Endotoxemia contributes to CD27+ memory B-cell apoptosis via enhanced sensitivity to Fas ligation in patients with Cirrhosis.
Endotoxemia contributes to CD27+ memory B-cell apoptosis via enhanced sensitivity to Fas ligation in patients with Cirrhosis.
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DOI：
10.1038/srep36862
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发表时间：
2016-11-18
影响因子：
4.6
通讯作者：
Kaplan DE
中科院分区：
文献类型：
--
作者：
Chang LY;Li Y;Kaplan DE
肝硬化患者外周血CD27+记忆b细胞数量减少和功能失调的机制尚不清楚。我们假设CD27+记忆b细胞的消失是由于暴露于肠道微生物易位产物引起的细胞凋亡敏感性增强所致。使用来自肝硬化患者和年龄匹配对照的分离naïve和记忆b细胞，在相关实验条件下评估体外和激活诱导对fas介导的细胞凋亡的敏感性。我们观察到肝硬化患者CD27+ b细胞中CD95（Fas）的差异表达与外周血CD27+ b细胞频率呈负相关。虽然肝硬化患者的记忆b细胞对fas介导的体外凋亡有抵抗性，但toll样受体4（TLR4）连接恢复了fas敏感性。对Fas介导的凋亡的敏感性可以通过与肝硬化患者的血浆共培养转移到健康的供体记忆b细胞，这种敏感性部分由Fas和TLR4信号介导，部分通过b细胞受体交联恢复。我们得出结论，肝硬化的外周CD27+记忆b细胞对fas诱导的凋亡表现出更高的敏感性，其激活依赖于内毒素，与循环记忆b细胞频率降低有关。这一关键细胞亚群的破坏可能导致肝硬化免疫缺陷状态，并增加晚期肝病全身性感染的风险。
Peripheral CD27+ memory B-cells become quantitatively reduced and dysfunctional in patients with cirrhosis through poorly characterized mechanisms. We hypothesized that the disappearance of CD27+ memory B-cells results from enhanced sensitivity to apoptosis caused by exposure to gut microbial translocation products. Using isolated naïve and memory B-cells from patients with cirrhosis and age-matched controls, ex vivo and activation-induced sensitivity to Fas-mediated apoptosis was assessed under relevant experimental conditions. We observed differential expression of CD95(Fas) in CD27+ B-cells from cirrhotic patients that was inversely correlated with peripheral CD27+ B-cell frequency. While memory B-cells from cirrhotic patients were resistant to Fas-mediated apoptosis ex vivo, Toll-like receptor 4(TLR4)-ligation restored Fas-sensitivity. Sensitivity to Fas-mediated apoptosis could be transferred to healthy donor memory B-cells by co-culturing these cells with plasma from cirrhotic patients, a sensitivity partially mediated by Fas and TLR4 signaling, and partially rescued via B-cell receptor crosslinking. We conclude that peripheral CD27+ memory B-cells in cirrhosis exhibit increased sensitivity to Fas-induced apoptosis in an activation-dependent manner to which endotoxin contributes, associated with reduced frequency of circulating memory B-cells. Destruction of this critical cell subset may contribute to the cirrhotic immunodeficiency state and heightened risk of systemic infections in advanced liver disease.
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