Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C.
Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C.
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DOI：
10.1002/hep.24556
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发表时间：
2011-11
期刊：
影响因子：
13.5
通讯作者：
Rosen, Hugo R.
中科院分区：
文献类型：
--
作者：
Golden-Mason, Lucy;Bambha, Kiran M.;Cheng, Linling;Howell, Charles D.;Taylor, Milton W.;Clark, Paul J.;Afdhal, Nezam;Rosen, Hugo R.
自然杀伤（NK）细胞构成了抵抗病毒感染的第一道防线;它们的功能由来自多个活化和抑制表面受体的信号整合所控制。我们假设，由于NK细胞被细胞因子迅速激活，抗HCV治疗的反应将通过NK细胞的表型和功能来预测。我们使用了一组101例患者（56名非洲人，45名白人美国人）谁接受聚乙二醇干扰素和利巴韦林48周。使用多参数FACS分析来检查14种不同抑制/活化受体的相对表达。还进行了IL-28 B基因分型（rs 12979860）。在治疗的前28天内病毒下降较差的患者中，抑制性受体CD 158 a、CD 158 b和CD 158 e的治疗前水平较高。抑制性受体NKG 2A、CD 158 b和CD 158 e的表达水平在未能实现SVR的患者中较高。携带IL-28 B T等位基因的患者在效应NK上具有更高的NKG 2A表达。我们创建了一个数学回归模型，其中纳入了种族、病毒水平和两种抑制性受体。曲线下面积为0.88，对SVR具有高度预测性。此外，该模型在CC、CT和TT基因型中与IL-28 B互补。用聚乙二醇化IFN-α处理4小时的纯化NKG 2Aneg NK与NKG 2Apos相比，表现出更高水平的干扰素-γ诱导蛋白-10（IP-10）和肿瘤坏死因子相关凋亡诱导配体（TRAIL）。这些结果为NK表型与IL-28 B基因型和基因表达模式的关联以及NK在介导IFN诱导的慢性HCV感染的病毒清除中的作用提供了新的见解。
Natural killer (NK) cells constitute a first line of defense against viral infections; their function is governed by the integration of signals from multiple activating and inhibitory surface receptors. We hypothesized that since NKs become rapidly activated by cytokines, response to anti-HCV therapy would be predicted by the phenotype and function of NKs. We used a cohort of 101 patients (56 African-, 45 Caucasian-American) who received Pegylated-IFN and Ribavirin for 48 weeks. Multiparameter FACS analysis was used to examine relative expression of 14 different inhibitory/activating receptors. IL-28B genotyping (rs12979860) was also performed. Pre-treatment levels of inhibitory receptors CD158a, CD158b and CD158e were higher in patients who demonstrated poor viral decline within the first 28 days of therapy. Higher expression levels of inhibitory receptors NKG2A, CD158b and CD158e were demonstrable in patients who failed to achieve SVR. Patients carrying the IL-28B T allele had higher NKG2A expression on effector NKs. We created a mathematical regression model incorporating race, viral level, and two inhibitory receptors. The area-under-the curve was 0.88 which is highly predictive of SVR. Moreover, the model performed complementarily with IL-28B across the CC, CT, and TT genotypes. Purified NKG2Aneg NKs treated with pegylated-IFN-α for 4 hours demonstrated higher levels of interferon-γ–inducible protein-10 (IP-10) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) compared to their NKG2Apos counterparts. These results provide novel insights into the associations of NK phenotype with IL-28B genotype and gene expression patterns, as well as the role of NKs in mediating IFN-induced viral clearance of chronic HCV infection.
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影响因子：
29.4
作者：
McCarthy JJ;Li JH;Thompson A;Suchindran S;Lao XQ;Patel K;Tillmann HL;Muir AJ;McHutchison JG
通讯作者：
McHutchison JG
影响因子：
3.7
作者：
Koehler, Karsten;Xiong, Shiqiu;Davis, Daniel M.
通讯作者：
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影响因子：
13.5
作者：
Askarieh, Galia;Alsio, Asa;Lagging, Martin
通讯作者：
Lagging, Martin
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影响因子：
15.3
作者：
Bowen, David G;Walker, Christopher M
通讯作者：
Walker, Christopher M
影响因子：
25.7
作者：
Miyagi, Takuya;Takehara, Tetsuo;Hayashi, Norio
通讯作者：
Hayashi, Norio