Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis.
Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis.
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DOI：
10.1002/hep.32193
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Hayee B
中科院分区：
文献类型：
--
作者：
Graham JJ;Mukherjee S;Yuksel M;Sanabria Mateos R;Si T;Huang Z;Huang X;Abu Arqoub H;Patel V;McPhail M;Zen Y;Heaton N;Longhi MS;Heneghan MA;Liberal R;Vergani D;Mieli-Vergani G;Ma Y;Hayee B
“肠道归巢”假说表明，原发性硬化性胆管炎（PSC）的发病机制是由肠道粘附分子的肝脏异常表达和随后的肠道源性t细胞向肝脏募集驱动的。然而，这一理论存在不一致性，包括缺乏调查和与其他慢性肝病（CLD）的比较。在这里，我们研究了PSC合并相关炎症性肠病（PSC- ibd）和多种炎症性肝病患者的“肠道归巢理论”。采用RT-PCR方法对原位肝移植的CLD患者肝组织和正常肝组织中MAdCAM-1、CCL25和E-Cadherin的表达进行组织学和RT-PCR检测。从外植组织样本中分离出肝单个核细胞，利用流式细胞术评估肠归巢整合素和细胞因子在肝浸润性肠源性t细胞上的表达。与正常肝脏相比，所有CLDs的肝脏中MAdCAM-1、CCL25和E-Cadherin的表达均上调。不同疾病组之间没有差异。肝t细胞α4β7、αEβ7、CCR9和GPR15表达频率在PSC-IBD中升高，但在CLD对照组中与正常肝脏相比也升高。与β7阴性细胞相比，表达β7的肝t细胞表现出增加的炎症表型，尽管这种炎症细胞因子谱在炎症和正常肝脏中都存在。这些发现反驳了被广泛接受的“肠道归巢”假说是PSC的主要驱动因素，并表明肠道来源的t细胞的异常肝脏募集不是PSC所特有的，而是CLD的泛病因学特征。
The ‘gut-homing’ hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T-cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here we examine ‘the gut-homing theory’ in patients with PSC with associated inflammatory bowel disease (PSC-IBD) and across multiple inflammatory liver diseases. Expression of MAdCAM-1, CCL25 and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from CLD patients undergoing orthotopic liver transplantation and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut-derived T-cells was assessed using flow cytometry. Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was upregulated in all CLDs compared to normal liver. There were no differences between disease groups. Frequencies of α4β7, αEβ7, CCR9 and GPR15 expressing hepatic T-cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. β7 expressing hepatic T-cells displayed an increased inflammatory phenotype compared with β7 negative cells, though this inflammatory cytokine profile was present in both the inflamed and normal liver. These findings refute the widely accepted ‘gut-homing’ hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut-derived T-cells is not unique to PSC, but is a pan-aetiological feature of CLD.
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