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.

胆道闭锁 (BA) 是一种严重的胆管病，可导致婴儿肝功能衰竭，但其发病机制仍有待充分表征。通过单细胞 RNA 分析，我们观察到巨噬细胞低炎症、Kupffer 细胞清道夫功能缺陷、细胞毒性 T 细胞扩增和 CX3CR1 ^+缺乏BA 婴儿的效应 T 细胞和自然杀伤 (NK) 细胞。更重要的是，我们发现肝 B 细胞淋巴细胞生成并没有在出生后停止，并且耐受性缺陷导致免疫球蛋白 G (IgG)-自身抗体在 BA 中积累。在恒河猴轮状病毒诱导的 BA 模型中，消耗 B 细胞或阻断抗原呈递可改善肝损伤。在一项临床试验研究中，我们证明了利妥昔单抗可有效消耗肝 B 细胞并将巨噬细胞、枯否细胞和 T 细胞的功能恢复到与对照组相当的水平。总之，我们对 BA 婴儿的综合免疫分析表明，B 细胞修饰疗法可以缓解肝脏病理学。