乙肝病毒表面抗原激活髓细胞树突状细胞通过可溶性CD14依赖

StephenW

Hepatitis B Virus Surface Antigen Activates Myeloid Dendritic Cells via a Soluble CD14-Dependent Mechanism                                 

• Nadine van Montfoorta*,
• Evelyn van der Aaa,
• Aniek van den Boscha,
• Hilde Brouwersa,
• Thomas Vanwolleghema,
• Harry L. A. Janssena*,
• Hassan Javanbakhtb,
• Sonja I. Buschowa and
• Andrea M. Woltmana
  

                  

• aDepartment of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
• bInfectious Diseases Discovery & Translational Area, Roche Innovation Center Basel, Basel, Switzerland
  

               
                                 

• J.-H. J. Ou, Editor
  

                  

• University of Southern California
  

               
                        

ABSTRACT

Hepatitis B virus (HBV) infection can cause chronic liver disease, which is associated with increased risk of liver cirrhosis, liver failure, and liver cancer. Clearance of HBV infection requires effective HBV-specific immunity; however, the immunological mechanisms that determine the development of effective HBV-specific immunity are poorly understood. Dendritic cells (DC) play a pivotal role in the regulation of antiviral immunity. Here, we investigated the interaction between HBV surface antigen (HBsAg), the main envelope glycoprotein of HBV, and BDCA1+ myeloid dendritic cells (mDC). Exposure of peripheral blood-derived BDCA1+ mDC to HBsAg resulted in strong DC maturation, cytokine production, and enhanced capacity to activate antigen-specific cytotoxic T cells (CTLs). By using neutralizing antibodies, crucial roles for CD14 and Toll-like receptor 4 (TLR4) in HBsAg-mediated BDCA1+ mDC maturation were identified. Concordantly, HBsAg-mediated DC maturation required fetal calf serum (FCS) or human plasma, naturally containing soluble CD14 (sCD14). Intriguingly, HBsAg-induced DC maturation was significantly reduced in umbilical cord blood plasma, which contained less sCD14 than adult plasma, indicating that sCD14 is an important host factor for recognition of HBsAg by DC and subsequent DC activation. A direct interaction between sCD14 and HBsAg was demonstrated by using enzyme-linked immunosorbent assay (ELISA). Moreover, sCD14-HBsAg complexes were detected both in vitro and in sera of HBV-infected patients. The abundance of sCD14-HBsAg complexes varied between chronic HBV disease stages and correlated with activation of BDCA1+ mDC in vivo. We conclude that HBsAg activates BDCA1+ DC via an sCD14-dependent mechanism. These findings provide important novel insights into the initiation of HBV-specific immunity and facilitate development of effective immunotherapeutic interventions for HBV.

IMPORTANCE Hepatitis B virus (HBV) infection is a significant health problem, as it causes progressive liver injury and liver cancer in patients with chronic HBV infection, which affects approximately 250 million individuals worldwide. Some of the infected adults and the majority of neonates fail to mount an effective immune response and consequently develop chronic infection. The viral and host factors involved in the initiation of effective HBV-specific immune responses remain poorly understood. Here we identified CD14 and TLR4 as receptors for HBsAg, the main HBV envelope antigen. HBsAg induced strong maturation of dendritic cells (DC), which have a central role in regulation of virus-specific immunity. These results provide essential novel insights into the mechanisms underlying the initiation of HBV-specific immunity. Intriguingly, since neonates have naturally low sCD14, the finding that serum-derived sCD14 is a crucial host factor for recognition of HBsAg by DC may have implications for immunity of neonates to HBV infection.
FOOTNOTES

        Received 16 November 2015.
        Accepted 8 April 2016.
        Accepted manuscript posted online 20 April 2016.
    Address correspondence to Nadine van Montfoort, nvanmontfoort{at}lumc.nl, or Andrea M. Woltman, a.woltman{at}erasmusmc.nl.

    ↵* Present address: Nadine van Montfoort, Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands; Harry L. A. Janssen, Toronto Centre for Liver Disease, Division of Gastroenterology, University Health Network, Toronto, ON, Canada.

    Citation van Montfoort N, van der Aa E, van den Bosch A, Brouwers H, Vanwolleghem T, Janssen HLA, Javanbakht H, Buschow SI, Woltman AM. 2016. Hepatitis B virus surface antigen activates myeloid dendritic cells via a soluble CD14-dependent mechanism. J Virol 90:6187–6199. doi:10.1128/JVI.02903-15.

    Copyright © 2016, American Society for Microbiology. All Rights Reserved.

