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).作者: StephenW 时间: 2018-11-14 18:27
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
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）。作者: StephenW 时间: 2018-11-16 11:36
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
作者: StephenW 时间: 2018-11-16 11:37
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