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标题: 细胞与分子免疫学特刊对乙肝病毒的免疫力 [打印本页]

作者: StephenW 时间: 2015-6-1 14:09 标题: 细胞与分子免疫学特刊对乙肝病毒的免疫力

Editorial

Cellular & Molecular Immunology advance online publication 13 April 2015; doi: 10.1038/cmi.2015.24

Overview of the special issue on HBV immunity

Antonio Bertoletti1,2 and Fu-Sheng Wang3

1Emerging infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
2Singapore Institute for Clinical Sciences, A*STAR, Singapore, Singapore
3Research Center for Biological Therapy, The Institute of Translational Hepatology, Beijing, China

Correspondence: Antonio Bertoletti, Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Phone: +65 66011372. E-mail: [email protected]; Fu-Sheng Wang, Research Center for Biological Therapy, The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing 100039, China. E-mail: [email protected]

Received 24 February 2015; Revised 25 February 2015; Accepted 25 February 2015
Advance online publication 13 April 2015

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Hepatitis B virus (HBV) has a unique relationship with humans. It is not only very successful in spreading amongst our species (a third of the human population has been in contact with the virus and approximately 200–300 million people are actively infected),1 but it has adapted to and co-evolved with us. This long-term relationship is demonstrated by the recent detection of hepadnavirus genomes in Mesozoic birds2 and by the estimation that HBV was already present in early humans at least 40, 000 years ago.3

Dr. Antonio Bertoletti
Full figure and legend (78K)

Dr. Fu-Sheng Wang
Full figure and legend (47K)

The HBV co-evolution and adaptation with humans have affected the way that our immune system responds to this virus and can explain the primary characteristic of anti-HBV immunity: its subtle and often barely detectable nature in the infected subjects. Indeed, HBV is not highly immunogenic, and this virus is highly capable of avoiding or escaping immune detection rather than eliciting a strong immune reaction. Innate immune recognition, cytokine production, and HBV-specific T-cell responses can be detected in HBV-infected individuals, but often at levels lower than the levels observed in infections with other persistent human viruses such as Epstein-Barr virus, human immunodeficiency virus, or hepatitis C virus.4 HBV is also not directly pathogenic to the host. HBV-related severe diseases are not directly caused by viral replication, but rather, are due to chronic immune-mediated inflammatory events that occur only in some actively infected subjects and often only present at an advanced age.

In this special issue of CMI dedicated to the discussion of immune response against HBV, we invited experts to summarize aspects of HBV immune pathogenesis that highlight this special relationship of HBV with human immunity.

In the first review “Contribution of toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses,”5 Zhiyong Ma and colleagues addressed the complex interaction of HBV with the innate immune system, particularly with the toll-like receptors (TLR) system. The ability of HBV to evade and suppress the TLR-recognition system and the therapeutic potential of TLR agonists are discussed utilizing data derived from novel in vivo model systems.

The controversy regarding the impact of HBV on the functionality of the innate immune system is also the focus of a review by Adam J. Gehring and June Ann D'Angelo. In their chapter titled “Dissecting the dendritic cell controversy in chronic hepatitis B virus infection,”6 the authors summarize multiple studies investigating Dendritic cell (DC) function in chronic hepatitis B (CHB) patients to determine whether common observations can be drawn. DCs are central players in the induction of adaptive immunity, and the authors discuss data suggesting that dendritic cell defects are induced by HBV.

The relationship of HBV and innate immunity is also the focus of a review by Cheng Sun and colleagues. In their article “NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma,”7 the authors focused their attention not only on the functionality of natural killer (NK) cells during the early phases of HBV infection but particularly after the development of the most severe complication derived from HBV infection: hepatocellular carcinoma (HCC). The authors summarize data suggesting that, in CHB, the progression to HCC is linked with a decrease in the frequency and functionality of intrahepatic NK cells. They also discussed the possibility of increasing NK cell function for therapeutic purposes.

The mechanisms and causes of liver damage during CHB infection in various infected subjects are the main focus of the following three distinct reviews by A Bertoletti and P. Kennedy, Roberto Aiolfi and Giovanni Sitia, and by Matteo Iannacone.

