Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):E11369-E11378. doi: 10.1073/pnas.1809028115. Epub 2018 Nov 12.

Role of humoral immunity against hepatitis B virus core antigen in the pathogenesis of acute liver failure.

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; roberthpurcell@gmail.com pfarci@niaid.nih.gov.

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
PMCID:
PMC6275524
DOI:
10.1073/pnas.1809028115
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center