Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B.
Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B.
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DOI：
10.1053/j.gastro.2015.11.050
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发表时间：
2016-03
期刊：
影响因子：
29.4
通讯作者：
Hepatitis B Research Network
中科院分区：
文献类型：
--
作者：
Park JJ;Wong DK;Wahed AS;Lee WM;Feld JJ;Terrault N;Khalili M;Sterling RK;Kowdley KV;Bzowej N;Lau DT;Kim WR;Smith C;Carithers RL;Torrey KW;Keith JW;Levine DL;Traum D;Ho S;Valiga ME;Johnson GS;Doo E;Lok AS;Chang KM;Hepatitis B Research Network
T细胞在病毒感染中起关键作用。我们研究了T细胞效应和调节反应是否可以定义慢性乙型肝炎（CH B）的临床分期。B。我们招募了2011年至2013年参加NIH支持的B型肝炎研究网络的200名CH B成人和20名未感染者（对照组）。分析这些受试者的外周血淋巴细胞对重叠B肝炎病毒（HBV）肽（preS、S、preC、核心和逆转录酶）、流感基质肽和脂多糖的T细胞应答（干扰素-γ和白细胞介素-10的增殖和产生）。通过流式细胞术检查调节标志物FOXP 3、程序性死亡-1（PD 1）和细胞毒性T淋巴细胞相关抗原-4（CTLA 4）的T细胞表达。免疫指标与临床参数进行比较，包括医生定义的免疫活性、免疫耐受或非活性CHB表型，以盲法进行。与对照组相比，CHB患者对HBV的T细胞增殖、干扰素-γ和白细胞介素-10应答较弱，循环FOXP 3 + CD 127 −调节性T细胞和CD 4 + T细胞表达PD 1和CTLA 4的频率增加。T细胞测量不能明确区分临床CHB表型，尽管HBeAg+患者的HBV核心特异性T细胞应答弱于HBeAg-患者（应答者%：3% vs 23%，P=.00008）。尽管体外阻断PD 1或CTLA 4可增加T细胞对HBV的应答，但在HBeAg+患者中的作用弱于HBeAg−患者。此外，T细胞对流感和脂多糖的反应在CHB患者中比对照组弱。HBV持续存在病毒特异性和整体T细胞功能障碍，由多种调节机制介导，包括循环HBeAg，但临床表型没有明显的基于T细胞的免疫特征。这些发现提示了CHB发病机制的其他T细胞非依赖性或调节机制，值得进一步研究。
T cells play a critical role in in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). We enrolled 200 adults with CHB who participated in the NIH-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon-γ and interleukin-10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1 (PD1), and cytotoxic T lymphocyte-associated antigen-4 (CTLA4) was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. Compared to controls, patients with CHB had weak T-cell proliferative, interferon-γ, and interleukin-10 responses to HBV, with increased frequency of circulating FOXP3+CD127− regulatory T cells and CD4+ T-cell expression of PD1 and CTLA4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in HBeAg+ than HBeAg− patients (% responders: 3% vs 23%, P=.00008). Although in vitro blockade of PD1 or CTLA4 increased T-cell responses to HBV, the effect was weaker in HBeAg+ than HBeAg− patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms including circulating HBeAg, but without distinct T-cell–based immune signatures for clinical phenotypes. These findings suggest additional T-cell independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.