调节。在体外研究中，通过高通量RNA测序以及定量RT-PCR验证发现IL-9可以上调人类胆管上皮细胞NIK以及趋化因子MCP-1和VCAM1的表达，提示IL-9可能通过非经典NF-kB信号通路促进胆管上皮损伤。本研究有利于阐明慢性胆汁淤积疾病的免疫调节机制，提供潜在治疗靶点。