几十年来，从乙型肝炎和HBsAg清除恢复后对HBV核心的CD8 + T细

StephenW

Research Article
Decades after recovery from hepatitis B and HBsAg clearance the CD8+ T cell response against HBV core is nearly undetectable

    Helenie Kefalakes1, 2, Christoph Jochum2, Gudrun Hilgard2, Alisan Kahraman2, Anna Margarethe Bohrer3, Nicolai El Hindy3, Falko Markus Heinemann4, Jens Verheyen1, Guido Gerken2, Michael Roggendorf5, Joerg Timm1, 6, ,

    1 Institute of Virology, University of Duisburg-Essen, University Hospital Essen, Essen, Germany
    2 Department of Gastroenterology, University Hospital Essen, Essen, Germany
    3 Department of Neurosurgery, University Hospital Essen, Essen, Germany
    4 Institute for Transfusion Medicine, University of Duisburg-Essen, University Hospital Essen, Essen, Germany
    5 Institute of Virology, Technical University of Munich, Munich, Germany
    6 Institute of Virology, Heinrich-Heine-University, University Hospital, Düsseldorf, Germany

    Received 15 August 2014, Revised 16 January 2015, Accepted 23 January 2015, Available online 31 January 2015


        doi:10.1016/j.jhep.2015.01.030
    Get rights and content

Background & Aims

CD8+ T cells are an essential component of a successful immune response against hepatitis B virus (HBV). Patients who spontaneously clear HBsAg after acute HBV infection have a strong CD8+ T cell immune response, predominantly directed against the HBV core protein (HBcAg). However, the fate and phenotype of HBcAg-specific CD8+ T cells after immune control are unclear.
Methods

The CD8+ T cell immune response against HBV core was determined in 65 patients with chronic HBV infection, 16 patients after recovery from acute HBV infection, and four patients with acute HBV infection utilizing overlapping peptides and HLA class I/peptide-multimers.
Results

Patients who had cleared HBsAg >30 years ago had significantly weaker CD8+ T cell responses after antigen-specific expansion compared to patients who had cleared the virus <10 years ago and patients with HBeAg negative chronic infection and low viral load (<2000 IU/ml; p <0.01). Also directly ex vivo, patients who had cleared the HBsAg >30 years ago had less HBV-specific CD8+ T cells compared to patients with HBeAg negative chronic infection (p = 0.0025). In patients with acute HBV infection, the frequency of HBc-specific CD8+ T cells continued to decline after clearance of HBV-DNA and HBsAg even at a time when ALT levels had already normalized (p = 0.0313).
Conclusions

The frequency of HBcAg-specific CD8+ T cells continuously declines after HBsAg clearance. In line with clinical observations, this suggests that humoral and not CD8+ T cell immune responses mainly contribute to prevention of HBV reactivation decades after HBsAg clearance.
Abbreviations

    HBV, hepatitis B virus; HBcAg, hepatitis B core antigen; HLA, human leucocyte antigen; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B excretory antigen; HBc, hepatitis B core; ALT, alanine amino-transferase; Anti-HBs, antibodies to hepatitis B surface antigen; cccDNA, covalently closed circular deoxyribonucleic acid; HCV, hepatitis C virus; anti-HBc, antibodies to hepatitis B core antigen; PBMC, peripheral blood mononuclear cells; CEF, cytomegalovirus, Epstein-Barr virus, flu; CMV, cytomegalovirus; EBV, Epstein-Barr virus; AIDS, acquired immunodeficiency syndrome; IL-2, interleukin-2; IFN-γ, interferon-γ; ICS, intracellular cytokine staining; PerCP-Cy 5.5, peridinin-chlorophyl-cyanin 5.5; PE, phycoerythrin; APC, allophycocyanin; FITC, fluorescein isothiocyanate; MHC, major histocompatibility complex; anti-HCV, antibodies to hepatitis C virus; Bim, Bcl2-interacting molecule; HIV, human immunodeficiency virus; PD-1, programmed death 1; CTLA-4, cytotoxic T lymphocyte antigen-4; Tim-3, T cell immunoglobulin and mucin domain; CXCR-4, chemokine receptor-4

Keywords

    CD8+ T cell response; HBV core; HBcAg; HBsAg; Anti-HBs

    Corresponding author. Address: Institute of Virology, Heinrich-Heine-University, University Hospital, Universitätsstr. 1, 40225 Düsseldorf, Germany. Tel.: +49 211 81 12225; fax: +49 211 81 10792.

Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier Ireland Ltd. All rights reserved.

