https://pubmed.ncbi.nlm.nih.gov/33248023/ Biliary atresia

Cell. 2020 Nov 26;S0092-8674(20)31455-0.
doi: 10.1016/j.cell.2020.10.048.Online ahead of print.

Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia

Jun Wang 1, Yanhui Xu 1, Zhanghua Chen 2, Jiankun Liang 1, Zefeng Lin 1, Huiying Liang 1, Yiping Xu 1, Qi Wu 1, Xuanjie Guo 1, Junli Nie 1, Bingtai Lu 1, Bing Huang 1, Huifang Xian 1, Xiaohui Wang 3, Qiang Wu 1, Jixiao Zeng 1, Chengwei Chai 1, Meixue Zhang 1, Yuzhen Lin 1, Li Zhang 1, Shanmeizi Zhao 1, Yanlu Tong 1, Liang Zeng 1, Xiaoqiong Gu 1, Zhuang-Gui Chen 4, Shuhong Yi 4, Tong Zhang 4, David Delfouneso 1, Yan Zhang 1, Stephen L Nutt 5, Andrew M Lew 5, Liwei Lu 3, Fan Bai 6, Huimin Xia 7, Zhe Wen 8, Yuxia Zhang 9

Abstract

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.