In the article “The immune tolerant phase of chronic HBV infection: new perspectives on an old concept,”8 Bertoletti and Kennedy discussed the impact of the age of the infected host on the immune pathological process caused by HBV. The authors discussed the immunological significance of the concept of HBV immunotolerance during the early phases of infection, arguing that the modulation of liver disease during the life of HBV-infected individuals is driven by the physiological modifications of the inflammatory processes during aging and not by the often highly elusive CD8 T-cell response present in chronically infected patients.

Aiolfi and Sitia not only summarize the data that depicted the role of platelets in HBV infection in their article “Chronic hepatitis B: role of anti-platelet therapy in inflammation control”9 but also introduce the concept of CHB as a primary inflammatory disease. The demonstration in animal models that the inhibition of platelet functionality can favorably modulate the extent of liver damage calls for an evaluation of this unconventional but simple anti-inflammatory therapeutic strategy in the clinical management of CHB patients.

CD8 T cells, the immune cell population with a pivotal role in the control and pathogenesis of HBV infection, is the focus of “Hepatic effector CD8+ T-cell dynamics,”10 a review by Matteo Iannacone. The author noted that “Understanding the signals that modulate the dynamics of CD8+ T cells in the liver is critical to gaining insight into the pathogenesis of acute and chronic HBV infection.” This review presents new and interesting data that illustrate how T cells are trafficked in the liver and how they gain access to target cells, with a discussion on how technology can further increase our understanding of this important immunological process.

Finally, our review presents two articles that analyze components of the immune system that have been often overlooked in studies of HBV-specific immunity: T helpers and B-cell responses. In their review “Role of interleukin-21 in HBV infection: friend or foe?”11 Yin Lin and colleagues recapitulate the present knowledge of the importance of the former factor in HBV infection, with a particular emphasis on the role of T helper follicular cells in HBV-infected individuals. The dual role of this cytokine in boosting the B-cell-specific antiviral response, or as a mediator of inflammation, was thoroughly discussed.

Lastly, due to the limited past knowledge of the B-cell response in HBV, Fu-Shen Wang and colleagues provided new findings that highlight the changes of B-cell functionality in CHB patients.12 Their article “Reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients” provides long-awaited data on this aspect of human HBV immunity.

A cure for chronic hepatitis C has recently been achieved, leading to more attention and research focusing on HBV. The present therapeutic regimen for CHB patients involves antiviral treatments (using nucleotide analogs or interferon-alpha), which only suppress HBV replication without a clear effect on cccDNA and HBV antigens (especially HBsAg). It is difficult for the exhausted adaptive immunity present in CHB patients to play a role in complete control of the cccDNA and clearance of large amounts of HBsAg. Therefore, fully understanding the immune pathogenesis in these patients will help to promote the development of novel therapeutic approaches to boost antiviral immunity.

The aim of this special issue was certainly not to comprehensively cover all aspects of HBV immunity. Rather, we selected specific controversial areas of HBV immunity with the hope that by emphasizing the gaps in our knowledge, we can promote the generation of new ideas to cure CHB. We hope that this collection will offer an inspiration to all researchers fascinated by the complex relationship of HBV with its host.

作者: StephenW 时间: 2015-6-1 14:10

社论

细胞与分子免疫学推进网上公布2015年4月13日; DOI：10.1038 / cmi.2015.24
特刊对乙肝病毒的免疫力概述

安东尼奥Bertoletti1,2和傅盛Wang3

1Emerging传染病，杜克 - 新加坡国立大学医学院，新加坡，新加坡
2Singapore临床科学研究所，A * STAR，新加坡，新加坡
3Research中心的生物治疗，转化肝病研究所，北京，中国

函授：安东尼BERTOLETTI，新发传染性疾病，杜克 - 新加坡国立大学医学研究生院，8个学院路，新加坡169857，电话：+65 66011372.电子邮件：[email protected];王福生，研究中心，生物治疗，肝脏转化，北京302医院，北京100039，中国研究所。电子信箱：[email protected]

收到2015年2月24日;修订后的2015年2月25日;接受2015年2月25日
提前在网上公布2015年4月13日
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乙型肝炎病毒（HBV）具有与人类的唯一关系。它不仅在传播之中我们物种非常成功（第三人类群体已经在与病毒接触，并大约200-300万人正在积极感染），1，但它已经适应和共同进化我们。这种长期的合作关系是由近期检测中生代birds2嗜肝DNA病毒基因组和估计表明，乙肝病毒已经存在于早期人类至少40 5000年ago.3
不幸的是，我们无法对这种提供方便的替代文本。如果您需要帮助来访问此图片，请与[email protected]或作者

