Unique DUOX2(+)ACE2(+) small cholangiocytes are pathogenic targets for primary biliary cholangitis.
Unique DUOX2(+)ACE2(+) small cholangiocytes are pathogenic targets for primary biliary cholangitis.
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DOI：
10.1038/s41467-022-34606-w
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发表时间：
2023-02-09
影响因子：
16.6
通讯作者：
Chai, Jin
中科院分区：
文献类型：
--
作者：
Li, Xi;Li, Yan;Xiao, Jintao;Wang, Huiwen;Guo, Yan;Mao, Xiuru;Shi, Pan;Hou, Yanliang;Zhang, Xiaoxun;Zhao, Nan;Zheng, Minghua;He, Yonghong;Ding, Jingjing;Tan, Ya;Liao, Min;Li, Ling;Peng, Ying;Li, Xuan;Pan, Qiong;Xie, Qiaoling;Li, Qiao;Li, Jianwei;Li, Ying;Chen, Zhe;Huang, Yongxiu;Assis, David N.;Cai, Shi-Ying;Boyer, James L.;Huang, Xuequan;Tang, Can-E;Liu, Xiaowei;Peng, Shifang;Chai, Jin
胆管细胞在胆汁形成中起着至关重要的作用。胆管细胞损伤引起胆汁淤积，包括原发性胆道胆管炎（PBC）。然而，PBC的病因尚不清楚，尽管它被定性为一种自身免疫性疾病。通过单细胞RNA测序（scRNA-seq）、荧光激活细胞分选、多重免疫荧光（IF）和RNAscope分析，我们在人和小鼠肝脏中鉴定出独特的DUOX2+ACE2+小胆管细胞。它们在PBC患者中的选择性减少与疾病的严重程度有关。此外，蛋白质组学、scRNA-seq和qPCR分析表明，聚合免疫球蛋白受体（pIgR）在DUOX2+ACE2+胆管细胞中高表达。无论AMA-M2阳性还是阴性，PBC患者血清抗pigr自身抗体水平均显著升高。空间转录组学和多重IF揭示了PBC患者肝门静脉束中CD27+记忆B和浆细胞的积累。总之，DUOX2+ACE2+小胆管细胞是PBC的致病靶点，保存DUOX2+ACE2+胆管细胞和靶向抗pigr自身抗体可能是PBC治疗干预的有价值的策略。原发性胆管炎（PBC）的病因尚不清楚。在这里，作者发现人类和小鼠肝脏中DUOX2 + ACE2 +小胆管细胞的数量与疾病严重程度呈负相关，并且目前的数据表明它们可能是聚合免疫球蛋白受体（pIgR）介导的体液反应的目标，这表明保存这些细胞和靶向抗pIgR自身抗体可能是PBC治疗干预的有价值的策略。
Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2+ACE2+ small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2+ACE2+ cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27+ memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2+ACE2+ small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2+ACE2+ cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC. The aetiology of primary biliary cholangitis (PBC) remains unclear. Here, the authors find that the numbers of DUOX2 + ACE2 + small cholangiocytes in human and mouse livers are inversely associated with disease severity, and present data indicating that they may be the target of polymeric immunoglobulin receptor (pIgR) -mediated humoral responses, suggesting that preservation of these cells and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.
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DOI：
10.1016/j.clinre.2019.05.002
发表时间：
2020-02-01
影响因子：
2.7
作者：
Liberal, Rodrigo;Gaspar, Rui;Macedo, Guilherme
通讯作者：
Macedo, Guilherme
影响因子：
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影响因子：
25.7
作者：
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通讯作者：
Trautwein, Christian