StephenW

通过可溶性CD14依赖机制乙肝病毒表面抗原激活髓细胞树突状细胞
乙肝病毒表面抗原激活髓细胞树突状细胞通过可溶性CD14依赖机制乙肝病毒表面抗原激活髓细胞树突状细胞
    纳丁面包车Montfoorta *，伊夫林·范德AAA，Aniek范登Boscha希尔德Brouwersa，托马斯Vanwolleghema，哈里L. A. Janssena *，哈桑Javanbakhtb，宋佳一Buschowa和Andrea M. Woltmana

    胃肠病学和肝病，伊拉兹马斯MC大学医学中心的鹿特丹，荷兰鹿特丹的aDepartment
    bInfectious疾病发现与转化区，罗氏创新中心巴塞尔，巴塞尔，瑞士

    J.-H. J.欧，编辑器

    南加州大学

抽象

乙型肝炎病毒（HBV）感染可导致慢性肝病，其与肝硬化的风险增加，肝功能衰竭，以及肝癌有关。 HBV感染的清除需要有效的HBV特异性免疫力;然而，确定有效HBV特异性免疫的发展的免疫学机制知之甚少。树突状细胞（DC）发挥抗病毒免疫的调节了举足轻重的作用。这里，我们调查HBV表面抗原（HBsAg），乙型肝炎病毒的主要包膜糖蛋白，和BDCA1 +骨髓树突状细胞（MDC）之间的相互作用。外周血衍生BDCA1 +的mDC对HBsAg的曝光导致强DC成熟，细胞因子的产生，和增强的激活抗原特异性细胞毒性T细胞的能力（CTL的）。通过使用中和抗体，对CD14关键的角色和在HBsAg的介导BDCA1 +的mDC成熟Toll样受体4（TLR4）进行了鉴定。一致地，乙肝表面抗原介导的DC成熟所需的胎牛血清（FCS）或人血浆，自然含可溶性CD14（的sCD14）。有趣的是，HBsAg的诱导DC成熟中脐带血等离子体，其含有比成人等离子体的sCD14少，这表明的sCD14为识别的HBsAg直流和随后的DC激活的重要宿主因子被显著降低。的sCD14与HBsAg之间的直接相互作用是通过采用酶联免疫吸附试验（ELISA）证实。此外，无论是在体外和HBV感染的病人的血清中检测到的sCD14-HBsAg的复合物。的sCD14-HBsAg的复合物丰慢性乙肝疾病阶段之间变化，并与体内BDCA1 +的mDC激活相关。我们的结论是乙肝表面抗原通过的sCD14依赖机制激活BDCA1 + DC。这些发现提供了重要的新的见解HBV特异性免疫的启动和促进乙肝免疫治疗有效的干预措施的发展。

重要性乙型肝炎病毒（HBV）感染是一个显著的健康问题，因为它会导致进行性肝损伤和肝癌患者的慢性HBV感染，这影响了全世界大约有250万人。一些被感染的成人和大多数新生儿的无法装入有效的免疫反应，从而发展成慢性感染。参与有效的HBV特异性免疫反应引发的病毒和宿主因素仍然知之甚少。在这里，我们确定CD14和TLR4受体作为乙型肝炎表面抗原，主要HBV包膜抗原。 HBsAg的诱导的树突状细胞（DC），其具有在病毒特异性免疫调节中发挥中心作用的强成熟。这些结果提供了重要的新的见解HBV特异性免疫的启动基本的机制。有趣的是，因为新生儿有自然不低的sCD14时，发现血清来源的sCD14是认可的HBsAg直流可能对新生儿HBV感染的免疫力影响的重要宿主因子。
脚注

        16收到的2015年11月。
        接受2016年4月8。
        接受手稿2016年4月20在网上公布。
    通讯地址纳迪娜面包车蒙特福特，nvanmontfoort {}在lumc.nl，或者安德烈M.螺翼，a.woltman {}在erasmusmc.nl。

    ↵*现住址：纳丁面包车蒙特福特，临床肿瘤学，莱顿大学医学中心，荷兰莱顿系;哈里L. A.扬森，多伦多中心肝病，胃肠科，大学健康网络，多伦多，加拿大。

    引文面包车蒙特福特N，范德机管局E，范登博世A，Brouwers的H，Vanwolleghem T，扬森HLA，Javanbakht H，Buschow SI，螺翼AM。 2016年乙型肝炎病毒表面抗原经由可溶性CD14依赖性机制激活骨髓树突状细胞。病毒学杂志90：6187-6199。 DOI：10.1128 / JVI.02903-15。

    版权所有©2016年，美国微生物学会。版权所有。