安东尼博士BERTOLETTI
全图和传说（78K）

不幸的是，我们无法对这种提供方便的替代文本。如果您需要帮助来访问此图片，请与[email protected]或作者

王福生博士
全图和传说（47K）

乙肝病毒协同进化和适应与人类已经影响了我们的免疫系统响应该病毒可以解释的抗乙肝病毒的免疫力主要特征的方式：在感染者及其微妙的，往往几乎检测不到的性质。事实上，乙肝病毒是不是高度免疫原性，而这个病毒具有高度可避免或逃避免疫检测，而不是引发强烈的免疫反应。先天免疫识别，细胞因子的产生，和HBV特异性T细胞反应可在HBV感染的个体进行检测，但往往在水平比感染观察其他持久性人类病毒，如Epstein-Barr病毒，人类免疫缺陷病毒的水平降低或丙型肝炎virus.4 HBV也不能直接致病到主机。 HBV相关的严重疾病不直接由病毒复制引起的，而是，都是由于只出现在某些积极感染者和经常只存在于高龄慢性免疫介导的炎症事件。

在CMI这个特刊抗HBV免疫应答的讨论中，我们请专家总结的HBV免疫发病机制方面，突出乙肝病毒与人体免疫力的特殊关系。

在第一次审查“toll样受体乙肝病毒感染的控制，通过启动抗病毒先天的反应和促进特定适应性免疫应答贡献，”智勇5马云和他的同事解决乙肝病毒的复杂的相互作用与先天免疫系统，特别是与toll样受体（TLR）的系统。乙肝病毒的逃避和抑制TLR识别系统和TLR激动剂的治疗潜力的能力，进行了讨论利用在体内模型系统是来自于新颖的数据。

关于乙肝的先天免疫系统的功能的影响的争论也是审查亚当J. Gehring集团和安月德安杰洛的焦点。在他们的一章标题为“解剖慢性乙型肝炎病毒感染的树突状细胞的争论，”6笔者总结多项研究调查树突状细胞在慢性乙型肝炎（DC）功能（CHB）患者，以确定共同的意见是否可以得出。区议会是核心球员在适应性免疫诱导，与作者讨论数据表明，树突状细胞缺陷是由乙肝病毒引起的。

HBV和先天免疫的关系也是一个审查程Sun和同事们关注的焦点。在他们的文章“NK细胞受体的不平衡和在HBV感染和肝癌NK细胞功能障碍，”7作者紧盯不仅在自然杀伤（NK）细胞中HBV感染的早期阶段的功能，但特别是在发展最严重的并发症，从HBV感染来源：肝细胞癌（HCC）。笔者总结的数据表明，慢性乙型肝炎，进展为肝癌与在频率的降低肝内NK细胞和功能联系起来。他们还讨论了增加的NK细胞功能用于治疗目的的可能性。

慢性乙型肝炎感染各种感染者中的机制和肝损害的原因是以下三种不同的评价由A BERTOLETTI和P·肯尼迪，罗伯特·Aiolfi和Giovanni锡蒂亚，并通过利玛窦Iannacone的主要焦点。

在文章“慢性HBV感染的免疫耐受期，新观点上的旧观念，”8 BERTOLETTI和肯尼迪讨论的感染宿主的年龄引起的HBV免疫病理过程的影响。作者讨论了乙肝病毒免疫耐受的概念的免疫学意义在感染的早期阶段，认为肝病的HBV感染个体的生命期间调制由炎症过程的生理修改从动老化，而不是由在常高度难以捉摸的CD8 T细胞应答存在于慢性感染病人。

Aiolfi和锡蒂亚不仅总结了描绘在他们的文章血小板在HBV感染的作用数据：9“慢性乙肝炎症控制抗血小板治疗作用”，而且还介绍了慢性乙型肝炎的概念，作为一个主要的炎症性疾病。在动物模型中证明了血小板功能抑制能够有利调节为慢性乙型肝炎患者的临床管理这个非常规的，但简单的消炎治疗策略的评价肝脏损害通话的程度。

