原发性胆汁性胆管炎（PBC）是一种自身免疫性肝脏疾病，其发病起于自身免疫系统攻击肝内小胆管造成胆管损伤及肝脏炎症，引起胆汁淤积，可发展为肝纤维化、肝硬化，甚至肝癌。由于其免疫学发病机制不清楚，目前尚无有效治疗手段。自身反应性T细胞在PBC发病过程中扮演了重要的角色，而免疫检查点分子对T细胞活化功能起到了重要的调控作用。我们前期研究发现，PBC患者肝脏胆管周围可检测到特异表达T细胞活化相关共刺激分子4-1BB的细胞浸润，而胆管上皮细胞则高表达4-1BBL。在PBC模型小鼠肝脏中我们同样发现特异高表达4-1BB的CD8+T细胞的存在，且其具有特殊的功能活化表型。本项目将明确4-1BB-4-1BBL通路活化与PBC疾病的相关性，深入探究该通路在CD8+T细胞损伤胆管细胞促进疾病发展中的作用及机制，并利用小鼠模型尝试靶向4-1BB/4-1BBL通路的PBC疗法，从而为PBC的临床治疗提供新的思路。

Primary biliary cholangitis (PBC) is a chronic biliary autoimmune disease characterized by immune system mediated bile duct damage and liver inflammation. PBC progresses from chronic inflammation at early stage, to liver fibrosis and eventually to cirrhosis and liver failure. The immunological pathogenesis of PBC remains unclear now, and the approved drugs can only slow down disease progression but fail to inhibit the autoimmune response. Auto-reactive T cells are believed to play an important role in the pathogenesis of PBC, and the activation or suppression of T cells is regulated by immune checkpoint molecules. 4-1BB is a kind of co-stimulatory checkpoint molecule. In our previous work, it is found that 4-1BB+ cells infiltrating around small bile duct in the liver of PBC patient but not healthy controls or other disease controls, while the bile duct epithelial cells express high level of 4-1BBL. On the other hand, 4-1BB+ CD8+T cells also are found to be infilatrating in the liver of PBC murine model, in which CD8+T cells mediate bile duct damage and portal inflammation. In this project, we aim to identify the relationship between 4-1BB/4-1BBL signaling and PBC disease, and then to investigate the role of 4-1BB/4-1BBL signaling in the pathogenesis of PBC, thus to help to provide novel therapeutic strategies of PBC.