StephenW

研究论文
几十年来，从乙型肝炎和HBsAg清除恢复后对HBV核心的CD8 + T细胞反应是几乎不可检测

    Helenie Kefalakes1，2，克里斯托夫Jochum2，戈珍Hilgard2，阿里山Kahraman2，安娜玛格丽特​​Bohrer3，尼古拉萨尔瓦多Hindy3，Falko酒店马库斯Heinemann4，延Verheyen1，圭多Gerken2，迈克尔Roggendorf5，约尔格Timm1，6，

    病毒学杜伊斯堡 - 埃森大学研究所1，大​​学医院埃森，德国埃森
    消化内科，大学医院埃森，德国埃森2部
    神经外科，大学医院埃森，德国埃森的3系
    4研究所输血医学，杜伊斯堡 - 埃森大学，大学医​​院埃森，德国埃森
    慕尼黑工业大学5病毒学研究所的，德国慕尼黑
    海因里希 - 海涅大学6研究所病毒学，大学医​​院，杜塞尔多夫，德国

    收到2014年8月15日，修订2015年1月16日，接受2015年1月23日，可在线2015年1月31日


        DOI：10.1016 / j.jhep.2015.01.030
    获取权利和内容

背景与目的

CD8 + T细胞是对乙肝病毒成功的免疫应答（HBV）的一个重要组成部分。谁自发明确乙肝表面抗原后急性HBV感染有较强的CD8 + T细胞免疫应答的患者，主要是针对乙肝病毒核心蛋白（HBcAg的）。然而，免疫控制后的HBcAg特异性CD8 + T细胞的命运和表现型都不清楚。
方法

抗HBV核心的CD8 + T细胞免疫反应的65例慢性HBV感染者，16例急性HBV感染恢复后，4例急性HBV感染重叠利用肽和HLA I类/肽多聚确定。
结果

谁已清除的HBsAg患者> 30年前有后的抗原特异性扩张的病人相比，谁在10年前已清除了病毒<和显著较弱的CD8 + T细胞应答例HBeAg阴性慢性感染和低病毒载量（<2000国际单位/毫升; P <0.01）。也直接离体，谁清除了的HBsAg>患者30年前有较少HBV特异性CD8 + T细胞相比，例HBeAg阴性慢性感染（p值= 0.0025）。在急性HBV感染，的HBc特异性CD8 + T细胞的频率持续即使在时间HBV-DNA与HBsAg的清除后下降时ALT水平已归一（p值= 0.0313）。
结论

核心抗原特异性CD8 + T细胞的频率HBsAg清除后，继续下降。在临床观察线，这表明体液，而不是CD8 + T细胞免疫应答，主要承担预防HBsAg清除后HBV再激活十年。
缩写

    乙肝病毒，B型肝炎病毒;核心抗原，乙型肝炎核心抗原; HLA，人类白细胞抗原;乙型肝炎表面抗原，乙型肝炎表面抗原;大三阳，乙肝抗原排泄;的HBc，乙肝核心; ALT，丙氨酸氨基转移酶;抗-HBs抗体对乙型肝炎表面抗原; cccDNA的，共价闭合环状脱氧核糖核酸;丙型肝炎病毒，丙型肝炎病毒;抗-HBc抗体对乙型肝炎核心抗原; PBMC外周血单核细胞; CEF，巨细胞病毒，Epstein-Barr病毒，流感;巨细胞病毒，巨细胞病毒; EB病毒，爱泼斯坦 - 巴尔病毒;艾滋病，获得性免疫缺陷综合征;的IL-2，白细胞介素2; IFN-γ，干扰素γ; ICS，细胞内细胞因子染色; PerCP-赛扬5.5，多甲藻素，叶绿素，花青素5.5; PE，藻红蛋白; APC，别藻蓝蛋白; FITC异硫氰酸荧光素; MHC，主要组织相容性复合体;抗HCV抗体对丙型肝炎病毒; BIM，Bcl2的相互作用分子;艾滋病毒，人类免疫缺陷病毒; PD-1，程序性死亡1; CTLA-4的细胞毒性T淋巴细胞抗原4; TIM-3，T细胞免疫球蛋白及黏蛋白域; CXCR-4，趋化因子受体-4

关键词

    CD8 + T细胞应答; HBV核心;核心抗原;乙肝表面抗原;抗-HBs

    通讯作者。地址：海因里希 - 海涅大学研究所病毒学，大学医​​院，Universitätsstr。 1，40225杜塞尔多夫，德国。电话：+49 211 81 12225;传真：+49 211 10792 81。

版权所有©2015年欧洲协会为肝脏的研究。发布时间由Elsevier爱尔兰有限公司保留所有权利