CD8 T细胞，免疫细胞群与对照和HBV感染的发病机理中发挥关键作用，是“肝效应CD8 + T细胞动力学”，10条所作利玛Iannacone的焦点。笔者注意到，“了解调节CD8 + T细胞的动力在肝脏的信号是要深入了解急性和慢性HBV感染的发病机制是至关重要的。”这次审查提出了新的，有趣的数据来说明如何T细胞贩运肝脏以及他们如何获得靶细胞，对技术如何能够进一步提高我们对这一重要的免疫过程的理解进行了讨论。

最后，我们的审查提出了两种用于分析已经常常被忽视的HBV特异性免疫研究免疫系统的组成部分的文章：T佣工和B细胞反应。在审查“白介素21在乙型肝炎病毒感染的作用：朋友还是敌人”11银鳞和同事概括的HBV感染前的因素的重要性，目前的认识，并特别强调对T辅助滤泡细胞的作用乙肝病毒感染者。这种细胞因子在促进B细胞特异性抗病毒反应的双重作用下，或炎症的调解员，被彻底讨论。

最后，由于乙肝病毒的B细胞应答的有限过去的知识，傅慎与同事王某提供了新的研究结果，强调在CHB B细胞功能变化patients.12他们的文章“B细胞过度活化和逆转功能障碍与乙肝表面抗原血清学转换的慢性乙肝患者相关的“提供人体免疫力乙肝这方面期待已久的数据。

一种治疗慢性丙型肝炎最近已经实现，导致更多的关注和研究，重点对HBV。目前治疗方案慢性乙肝患者涉及抗病毒治疗（使用核苷类似物或干扰素α），其中仅抑制HBV的复制，而不对cccDNA的和HBV抗原（HBsAg的特别），效果清晰。这是困难的疲惫适应性免疫目前慢性乙型肝炎患者起到完全控制的cccDNA和大量乙肝表面抗原的清除作用。因此，充分了解这些患者免疫发病机制将有助于促进新的治疗方法的发展，以提高抗病毒免疫。

这期特刊的目的当然不是全面覆盖HBV免疫的所有方面。相反，我们选择了乙肝病毒的免疫力具体争议的领域，希望通过强调了我们的知识差距，我们可以促进新思想的产生治愈乙肝。我们希望这一系列将提供一个灵感，由乙肝病毒与宿主之间的复杂关系迷住了所有的研究人员。

作者: StephenW 时间: 2015-6-1 14:11

The immune tolerant phase of chronic HBV infection: new perspectives on an old concept

Antonio Bertoletti1,2 and Patrick T Kennedy3

1Emerging Infectious Diseases (EID) Program, Duke-NUS Graduate Medical School, Singapore
2Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*STAR), Singapore
3Blizard Institute, Barts and The London School of Medicine & Dentistry, London, UK

Correspondence: Dr A Bertoletti, Emerging Infectious Diseases Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore. E-mail: [email protected]; Dr P Kennedy, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK. E-mail: [email protected]

Received 11 July 2014; Revised 28 July 2014; Accepted 29 July 2014
Advance online publication 1 September 2014
Top of page
Abstract

Chronic hepatitis B virus (HBV) infection progresses through distinct disease phases that are strongly associated with patient age. The so-called immune tolerant (IT) phase represents the classical early phase of infection; it is associated with high levels of HBV replication and lack of clinical signs of liver Inflammation. Whether this phase of HBV infection is also associated with immunological features of “tolerance' has recently been challenged. Here, we review the data that dispute this concept of immune tolerance and then propose an alternative interpretation of the immunopathological events that take place during this early phase of CHB infection.
Keywords:

Hepatitis B; antiviral immunity; T cells

慢性HBV感染的免疫耐受期：一个古老的概念，新观点

安东尼奥Bertoletti1,2和帕特里克牛逼Kennedy3

1Emerging传染病（EID）计划，杜克 - 新加坡国立大学医学研究生院，新加坡
2Viral肝炎实验室，新加坡临床科学研究所，科学技术与研究局（A * STAR），新加坡的机构
3Blizard学院，巴茨和医学及牙科，伦敦，英国伦敦学校

