Unique DUOX2+ACE2+ small cholangiocytes are pathogenic targets for primary biliary cholangitis

Xi Li, Yan Li, Jintao Xiao, Huiwen Wang, Yan Guo, Xiuru Mao, Pan Shi, Yanliang Hou, Xiaoxun Zhang, Nan Zhao, Minghua Zheng, Yonghong He, Jingjing Ding, Ya Tan, Min Liao, Ling Li, Ying Peng, Xuan Li, Qiong Pan, Qiaoling Xie, Qiao Li, Jianwei Li, Ying Li, Zhe Chen, Yongxiu Huang, David N. Assis, Shi-Ying Cai, James L. Boyer, Xuequan Huang (), Can-E Tang (), Xiaowei Liu (), Shifang Peng () and Jin Chai ()
Additional contact information
Xi Li: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Yan Li: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Jintao Xiao: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Huiwen Wang: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Yan Guo: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Xiuru Mao: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Pan Shi: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Yanliang Hou: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Xiaoxun Zhang: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Nan Zhao: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Minghua Zheng: the First Affiliated Hospital of Wenzhou Medical University
Yonghong He: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Jingjing Ding: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Ya Tan: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Min Liao: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Ling Li: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Ying Peng: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Xuan Li: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Qiong Pan: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Qiaoling Xie: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Qiao Li: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)
Jianwei Li: Third Military Medical University (Army Medical University)
Ying Li: Third Military Medical University (Army Medical University)
Zhe Chen: Third Military Medical University (Army Medical University)
Yongxiu Huang: Third Military Medical University (Army Medical University)
David N. Assis: Yale University School of Medicine
Shi-Ying Cai: Yale University School of Medicine
James L. Boyer: Yale University School of Medicine
Xuequan Huang: Third Military Medical University (Army Medical University)
Can-E Tang: Central South University
Xiaowei Liu: Central South University
Shifang Peng: Central South University
Jin Chai: the First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University)

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-022-34606-w

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