Wang Yu-Wen, Lin Chia-I, Chen Hung-Wen, Wu Jui-Ching, Chuang Ya-Hui
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
J Transl Autoimmun. 2022 Dec 21;6:100182. doi: 10.1016/j.jtauto.2022.100182. eCollection 2023.
Primary biliary cholangitis (PBC) is a female-predominant liver autoimmune disease characterized by the specific immune-mediated destruction of the intrahepatic small bile duct. Although apoptosis of biliary epithelial cells (BECs) and alterations in gut microbiota are observed in patients with PBC, it is still unclear whether these events happen in the early stage and cause the breakdown of tolerance in PBC. In this study, we examined the early events in the loss of tolerance in our well-defined 2-OA-OVA-induced murine autoimmune cholangitis (AIC) model. We report herein that apoptosis of BECs was notable in the early stage of murine AIC. An altered gut microbiota, in particular, an increased percentage of gram-positive in AIC mice was also observed. BECs in AIC mice expressed adhesion molecule ICAM-1, cytokines/chemokines TNF-α, CCL2, CXCL9, CXCL10, and toll-like receptor (TLR) 2. Moreover, BECs treated with TLR2 ligand had elevated apoptosis and CXCL10 production. These data collectively suggest a new mechanism of tolerance breakdown in AIC. Altered gut microbiota induces apoptosis of BECs through TLR2 signaling. BECs secrete chemokines to recruit CD8 T cells to damage BECs further.
原发性胆汁性胆管炎（PBC）是一种以女性为主的肝脏自身免疫性疾病，其特征是肝内小胆管受到特异性免疫介导的破坏。尽管在PBC患者中观察到胆管上皮细胞（BEC）凋亡和肠道微生物群改变，但仍不清楚这些事件是否发生在早期并导致PBC的耐受性破坏。在本研究中，我们在明确的2-OA-OVA诱导的小鼠自身免疫性胆管炎（AIC）模型中研究了耐受性丧失的早期事件。我们在此报告，BEC凋亡在小鼠AIC早期很明显。还观察到肠道微生物群改变，特别是AIC小鼠中革兰氏阳性菌百分比增加。AIC小鼠中的BEC表达粘附分子ICAM-1、细胞因子/趋化因子TNF-α、CCL2、CXCL9、CXCL10和Toll样受体（TLR）2。此外，用TLR2配体处理的BEC凋亡增加且CXCL10产生增加。这些数据共同提示了AIC中耐受性破坏的新机制。肠道微生物群改变通过TLR2信号传导诱导BEC凋亡。BEC分泌趋化因子以募集CD8 T细胞进一步损伤BEC。