函授：一个BERTOLETTI博士，新发传染性疾病计划，杜克 - 新加坡国立大学医学研究生院，学院路8号，新加坡169857，新加坡。电子信箱：[email protected]; P医生肯尼迪，暴雪的学院，巴茨和医学和牙科，伦敦，英国伦敦学校。电子信箱：[email protected]

收到2014年7月11日;修订后的2014年7月28日;接受2014年7月29日
提前在网上公布2014年9月1日
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抽象

慢性乙型肝炎病毒（HBV）感染的进展通过强烈与患者年龄相关不同疾病阶段。所谓免疫耐受（IT）的相代表感染的经典早期阶段;它是与高水平乙型肝炎病毒复制和缺乏肝炎的临床症状相关联。无论是HBV感染这一阶段也与宽容的“免疫功能有关”最近受到了挑战。在这里，我们回顾了争议免疫耐受这一概念，然后提出了免疫病理的事件，在采取乙肝感染的早期阶段发生的另一种解读数据。
关键词：

乙型肝炎;抗病毒免疫力; T细胞

作者: StephenW 时间: 2015-6-1 14:13

Mini Review

Cellular & Molecular Immunology advance online publication 12 January 2015; doi: 10.1038/cmi.2014.124
Chronic hepatitis B: role of anti-platelet therapy in inflammation control

Roberto Aiolfi and Giovanni Sitia

Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy

Correspondence: G Sitia, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. E-mail: [email protected]

Received 14 2014; Revised 30 2014; Accepted 19 2014
Advance online publication 12 January 2015
Top of page
Abstract

Platelets play a known role in the maintenance of vascular homeostasis, but these cells are emerging as important cellular mediators of acute and chronic inflammatory diseases. Platelets are key elements in the pathogenesis of acute and chronic liver disease associated with hepatitis B virus (HBV) infection by promoting the accumulation of virus-specific CD8+ T cells and nonspecific inflammatory cells into the liver parenchyma. This review discusses major platelet functions in immune and inflammatory responses, with an emphasis on recent pre-clinical studies that suggest that the inhibition of platelet activation pathways represent an alternative therapeutic strategy with potential use in the reduction of virus-specific T cell-mediated chronic inflammation, liver fibrosis and hepatocellular carcinoma in patients who are chronically infected with HBV.
Keywords:

anti-platelet drugs; CD8+ T cells; chronic hepatitis B; hepatocellular carcinoma; platelets

迷你回顾

细胞与分子免疫学推进网上公布2015年1月12日; DOI：10.1038 / cmi.2014.124
慢性乙型肝炎：抗血小板治疗炎症控制作用

罗伯托Aiolfi和Giovanni锡蒂亚

免疫学，移植和传染病，IRCCS圣拉斐尔科学研究所，意大利米兰的司

函授：摹锡蒂亚，免疫学，移植和传染病，IRCCS圣拉斐尔科学研究所科，威盛Olgettina 58，20132米兰，意大利。电子信箱：[email protected]

收到14 2014年;修订后的2014年30;接受2014年19
提前在网上公布2015年1月12日
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抽象

血小板在血管稳态的维持一个已知的作用，但这些细胞正在成为急性和慢性炎性疾病的重要细胞介质。血小板是在与乙型肝炎病毒（HBV）感染，促进病毒特异性CD8 + T细胞和非特异性炎症细胞堆积成肝实质相关的急性和慢性肝脏疾病的发病机理的关键因素。本文综述了在免疫和炎症反应的主要功能血小板，并强调这表明，血小板活化途径抑制代表与病毒特异性T细胞介导的慢性的还原电位使用替代治疗策略近期的临床前研究炎症，肝纤维化和肝癌谁是慢性乙型肝炎病毒感染的患者。
关键词：

抗血小板药物; CD8 + T细胞;慢性乙型肝炎;肝癌;血小板

作者: StephenW 时间: 2015-6-1 14:17

Mini Review

Cellular & Molecular Immunology advance online publication 22 September 2014; doi: 10.1038/cmi.2014.78
Hepatic effector CD8+ T-cell dynamics

Matteo Iannacone

Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy

Correspondence: Dr M Iannacone, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Via Olgettina 58, Milan 20132, Italy. E-mail: [email protected]

Received 4 July 2014; Revised 25 July 2014; Accepted 26 July 2014
Advance online publication 22 September 2014
Top of page
Abstract

