NIH科学家阐明了乙型肝炎病毒相关的急性肝衰竭的原因

StephenW

Tuesday, November 13, 2018
NIH scientists illuminate causes of hepatitis b virus-associated acute liver failure

Transmission electron microscopic (TEM)
This transmission electron microscopic (TEM) image revealed the presence of hepatitis B virus (HBV) particles (orange). The round virions, which measure 42nm in diameter, are known as Dane particles.CDC/ Dr. Erskine Palmer
What

National Institutes of Health scientists and their collaborators found that hepatitis B virus (HBV)-associated acute liver failure (ALF) — a rare condition that can turn fatal within days without liver transplantation — results from an uncommon encounter between a highly mutated HBV variant and an unusual immune response in the patient’s liver that is mainly sustained by antibody-producing B cells.

By applying state-of-the-art technologies, the researchers discovered important new mechanisms about the disease by examining liver samples taken from four patients who developed HBV-ALF. HBV-ALF is one of the most dramatic clinical syndromes in medicine, according to the research team, but so rare that samples of this type are seldom available for study.

Scientists from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) led the project with colleagues from two Italian universities. Their study is published in Proceedings of the National Academy of Sciences.

The investigators used advanced gene sequencing and tissue and cell analysis technologies to determine specific molecular events occurring at the site where HBV replicates and damages liver tissue. They identified processes that are distinct to HBV-ALF cases compared with cases of classic acute HBV infection. Some of these unique events involve a highly mutated virus antigen, the HBV core antigen. The scientists believe that this antigen plays a key role in disease development because it interacts with specific antibodies that are — unusually, they say — already present in these patients. Because of ethical reasons in obtaining liver tissues from patients with classic acute HBV, for their comparison study the scientists used archived liver specimens from two chimpanzees with acute HBV that had been studied many years earlier. They found the mechanism of acute HBV disease to be completely different from that of ALF.

According to the scientists, the HBV-ALF findings were consistent among samples taken from all four patients studied. That is important validation, they say, because virtually no studies have been done on the molecular pathogenesis of HBV-ALF in the liver. They hope their new work provides a model of how the disease develops and will lead to new diagnostic, treatment and prevention strategies.
Article

Z Chen et al. Role of humoral immunity against hepatitis B virus core antigen in the pathogenesis of acute liver failure (link is external). Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1809028115 (2018).

StephenW

018年11月13日，星期二
NIH科学家阐明了乙型肝炎病毒相关的急性肝衰竭的原因

透射电子显微镜（TEM）
该透射电子显微镜（TEM）图像显示存在乙型肝炎病毒（HBV）颗粒（橙色）。圆形病毒粒子的直径为42nm，被称为Dane粒子.CDC / Dr. Erskine Palmer
什么

美国国立卫生研究院的科学家及其合作者发现乙型肝炎病毒（HBV）相关的急性肝功能衰竭（ALF） - 一种罕见的疾病，可以在没有肝移植的情况下在几天内致命致死 - 是由于高度突变的HBV变异和患者肝脏中的一种不寻常的免疫反应主要由产生抗体的B细胞维持。

通过应用最先进的技术，研究人员通过检查从4名患有HBV-ALF的患者中采集的肝脏样本，发现了有关该疾病的重要新机制。研究小组表示，HBV-ALF是医学界最具戏剧性的临床综合症之一，但很少见，因此很少有此类样本可供研究。

美国国立卫生研究院国家过敏和传染病研究所（NIAID）的科学家与两所意大利大学的同事共同领导了该项目。他们的研究发表在美国国家科学院院刊上。

研究人员使用先进的基因测序和组织和细胞分析技术来确定HBV复制和损害肝组织的部位发生的特定分子事件。与典型的急性HBV感染病例相比，他们确定了与HBV-ALF病例不同的过程。这些独特事件中的一些涉及高度突变的病毒抗原，即HBV核心抗原。科学家认为，这种抗原在疾病发展中发挥着关键作用，因为它与特定的抗体相互作用 - 他们说 - 这些抗体已经存在于这些患者身上。由于从经典急性HBV患者获得肝组织的伦理原因，对于他们的比较研究，科学家使用了两年前曾研究过的急性HBV黑猩猩的存档肝脏标本。他们发现急性HBV疾病的机制与ALF完全不同。

根据科学家的研究，HBV-ALF的研究结果与所有四名研究患者的样本一致。他们说，这是重要的验证，因为实际上没有对肝脏中HBV-ALF的分子发病机制进行过研究。他们希望他们的新工作提供疾病如何发展的模型，并将导致新的诊断，治疗和预防策略。
文章

Z Chen等。乙型肝炎病毒核心抗原体液免疫在急性肝功能衰竭发病机制中的作用（link is external）。美国国家科学院院刊DOI：10.1073 / pnas.1809028115（2018）。

StephenW

Proc Natl Acad Sci U S A. 2018 Nov 12. pii: 201809028. doi: 10.1073/pnas.1809028115. [Epub ahead of print]
Role of humoral immunity against hepatitis B virus core antigen in the pathogenesis of acute liver failure.
Chen Z1, Diaz G2, Pollicino T1,3, Zhao H4, Engle RE1, Schuck P4, Shen CH5, Zamboni F6, Long Z7, Kabat J8, De Battista D1, Bock KW9, Moore IN9, Wollenberg K10, Soto C5, Govindarajan S11, Kwong PD5, Kleiner DE12, Purcell RH13, Farci P13.
Author information

1
    Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
2
    Department of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy.
3
    Department of Human Pathology, University of Messina, 98122 Messina, Italy.
4
    Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892.
5
    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
6
    Liver Transplantation Center, Azienda Ospedaliera Brotzu, 09134 Cagliari, Italy.
7
    Personal Diagnostix, Inc., Gaithersburg, MD 20879.
8
    Biological Imaging Facility/Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
9
    Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
10
    Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastucture and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
11
    Department of Pathology, Rancho Los Amigos Hospital, University of Southern California, Downey, CA 90242.
12
    Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
13
    Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; [email protected] [email protected].

