Department of Hepatology and Gastroenterology, Charité Universitätsmedizin, CVK, Berlin, Germany.
Hepatology. 2014 Feb;59(2):601-11. doi: 10.1002/hep.26702. Epub 2013 Dec 18.
The pathogenesis of primary sclerosing cholangitis (PSC) remains poorly understood. Since PSC predominantly occurs in patients with inflammatory bowel disease, autoimmunity triggered by activated T cells migrating from the gut to the liver is a possible mechanism. We hypothesized that T cells primed in the gut-associated lymphoid tissue (GALT) by a specific antigen migrate to the liver and cause cholangitis when they recognize the same antigen on cholangiocytes. We induced ovalbumin-dependent colitis in mice that express ovalbumin in biliary epithelia (ASBT-OVA mice) and crossed ASBT-OVA mice with mice that express ovalbumin in enterocytes (iFABP-OVA mice). We analyzed T-cell activation in the GALT and crossreactivity to the same antigen in the liver as well as the effects of colitis per se on antigen-presentation and T-cell activation in the liver. Intrarectal application of ovalbumin followed by transfer of CD8 OT-I T cells led to antigen-dependent colitis. CD8 T cells primed in the GALT acquired effector function and the capability to migrate to the liver, where they caused cholangitis in a strictly antigen-dependent manner. Likewise, cholangitis developed in mice expressing ovalbumin simultaneously in biliary epithelia and enterocytes after transfer of OT-I T cells. Dextran sodium sulfate colitis led to increased levels of inflammatory cytokines in the portal venous blood, induced activation of resident liver dendritic cells, and promoted the induction of T-cell-dependent cholangitis.
Our data strengthen the notion that immune-mediated cholangitis is caused by T cells primed in the GALT and provide the first link between colitis and cholangitis in an antigen-dependent mouse model.
原发性硬化性胆管炎（PSC）的发病机制仍不清楚。由于 PSC 主要发生在炎症性肠病患者中，因此由从肠道迁移到肝脏的活化 T 细胞引发的自身免疫可能是一种机制。我们假设在肠道相关淋巴组织（GALT）中被特定抗原激活的 T 细胞迁移到肝脏，并在识别到胆管细胞上的相同抗原时引起胆管炎。我们在表达胆道上皮细胞中卵清蛋白的小鼠（ASBT-OVA 小鼠）中诱导卵清蛋白依赖性结肠炎，并将 ASBT-OVA 小鼠与表达肠细胞中卵清蛋白的小鼠（iFABP-OVA 小鼠）杂交。我们分析了 GALT 中的 T 细胞活化以及肝脏中对相同抗原的交叉反应性，以及结肠炎本身对肝脏中抗原呈递和 T 细胞活化的影响。卵清蛋白经直肠内应用后，转移 CD8 OT-I T 细胞导致抗原依赖性结肠炎。在 GALT 中被激活的 CD8 T 细胞获得了效应功能和迁移到肝脏的能力，在肝脏中它们以严格依赖抗原的方式引起胆管炎。同样，在胆管上皮细胞和肠细胞中同时表达卵清蛋白的小鼠在转移 OT-I T 细胞后发生了胆管炎。葡聚糖硫酸钠结肠炎导致门静脉血液中炎症细胞因子水平升高，诱导驻留肝树突状细胞激活，并促进 T 细胞依赖性胆管炎的诱导。
我们的数据加强了这样一种观点，即免疫介导的胆管炎是由 GALT 中被激活的 T 细胞引起的，并为抗原依赖性小鼠模型中结肠炎和胆管炎之间提供了第一个联系。