CD8+ T cells play a critical role in hepatitis B virus (HBV) pathogenesis. During acute, self-limited infections, these cells are instrumental to viral clearance; in chronic settings, they sustain repetitive cycles of hepatocellular necrosis that promote hepatocellular carcinoma development. Both CD8+ T-cell defensive and destructive functions are mediated by antigen-experienced effector cells and depend on the ability of these cells to migrate to the liver, recognize hepatocellular antigens and perform effector functions. Understanding the signals that modulate the spatiotemporal dynamics of CD8+ T cells in the liver, particularly in the context of antigen recognition, is therefore critical to gaining insight into the pathogenesis of acute and chronic HBV infection. Here, we highlight recent data on how effector CD8+ T cells traffic within the liver, and we discuss the potential for novel imaging techniques to shed light on this important aspect of HBV pathogenesis.
Keywords:

CD8+ T cells; hepatitis B virus; intravital microscopy; liver immunopathology; platelets

迷你回顾

细胞与分子免疫学推进网上公布2014年9月22日; DOI：10.1038 / cmi.2014.78
肝效应CD8 + T细胞动力学

利玛窦Iannacone

免疫学，移植和传染病，IRCCS圣拉斐尔科学研究所和VITA-礼炮圣拉斐尔大学，米兰，意大利分部

函授：博士M Iannacone，免疫学，移植和传染病，IRCCS圣拉斐尔科学研究所和VITA-礼炮圣拉斐尔大学分部，通过Olgettina 58，米兰20132，意大利。电子信箱：[email protected]

收到2014年7月4日;修订后的2014年7月25日;接受2014年7月26日
提前在网上公布2014年9月22日
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抽象

CD8 + T细胞发挥乙型肝炎病毒（HBV）发病机制中起关键作用。在急性，自限性的感染，这些细胞是有助于达到病毒清除;慢性设置，他们维持肝细胞坏死的重复循环促进肝癌发展。两者的CD8 + T细胞的防御和破坏性功能由抗原有经验的效应细胞介导的，并取决于这些细胞迁移到肝脏，识别肝癌抗原并执行效应功能的能力。应理解，调节CD8 + T细胞的时空动力学在肝脏，特别是在抗原识别的上下文中的信号，因此，关键的洞察的急性和慢性HBV感染的发病机制。在这里，我们强调如何效应CD8 + T细胞交通近期数据的肝脏内，和大家讨论了潜在的新型成像技术来阐明这一重要HBV发病机制方面的光。
关键词：

CD8 + T细胞;乙型肝炎病毒;活体显微镜;肝免疫病理学;血小板

作者: StephenW 时间: 2015-6-1 14:20

Mini Review

Cellular & Molecular Immunology advance online publication 24 November 2014; doi: 10.1038/cmi.2014.112
Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

Zhiyong Ma1,2, Ejuan Zhang3, Dongliang Yang4 and Mengji Lu1

1Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
2Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
3Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
4Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Correspondence: Professor MJ Lu, Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany. E-mail: [email protected]

Received 14 July 2014; Revised 16 October 2014; Accepted 16 October 2014
Advance online publication 24 November 2014
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Abstract

It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus (HBV) infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors (TLRs) sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons (IFNs) and pro-inflammatory cytokines. Experimental results from in vitro and in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T- and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.
Keywords:

Hepatitis B virus; Toll like receptor; Innate immune response; Adaptive immune response
迷你回顾

细胞与分子免疫学推进网上公布2014年11月24日; DOI：10.1038 / cmi.2014.112
的Toll样受体对乙肝病毒感染的控制通过启动抗病毒药先天应答，促进特定适应性免疫应答贡献

智勇Ma1,2，Ejuan Zhang3，栋梁Yang4和蒙基璐

病毒学，大学医院埃森，杜伊斯堡 - 埃森大学，德国埃森的1Institute
教研室传染病，武汉大学中南医院，武汉，中国
病毒学3Wuhan研究所，中国院士，武汉，中国
传染病，协和医院，同济医学院，华中科技大学，湖北武汉，中国的4Department

函授：MJ陆教授，病毒研究所，大学医院埃森，杜伊斯堡 - 埃森，55的Hufelandstraße，45122德国埃森大学。电子信箱：[email protected]

收到2014年7月14日;修订后的2014年10月16日;接受2014年10月16日
提前在网上公布2014年11月24日
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抽象