Abstract

Hepatitis B virus (HBV)-associated acute liver failure (ALF) is a dramatic clinical syndrome leading to death or liver transplantation in 80% of cases. Due to the extremely rapid clinical course, the difficulties in obtaining liver specimens, and the lack of an animal model, the pathogenesis of ALF remains largely unknown. Here, we performed a comprehensive genetic and functional characterization of the virus and the host in liver tissue from HBV-associated ALF and compared the results with those of classic acute hepatitis B in chimpanzees. In contrast with acute hepatitis B, HBV strains detected in ALF livers displayed highly mutated HBV core antigen (HBcAg), associated with increased HBcAg expression ex vivo, which was independent of viral replication levels. Combined gene and miRNA expression profiling revealed a dominant B cell disease signature, with extensive intrahepatic production of IgM and IgG in germline configuration exclusively targeting HBcAg with subnanomolar affinities, and complement deposition. Thus, HBV ALF appears to be an anomalous T cell-independent, HBV core-driven B cell disease, which results from the rare and unfortunate encounter between a host with an unusual B cell response and an infecting virus with a highly mutated core antigen.
KEYWORDS:

acute liver failure; hepatitis B core antigen; hepatitis B virus; humoral immunity; pathogenesis

PMID:
    30420516
DOI:
    10.1073/pnas.1809028115

StephenW

Proc Natl Acad Sci U S A. 2018 Nov 12. pii：201809028.doi：10.1073 / pnas.1809028115。 [提前打印]
乙型肝炎病毒核心抗原体液免疫在急性肝衰竭发病机制中的作用。
Chen Z1，Diaz G2，Pollicino T1,3，Zhao H4，Engle RE1，Schuck P4，Shen CH5，Zamboni F6，Long Z7，Kabat J8，De Battista D1，Bock KW9，Moore IN9，Wollenberg K10，Soto C5，Govindarajan S11 ，Kwong PD5，Kleiner DE12，Purcell RH13，Farci P13。
作者信息

1
    美国国立卫生研究院国家过敏和传染病研究所传染病实验室肝脏发病部，贝塞斯达，MD 20892。
2
    卡利亚里大学生物医学科学系，09124，意大利卡利亚里。
3
    墨西拿大学人类病理学系，98122墨西拿，意大利。
4
    美国国立卫生研究院国家生物医学成像和生物工程研究所细胞成像和大分子生物物理实验室，贝塞斯达，MD 20892。
五
    疫苗研究中心，国家过敏和传染病研究所，国立卫生研究院，贝塞斯达，MD 20892。
6
    肝移植中心，Azienda Ospedaliera Brotzu，09134卡利亚里，意大利。
7
    Personal Diagnostix，Inc.，Gaithersburg，MD 20879。
8
    生物成像设施/研究技术处，国家过敏和传染病研究所，国立卫生研究院，贝塞斯达，MD 20892。
9
    国立过敏与传染病研究所比较医学分会，国立卫生研究院，贝塞斯达，MD 20892。
10
    生物信息学和计算生物科学分部，网络基础设施和计算生物学办公室，国家过敏和传染病研究所，国立卫生研究院，贝塞斯达，MD 20892。
11
    南加州大学Rancho Los Amigos医院病理科，唐尼，加利福尼亚州90242。
12
    国立卫生研究院病理学实验室，国立卫生研究院，贝塞斯达，MD 20892。
13
    国立卫生研究院过敏和传染病研究所传染病实验室肝脏发病部，贝塞斯达，MD 20892; [email protected] [email protected]。

抽象

乙型肝炎病毒（HBV）相关的急性肝衰竭（ALF）是一种引起死亡或肝移植的显着临床综合征，占80％。由于临床过程非常迅速，获得肝脏标本的困难，以及缺乏动物模型，ALF的发病机制仍然很大程度上未知。在这里，我们对来自HBV相关ALF的肝脏组织中的病毒和宿主进行了全面的遗传和功能鉴定，并将结果与​​黑猩猩中经典急性乙型肝炎的结果进行了比较。与急性乙型肝炎相比，在ALF肝脏中检测到的HBV毒株显示高度突变的HBV核心抗原（HBcAg），与离体的HBcAg表达增加有关，这与病毒复制水平无关。联合基因和miRNA表达谱显示出显性B细胞疾病特征，在种系构型中广泛肝内产生IgM和IgG，专门针对具有亚纳摩尔亲和力的HBcAg和补体沉积。因此，HBV ALF似乎是异常的T细胞非依赖性HBV核心驱动的B细胞疾病，其由具有不寻常的B细胞应答的宿主和具有高度突变的核心抗原的感染病毒之间的罕见且不幸的相遇引起。
关键词：

急性肝功能衰竭;乙型肝炎核心抗原;乙型肝炎病毒;体液免疫;发病

结论：
    30420516
DOI：
    10.1073 / pnas.1809028115