Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia

Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency...

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Published in:	Cell Vol. 183; no. 7; p. 1867
Main Authors:	Wang, Jun, Xu, Yanhui, Chen, Zhanghua, Liang, Jiankun, Lin, Zefeng, Liang, Huiying, Xu, Yiping, Wu, Qi, Guo, Xuanjie, Nie, Junli, Lu, Bingtai, Huang, Bing, Xian, Huifang, Wang, Xiaohui, Wu, Qiang, Zeng, Jixiao, Chai, Chengwei, Zhang, Meixue, Lin, Yuzhen, Zhang, Li, Zhao, Shanmeizi, Tong, Yanlu, Zeng, Liang, Gu, Xiaoqiong, Chen, Zhuang-Gui, Yi, Shuhong, Zhang, Tong, Delfouneso, David, Zhang, Yan, Nutt, Stephen L, Lew, Andrew M, Lu, Liwei, Bai, Fan, Xia, Huimin, Wen, Zhe, Zhang, Yuxia
Format:	Journal Article
Language:	English
Published:	United States 23.12.2020
Subjects:	Animals Antigens, CD20 - metabolism B-Lymphocytes - immunology Biliary Atresia - blood Biliary Atresia - drug therapy Biliary Atresia - immunology Biliary Atresia - therapy Biopsy Cell Death Cell Line Cell Proliferation Cell Transdifferentiation Child Child, Preschool Cohort Studies CX3C Chemokine Receptor 1 - metabolism Cytotoxicity, Immunologic Disease Models, Animal Female Humans Immunoglobulin G - metabolism Infant Inflammation - pathology Killer Cells, Natural - immunology Kupffer Cells - pathology Liver - immunology Liver - pathology Liver Cirrhosis - blood Liver Cirrhosis - complications Liver Cirrhosis - immunology Liver Cirrhosis - pathology Lymphocyte Depletion Lymphopoiesis Male Mice, Inbred BALB C Phagocytosis Rituximab - administration & dosage Rituximab - pharmacology Rituximab - therapeutic use RNA - metabolism Rotavirus - physiology Single-Cell Analysis Th1 Cells - immunology Th17 Cells - immunology CX3CR1 B cell haematopoiesis biliary atresia scRNA-seq autoantibody hypo-inflammation Rituximab cytotoxicity TNFSF13B
ISSN:	1097-4172, 1097-4172
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Summary:	Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1 effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2020.10.048