Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia
Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia
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肝脏免疫分析揭示胆道闭锁的发病机制和治疗方法
DOI：
10.1016/j.cell.2020.10.048
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发表时间：
2020-12-23
期刊：
影响因子：
64.5
通讯作者：
Zhang, Yuxia
中科院分区：
文献类型：
--
作者：
Wang, Jun;Xu, Yanhui;Zhang, Yuxia
胆道闭锁是一种严重的胆道疾病，可导致婴儿肝功能衰竭，但其发病机制尚未完全阐明。通过单细胞RNA分析，我们观察到患有BA的婴儿的巨噬细胞炎症减少、枯否细胞清除功能缺陷、细胞毒性T细胞扩增以及CX 3CR 1（+）效应T和自然杀伤（NK）细胞缺乏。更重要的是，我们发现肝B细胞淋巴细胞生成在出生后并没有停止，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，耗尽B细胞或阻断抗原呈递可改善肝损伤。在一项初步临床研究中，我们证明利妥昔单抗可有效地消耗肝脏B细胞，并将巨噬细胞、枯否细胞和T细胞的功能恢复至与对照受试者相当的水平。总之，我们对BA婴儿的全面免疫分析表明，B细胞修饰疗法可以减轻肝脏病理。
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 iymphopoiesis 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.