Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia

• Published in: Cell Vol. 183; no. 7; pp. 1867 - 1883.e26
• 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 Elsevier Inc 23.12.2020
• Subjects: abnormal development; Animals; antigen presentation; Antigens, CD20 - metabolism; autoantibody; B cell haematopoiesis; B-lymphocytes; B-Lymphocytes - immunology; biliary atresia; 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; CX3CR1; cytotoxicity; Cytotoxicity, Immunologic; Disease Models, Animal; Female; Humans; hypo-inflammation; immunoglobulin G; Immunoglobulin G - metabolism; Infant; Inflammation - pathology; Killer Cells, Natural - immunology; Kupffer Cells - pathology; liver; Liver - immunology; Liver - pathology; Liver Cirrhosis - blood; Liver Cirrhosis - complications; Liver Cirrhosis - immunology; Liver Cirrhosis - pathology; liver failure; Lymphocyte Depletion; Lymphopoiesis; Male; Mice, Inbred BALB C; pathogenesis; Phagocytosis; Rituximab; Rituximab - administration & dosage; Rituximab - pharmacology; Rituximab - therapeutic use; RNA; RNA - metabolism; Rotavirus - physiology; scRNA-seq; Single-Cell Analysis; T-lymphocytes; Th1 Cells - immunology; Th17 Cells - immunology; therapeutics; TNFSF13B; CX3CR1; biliary atresia; B cell haematopoiesis; scRNA-seq; autoantibody; hypo-inflammation; Rituximab; cytotoxicity; TNFSF13B
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2020.10.048

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. [Display omitted] •trans-Differentiation of cytotoxic Th17 to Th1 cells promotes liver pathology•CX3CR1+CD8Teff cells inhibit fibrosis by granzyme-mediated killing of fibroblasts•Defective induction of hepatic B cell tolerance promotes autoimmunity in infants•B-cell-modifying therapies promote immune recovery in infants with biliary atresia Liver immune profiling in infants with biliary atresia suggests B-cell-modifying therapies may alleviate liver pathology