它被广泛接受该适应性免疫在乙型肝炎病毒（HBV）感染的控制的关键作用。与此相反，先天免疫的贡献仅受到关注，近年来。 toll样受体（TLR）感病原体相关分子模式和激活抗病毒机制，包括细胞内抗病毒途径和生产的抗病毒效应干扰素（干扰素）和促炎细胞因子。来自体外和体内模型中的实验结果表明，的TLR介导的细胞信号转导途径的活化和生产抗病毒细胞因子，导致HBV复制的抑制。然而，HBV感染与TLR表达对宿主细胞和下游信号传导途径的激活的阻断下调有关。在初级HBV感染，Toll样受体可能会减慢HBV感染，但病毒清除贡献只是间接。重要的是，TLR的可调节体内HBV特异性T细胞和B细胞反应，这些对乙肝病毒感染的终止是必不可少的。因此，TLR激动剂是有希望的候选人作为免疫调节剂用于治疗慢性HBV感染的治疗。抗病毒治疗可以恢复TLR在慢性HBV感染的表达和功能，可提高基于TLR活化治疗方法的疗效。具有抗病毒治疗和TLR活化的组合治疗策略可以促进的HBV特异性免疫应答的恢复并由此实现病毒清除在慢性感染HBV的患者。
关键词：

乙型肝炎病毒; Toll样受体;先天免疫应答;适应性免疫反应

作者: 9病成医 时间: 2015-6-1 16:02

总结归纳一下啊。

作者: StephenW 时间: 2015-6-1 16:07

回复 9病成医的帖子

哈哈，他们还在学习免疫系统.

作者: StephenW 时间: 2015-6-1 16:14

"While the central role of adaptive immunity in controlling HBV infection is well established, the contribution of innate immunity in this regard has been appreciated only in recent years. The development of new in vitro methods of HBV infection will soon shed some light on the recognition of HBV by PRRs.98,99,100 Previous studies indicated that HBV infection apparently does not activate innate immunity in chimpanzees and patients. HBV proteins, such as HBsAg, HBx and HBV polymerase, are associated with the inhibition of TLR or RLR signaling pathways and lead to impaired IFN production. However, it remains to be clarified whether the inhibition of TLR or RLR signaling pathways by HBV is the cause of the lack of early interferon and other innate responses in vivo. Whether the innate immune responses would control HBV infection if initiated in the early phase of HBV infection must be determined. It is well documented that the activation of TLR-mediated signaling pathways not only exhibits direct inhibition of HBV replication, but also enhances HBV-specific T-cell and B-cell responses. Although the expression of TLRs on host cells is downregulated by HBV infection, inhibition of HBV replication by antiviral treatment could partially restore TLR expression in patients. Thus, a treatment strategy with a combination of viral suppression, activation of TLR-mediated innate immunity and restoration of HBV-specific immune responses is needed to achieve effective long-term control of HBV infection and cure chronically HBV-infected patients."

虽然适应性免疫控制乙肝病毒感染的核心作用是公认的，在这方面先天免疫的贡献已升值近几年才。乙肝病毒感染的新的体外方法的发展将很快一些线索识别乙肝病毒通过PRRs.98,99,100以往的研究表明，乙肝病毒感染显然不激活黑猩猩和患者先天免疫。 HBV蛋白，如乙肝表面抗原，HBx蛋白和HBV聚合酶，与TLR或RLR信号通路的抑制有关，并导致受损的IFN的产生。但是，它仍然需要澄清的TLR或RLR信号通路由乙肝病毒的抑制是否是缺乏早期干扰素和体内其他先天应答的原因。是否先天免疫应答将控制HBV感染，如果在HBV感染的早期阶段，必须确定启动。它是有据可查的活化TLR介导的信号传导途径，不仅表现出直接抑制HBV复制的，而且还增强了HBV特异性T细胞和B细胞应答。尽管TLR的对宿主细胞中的表达是由HBV感染下调，通过抗病毒治疗抑制乙型肝炎病毒复制的可部分患者恢复TLR表达。因此，一种治疗策略以抑制病毒的结合，激活TLR介导的先天免疫和恢复的HBV特异性免疫反应是需要实现有效的长期控制HBV感染和治疗慢性HBV感染的患者。

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