Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease.
Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease.
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DOI：
10.1136/gutjnl-2017-314458
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发表时间：
2018-05
期刊：
影响因子：
24.5
通讯作者：
Chokshi S
中科院分区：
文献类型：
--
作者：
Riva A;Patel V;Kurioka A;Jeffery HC;Wright G;Tarff S;Shawcross D;Ryan JM;Evans A;Azarian S;Bajaj JS;Fagan A;Patel V;Mehta K;Lopez C;Simonova M;Katzarov K;Hadzhiolova T;Pavlova S;Wendon JA;Oo YH;Klenerman P;Williams R;Chokshi S
肠道通透性与细菌产物的全身分布是酒精性肝病（ALD）免疫发病机制的核心，但与肠道免疫的联系仍然难以捉摸。粘膜相关不变T细胞（MAIT）存在于肝脏、血液和肠粘膜中，是抗菌宿主防御的关键组成部分。其在ALD中的作用尚不清楚。我们分析了重度酒精性肝炎（SAH）、酒精相关性肝硬化（ARC）和健康对照（HC）中血液MAIT细胞的频率、表型、转录调控和功能。我们还研究了乙醇、粪便提取物的细菌产物和抗原过度刺激对MAIT细胞功能的直接影响。分别通过定量PCR和免疫组织化学/基因表达评估结肠和肝脏中MAIT细胞的存在。在ARC和SAH中，血液MAIT细胞显著耗尽，过度活化，并显示出有缺陷的抗菌细胞因子/细胞毒性反应。这些与抑制谱系特异性转录因子和归巢受体在肝内保存的MAIT细胞在ALD的肝脏中的高表达相关。这些变化在SAH中更强，其中细菌感染和微生物易位的替代标记物高于ARC。乙醇暴露在体外，在体内酒精戒断和治疗大肠杆菌MAIT细胞的频率没有影响，而暴露于粪便细菌/抗原诱导的功能障碍与血液MAIT细胞ALD和显着的MAIT细胞耗竭，这是没有观察到在其他T细胞室。在ALD中，MAIT细胞的抗菌效力由于与微生物产物和微生物群接触而受到损害，这表明在ALD中观察到的“泄漏”肠道驱动MAIT细胞功能障碍和这些患者对感染的易感性。
Intestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown. We analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively. In ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments. In ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the ‘leaky’ gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients.
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