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Role of Humoral Immunity Against Hepatitis B Virus Core Antigen in the Pathogenesis of Acute Liver Failure

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Role of Humoral Immunity Against Hepatitis B Virus Core Antigen in the Pathogenesis of Acute Liver Failure Role of humoral immunity against hepatitis B virus core antigen in the pathogenesis of acute liver failure Zhaochun Chena, Giacomo Diazb, Teresa Pollicinoa,c, Huaying Zhaod, Ronald E. Englea, Peter Schuckd, Chen-Hsiang Shene, Fausto Zambonif, Zhifeng Longg, Juraj Kabath, Davide De Battistaa, Kevin W. Bocki, Ian N. Moorei, Kurt Wollenbergj, Cinque Sotoe, Sugantha Govindarajank, Peter D. Kwonge, David E. Kleinerl, Robert H. Purcella,1, and Patrizia Farcia,1 aHepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; bDepartment of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy; cDepartment of Human Pathology, University of Messina, 98122 Messina, Italy; dLaboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892; eVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; fLiver Transplantation Center, Azienda Ospedaliera Brotzu, 09134 Cagliari, Italy; gPersonal Diagnostix, Inc., Gaithersburg, MD 20879; hBiological Imaging Facility/Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; iComparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; jBioinformatics 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; kDepartment of Pathology, Rancho Los Amigos Hospital, University of Southern California, Downey, CA 90242; and lLaboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 Contributed by Robert H. Purcell, October 4, 2018 (sent for review May 25, 2018; reviewed by Antonio Bertoletti and Stephen Locarnini) Hepatitis B virus (HBV)-associated acute liver failure (ALF) is a 14), often accompanied by low levels of HBV replication (15–17). dramatic clinical syndrome leading to death or liver transplantation The question of whether an enhanced humoral immune response in 80% of cases. Due to the extremely rapid clinical course, the plays a role in the pathogenesis of HBV-associated ALF remains difficulties in obtaining liver specimens, and the lack of an animal unanswered. More recently, high titers of IgM anticore were shown model, the pathogenesis of ALF remains largely unknown. Here, we to differentiate ALF that follows primary HBV infection from ALF performed a comprehensive genetic and functional characterization developing upon exacerbation of chronic HBV infection (18), sug- of the virus and the host in liver tissue from HBV-associated ALF gesting that an exaggerated IgM response against HBcAg may be and compared the results with those of classic acute hepatitis B implicated in the pathogenesis of this disease. Consistent with these in chimpanzees. In contrast with acute hepatitis B, HBV strains findings, we have previously shown that HBV-associated ALF is detected in ALF livers displayed highly mutated HBV core antigen characterized by an overriding B cell gene signature centered in the (HBcAg), associated with increased HBcAg expression ex vivo, which was independent of viral replication levels. Combined gene and Significance miRNA expression profiling revealed a dominant B cell disease signature, with extensive intrahepatic production of IgM and IgG in Hepatitis B virus (HBV)-associated acute liver failure (ALF), also germline configuration exclusively targeting HBcAg with subnano- known as fulminant hepatitis B, is a rare but often fatal com- molar affinities, and complement deposition. Thus, HBV ALF appears plication of acute HBV infection. The pathogenesis of ALF is still to be an anomalous T cell-independent, HBV core-driven B cell largely unknown due to the lack of experimental systems and disease, which results from the rare and unfortunate encounter the difficulties in obtaining liver samples. Our comprehensive between a host with an unusual B cell response and an infecting study of both liver tissue and serum samples from ALF patients virus with a highly mutated core antigen. using cutting-edge technologies allowed us to identify viral and host factors uniquely associated with this disease. In con- hepatitis B virus | acute liver failure | hepatitis B core antigen | humoral trast to classic acute hepatitis B where the liver damage ap- immunity | pathogenesis pears to be T cell-mediated, this study demonstrates a major role of the humoral immunity in the pathogenesis of HBV- cute liver failure (ALF), previously known as fulminant associated ALF, which may open new avenues for the diagnosis Ahepatitis, is a rare but dramatic clinical syndrome charac- and treatment of this dramatic disease. terized by the sudden loss of hepatocytes, leading to multiorgan failure in a person without preexisting liver disease (1). Hepatitis B Author contributions: Z.C., T.P., and P.F. designed research; Z.C., G.D., T.P., H.Z., R.E.E., virus (HBV) is a major cause of ALF worldwide (2). However, the P.S., F.Z., Z.L., J.K., D.D.B., K.W.B., and I.N.M. performed research; Z.C., G.D., T.P., H.Z., R.E.E., P.S., C.