重新评价由系统乙型肝炎病毒临床阶段的生物识别的先天免

StephenW

Re-evaluation of hepatitis B virus clinical phases by systems biology identifies unappreciated roles for the innate immune response and B cells

    Thomas Vanwolleghem1, Jun Hou1, Gertine van Oord1, Arno C. Andeweg2, A.D.M.E. Osterhaus2, Suzan D. Pas2, Harry L.A. Janssen1,3,† andAndre Boonstra1,†,*

Article first published online: 27 APR 2015

DOI: 10.1002/hep.27805

© 2015 by the American Association for the Study of Liver Diseases

I
Hepatology

Volume 62, Issue 1, pages 87–100, July 2015
Article has an altmetric score of 7


    1    Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
    2    Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands
    3    Liver Clinic, University Health Network, Toronto, Ontario, Canada

    †    These authors contributed equally.

*Address reprint requests to: Andre Boonstra, Ph.D., Department of Gastroenterology and Hepatology, Na10-11, Erasmus MC, University Hospital Rotterdam, 3000 CA Rotterdam, The Netherlands. E-mail: [email protected]; fax: +31-10-7044762.

    Potential conflict of interest: Prof. Janssen consults for and received grants from AbbVie, Bristol-Myers Squibb, Gilead, Innogenetics, Janssen, Medimmune, Medtronic, Merck, Novartis, and Roche. He consults for ISIS and Tekmira. Dr. Boonstra consults for and received grants from Bristol-Myers Squibb. He received grants from Gilead, Roche, and Janssen. Dr. Vanwolleghem received grants from Gilead and Bristol-Myers Squibb. Prof. Osterhaus consults for Viroclinics Biosciences.

    This study was supported by the Virgo Consortium, funded by the Dutch government (project no.: FES0908) and the Netherlands Genomics Initiative (project no.: 050-060-452). T.V. is the recipient of an Erasmus MC Fellowship 2011.



To identify immunological mechanisms that govern distinct clinical phases of a chronic hepatitis B virus (HBV) infection—immune tolerant (IT), immune active (IA), inactive carrier (IC), and hepatitis B e antigen (HBeAg)-negative (ENEG) hepatitis phases—we performed a systems biology study. Serum samples from untreated chronic HBV patients (n = 71) were used for multiplex cytokine measurements, quantitative hepatitis B surface antigen (HBsAg), HBeAg levels, HBV genotype, and mutant analysis. Leukocytes were phenotyped using multicolor flow cytometry, and whole-blood transcriptome profiles were generated. The latter were compared with liver biopsy transcriptomes from IA (n = 16) and IT (n = 3) patients. HBV viral load as well as HBeAg and HBsAg levels (P < 0.001), but not leukocyte composition, differed significantly between distinct phases. Serum macrophage chemotactic protein 1, interleukin-12p40, interferon (IFN)-gamma-inducible protein 10, and macrophage inflammatory protein 1 beta levels were different between two or more clinical phases (P < 0.05). Comparison of blood transcriptomes identified 64 differentially expressed genes. The gene signature distinguishing IA from IT and IC patients was predominantly composed of highly up-regulated immunoglobulin-encoding genes. Modular repertoire analysis using gene sets clustered according to similar expression patterns corroborated the abundant expression of B-cell function-related genes in IA patients and pointed toward increased (ISG) transcript levels in IT patients, compared to subsequent phases. Natural killer cell activities were clustered in clinical phases with biochemical liver damage (IA and ENEG phases), whereas T-cell activities were higher in all phases, compared to IT patients. B-cell-related transcripts proved to be higher in biopsies from IA versus IT patients. Conclusion: HBV clinical phases are characterized by distinct blood gene signatures. Innate IFN and B-cell responses are highly active during the IT and IA phases, respectively. This suggests that the presumed immune tolerance in chronic HBV infections needs to be redefined. (Hepatology 2015;62:87-100)

StephenW

重新评价由系统乙型肝炎病毒临床阶段的生物识别的先天免疫应答和B细胞赏识角色

    托马斯Vanwolleghem1，君Hou1，Gertine面包车Oord1，阿诺C. Andeweg2，ADME Osterhaus2，苏珊D. PAS2，哈利LA Janssen1,3，†andAndre Boonstra1，†，*

文章首次在线发表：2015年4月27日

DOI：10.1002 / hep.27805

©2015年肝病研究的美国协会

一世
肝病

第62卷，第1期，页87-100，2015年7月
文章有altmetric比分7


    胃肠病学和肝病，伊拉斯姆斯大学医学中心，鹿特丹，荷兰1系
    Viroscience，伊拉斯姆斯大学医学中心，鹿特丹，荷兰2部
    3肝门诊大学健康网络，多伦多，安大略省，加拿大

    †这些作者同等贡献。

*地址转载请：安德烈Boonstra，博士，胃肠病学和肝病，Na10-11，伊拉兹马斯MC，大学医院鹿特丹系，3000 CA荷兰鹿特丹。电子信箱：[email protected];传真：+ 31-10-7044762。

    潜在的利益冲突：詹森教授的咨询和艾伯维，施贵宝，Gilead公司，Innogenetics公司，扬森，MedImmune公司，美敦力公司，默克，诺华和罗氏公司获得补助。他咨询了ISIS和Tekmira。 Boonstra咨询医生并从施贵宝公司收到的补助。他从Gilead公司，罗氏公司，并收到扬森补助。 Vanwolleghem博士收到赠款基列和百时美施贵宝。奥斯特豪斯教授进行咨询生物科学Viroclinics。

    这项研究是由处女座联盟的支持下，由荷兰政府（项目编号：FES0908）和荷兰基因组计划（项目编号：050-060-452）的资助。电视是伊拉兹马斯MC奖学金2011的收件人。



要确定管理一个慢性乙型肝炎病毒（HBV）感染免疫耐受（IT），免疫活性（IA），活性载体（IC），乙肝e抗原（HBeAg）阴性的不同阶段临床免疫学机制（ENEG ）肝炎阶段，我们进行了一个系统生物学研究。从未经治疗的慢性HBV患者血清样品（n = 71）被用于多路传输的细胞因子的测量，定量乙肝表面抗原（HBsAg），HBeAg的水平，HBV基因型和突变体分析。白细胞用多色流式细胞术表型，并产生全血转录组配置文件。后者是与肝活检相比，转录从IA（N = 16）和IT（N = 3）患者。 HBV病毒负荷以及HBeAg和HBsAg的水平（P <0.001），但不是白细胞组合物，不同的相之间显著不同。血清巨噬细胞趋化蛋白1，白细胞介素12p40的，干扰素（IFN）-γ-诱导蛋白10，和巨噬细胞炎性蛋白1β的水平分别为两个或更多的临床阶段（P <0.05）之间的不同。血液转录的比较进行鉴定64个差异表达的基因。该基因标记从IT和间质性膀胱炎患者区分IA被主要由高度上调免疫球蛋白编码基因。使用根据相似表达模式聚簇基因组模块化剧目分析证实B细胞功能相关基因的大量表达在IA患者和指着的IT患者中增加（ISG）转录物水平相比，后续阶段。自然杀伤细胞的活动集中在生化肝损伤（IA和ENEG期）临床阶段，而T细胞活性均高于所有阶段，相对于IT的患者。 B细胞相关转录物被证明是在活组织检查更高从IA与IT的患者。结论：HBV的临床阶段的特征是不同的血液基因签名。先天IFN和B细胞的反应是在IT和IA阶段高活性，分别。这表明，需要推测免疫耐受的慢性HBV感染被重新定义。 （肝病2015; 62：87-100）

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