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

被引：67

作者：

Chen, Zhaochun ^{[1
]}

Diaz, Giacomo ^{[2
]}

Pollicino, Teresa ^{[1
,3
]}

Zhao, Huaying ^{[4
]}

Engle, Ronald E. ^{[1
]}

Schuck, Peter ^{[4
]}

Shen, Chen-Hsiang ^{[5
]}

Zamboni, Fausto ^{[6
]}

Long, Zhifeng ^{[7
]}

Kabat, Juraj ^{[8
]}

De Battista, Davide ^{[1
]}

Bock, Kevin W. ^{[9
]}

Moore, Ian N. ^{[9
]}

Wollenberg, Kurt ^{[10
]}

Soto, Cinque ^{[5
]}

Govindarajan, Sugantha ^{[11
]}

Kwong, Peter D. ^{[5
]}

Kleiner, David E. ^{[12
]}

Purcell, Robert H. ^{[1
]}

Farci, Patrizia ^{[1
]}

机构：

[1] NIAID, Hepat Pathogenesis Sect, Lab Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[2] Univ Cagliari, Dept Biomed Sci, I-09124 Cagliari, Italy

[3] Univ Messina, Dept Human Pathol, I-98122 Messina, Italy

[4] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA

[5] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[6] Azienda Osped Brotzu, Liver Transplantat Ctr, I-09134 Cagliari, Italy

[7] Personal Diagnostix Inc, Gaithersburg, MD 20879 USA

[8] NIAID, Biol Imaging Facil, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[9] NIAID, Comparat Med Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[10] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastuct & Computat Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[11] Univ Southern Calif, Rancho Los Amigos Hosp, Dept Pathol, Downey, CA 90242 USA

[12] NCI, Lab Pathol, NIH, Bethesda, MD 20892 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2018年 / 115卷 / 48期

关键词：

hepatitis B virus; acute liver failure; hepatitis B core antigen; humoral immunity; pathogenesis; INDUCED CYTIDINE DEAMINASE; FULMINANT-HEPATITIS; NUCLEOTIDE-SEQUENCE; FUNCTIONAL-ANALYSIS; NEGATIVE REGULATOR; PRECORE; PROTEIN; CELLS; ANTIBODIES; MUTATIONS;

D O I：

10.1073/pnas.1809028115

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：E11369 / E11378

页数：10

共 66 条

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