-H.S., F.Z., Z.L., J.K., D.D.B., K.W.B., I.N.M., K.W., C.S., S.G., P.D.K., D.E.K., difficulties in obtaining liver specimens and the extremely rapid R.H.P., and P.F. analyzed data; P.F. supervised the study; and Z.C., G.D., T.P., R.E.E., and clinical course of this disease, along with the lack of an animal P.F. wrote the paper. model, have hampered pathogenesis studies. While in the classic Reviewers: A.B., Duke-NUS Graduate Medical School; and S.L., The Royal Melbourne form of acute hepatitis B liver damage and viral clearance are me- Hospital. diated by specific antiviral T cell responses (3–5) with a dominant The authors declare no conflict of interest. intrahepatic T cell gene signature (6), little is known of the patho- Published under the PNAS license. genic mechanisms leading to ALF. On the viral side, variants of Data deposition: Next-generation sequencing data of HBV strains have been deposited in HBV containing precore or core promoter mutations that affect the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) (accession no. PRJNA422423). Microarray data (mRNA and miRNA) have been deposited hepatitis B e antigen (HBeAg) expression have been associated with in the NCBI Gene Expression Omnibus (GEO) database (accession nos. GSE96851 and MEDICAL SCIENCES ALF (7–11), although the same mutations are also commonly de- GSE62037). Heavy-chain variable region sequences have been deposited in GenBank (ac- tected in chronic hepatitis B surface antigen (HBsAg) carriers (12), cession nos. KX986360–KX986516 and KX986517–KX986558). Next-generation sequenc- ing data of IgG and IgM antibodies have been deposited in the NCBI SRA (accession no. suggestingthatALFistheresultofacomplexinterplaybetweenthe SRP126953). virus and the host (3). On the host side, early studies conducted in 1 To whom correspondence may be addressed. Email: [email protected] or the 1970s and 1980s demonstrated an unusually brisk antibody re- [email protected]. sponse against all HBV antigens, with significantly higher titers of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. IgM to hepatitis B core antigen (HBcAg) (13) and rapid clearance 1073/pnas.1809028115/-/DCSupplemental. of HBsAg and HBeAg, compared with classic acute hepatitis B (13, Published online November 12, 2018. www.pnas.org/cgi/doi/10.1073/pnas.1809028115 PNAS | vol. 115 | no. 48 | E11369–E11378 Downloaded by guest on September 30, 2021 liver, with extensive intrahepatic expression of IgG and IgM anti- A Nucleotide Amino acid bodies directed against the HBcAg (19). 10 10 Patient 241 Patient 31 Access to liver specimens from additional patients with HBV 8 8 ALF provided us with the unique opportunity to confirm and ex- 6 6 tend our original observations (19) and to perform a genetic and 4 4 mutation (%) mutation (%) Frequency of functional characterization of the HBV strains associated with 2 Frequency of 2 ALF. Here, we investigated the role of viral and host factors in the 0 0 pathogenesis of HBV ALF in primary liver tissue, which is the 10 10 Patient 219 Patient 32 anatomical site where the disease occurs, and compared the find- 8 8 ings in ALF with those in classic acute hepatitis B in chimpanzees. 6 6 By using cutting-edge molecular techniques, our study corrobo- 4 4 mutation (%) mutation (%) Frequency of rates the pathogenic role of humoral immunity in HBV ALF. 2 Frequency of 2 0 0 Results pre pre Pol HBx Enhl-EnhII- SP1 SP pre pre Pol HBx Enhl-EnhII-SP1 SP C/C S/S XP BCP C/C S/S XP BCP Clinical, Serologic, and Virologic Characteristics of the Patients. Four HBV genome HBV genome healthy young adult individuals, two males and two females with ± ± 1102030405060 a mean age SD of 42.2 7.2 y, suddenly developed HBV ALF, B ............................................................. with progressive coagulopathy and encephalopathy, and all un- V01460 (ayw) MDIDPYKEFGATVELLSFLPSDFFPSVRDLLDTASALYREALESPEHCSPHHTALRQAILC derwent liver transplantation within 8 d of the onset of symp- Patient 241 ...........S........Y.............T..F.D..................... toms. Two
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