Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remainsto be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffercell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1+effector T and naturalkiller (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did notcease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumula-tion in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation amelio-rated liver damage. Biliary atresia (BA) is a severe cholangiopathy mediated by extra-hepatic bile duct obstruction, causing pathological jaundice andliver failure in early infancy . The incidence of BA varies geographically, ranging from 1 in every 5,000–18,000 livebirths. Multifactorial etiological factors, fromboth developmental and environmental origins, contribute to dis-ease development. Hepatoportoenterostomy (Kasai’s operation) is required to re-move the duct remnants after diagnosis. If untreated, BA progression to end-stage liver cirrhosis is rapid, usually within 1 year. After Kasai’s operation, approximately50% of the BA patients will require liver transplantation with in the first 2 years of life due to liver cirrhosis, and most of theremainder children relying on their native livers will suffer long-term complications, including repeated cholangitis, portal hyper-tension, esophageal variceal bleeding, and hepatic osteodystro-phy. Virus-associated autoimmune destruction of the bile duct hasbeen considered an important contributor of BA pathogenesis. CD68+macro-phages and interferon-g(IFN-g)-secreting CD4+and CD8+T cells accumulated around the portal tracts (Mack et al.,2004) and biliary ductal epithelium in infants with BA. In a rhesus rotavirus (RRV)-induced BA mouse model, blocking IFN-g production prevented the inflammatory and fibrosing obstruction of the extrahepatic bile ducts. Analysis of T cell receptor (TCR) b-chain variable regions had uncovered oligoclonal expansion of infiltrating CD4+and CD8+T cells in infants with BA. In addition, the immunoglobulin (Ig) repertoire in the biliary remnants of BA patients was also oligoclonal. IgM and IgG autoantibodies deposited along the basement of the bileduct epithelia and autoantibodies that target epitheliala-enolase had been shown to cross-react withviral antigens in infants with BA. Auto antibodies were also highly elevated in the circulation in infants with BA. Notwithstanding the above information, a comprehensive description of immune dysfunction that leadsto rapid liver failure in infants with BA has yet to be established. Study, profiled mononuclear immune cells (granulo-cyte depleted) from liver biopsies and blood of infants with BA, and compared the profiles with those of control subjects at single-cell resolution. We identified 42 cell subsets encompassing tissue-resident and circulating conventional (CD4+and CD8+T)and unconventional (natural killer T [NKT], mucosal-associate dinvariant T [MAIT], gamma-delta T [gdT]) T cells, B cells, innate lymphoid cells (natural killer [NK], type 1 innate lymphoid cells[ILC1s]), monocytes, macrophages, dendritic cells (DCs), andKupffer cells. Importantly, we showed that B cell lymphopoiesisin the liver was extended beyond birth, persisting through at least the first few months of life. These B cells formed a functional hub, and their dysregulation contributed to autoantibody accumulation and liver failure in infants with BA. We provided pre-clinical and clinical evidence showing that B-cell-modifying therapies may be used to restore liver immune function for infants with BA.

In a pilot clinical study,  demonstrated that rituximab was effective in depleting hepaticB cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those ofcontrol subjects.

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