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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.<\/jats:p>","DOI":"10.1073\/pnas.1809028115","type":"journal-article","created":{"date-parts":[[2018,11,12]],"date-time":"2018-11-12T14:55:59Z","timestamp":1542034559000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":72,"title":["Role of humoral immunity against hepatitis B virus core antigen in the pathogenesis of acute liver failure"],"prefix":"10.1073","volume":"115","author":[{"given":"Zhaochun","family":"Chen","sequence":"first","affiliation":[{"name":"Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 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20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt","family":"Wollenberg","sequence":"additional","affiliation":[{"name":"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;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinque","family":"Soto","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sugantha","family":"Govindarajan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Rancho Los Amigos Hospital, University of Southern California, Downey, CA 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20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Farci","sequence":"additional","affiliation":[{"name":"Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2018,11,12]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1056\/NEJM199312163292508","article-title":"Acute liver failure","volume":"329","author":"Lee WM","year":"1993","unstructured":"WM Lee, Acute liver failure. N Engl J Med 329, 1862\u20131872 (1993).","journal-title":"N Engl J Med"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1055\/s-2008-1073114","article-title":"Etiologies of acute liver failure","volume":"28","author":"Lee WM","year":"2008","unstructured":"WM Lee, Etiologies of acute liver failure. Semin Liver Dis 28, 142\u2013152 (2008).","journal-title":"Semin Liver Dis"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev.iy.13.040195.000333","article-title":"Hepatitis B virus immunopathogenesis","volume":"13","author":"Chisari FV","year":"1995","unstructured":"FV Chisari, C Ferrari, Hepatitis B virus immunopathogenesis. 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J Virol 77, 68\u201376 (2003).","journal-title":"J Virol"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"6669","DOI":"10.1073\/pnas.0401771101","article-title":"Genomic analysis of the host response to hepatitis B virus infection","volume":"101","author":"Wieland S","year":"2004","unstructured":"S Wieland, R Thimme, RH Purcell, FV Chisari, Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci USA 101, 6669\u20136674 (2004).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1172\/JCI117006","article-title":"Hepatitis B virus precore mutation and fulminant hepatitis in the United States. A polymerase chain reaction-based assay for the detection of specific mutation","volume":"93","author":"Liang TJ","year":"1994","unstructured":"TJ Liang, , Hepatitis B virus precore mutation and fulminant hepatitis in the United States. A polymerase chain reaction-based assay for the detection of specific mutation. J Clin Invest 93, 550\u2013555 (1994).","journal-title":"J Clin Invest"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1002\/hep.1840140203","article-title":"Association of a precore genomic variant of hepatitis B virus with fulminant hepatitis","volume":"14","author":"Carman WF","year":"1991","unstructured":"WF Carman, , Association of a precore genomic variant of hepatitis B virus with fulminant hepatitis. 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