Role of Humoral Immunity against Hepatitis B Virus Core Antigen in the Pathogenesis of Acute Liver Failure
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE96851 | GEO | 2018/10/29
REPOSITORIES: GEO
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Project description:To investigate the role of viral and host factors in acute liver failure, we analyzed serum and multiple liver specimens obtained at the time of liver transplantation from four well-characterized patients. We carried out an integrated clinicopathological analysis, gene and microRNA expression profiling, next-generation sequencing, antibody-displaying phage libraries, and in vitro functional analysis of HBV variants. Liver samples were obtained from 4 patients with HBV-associated acute liver failure (ALF), 10 liver donors and 7 subjects who underwent hepatic resection for liver angioma. As this is the continuation of a previous study (Title: Integrated ordination of miRNA and mRNA expression profiles; Authors: Diaz et al.) miRNA (microRNA) data are already available at the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under the accession number GSE62037. The present submission concerns only mRNA data. This dataset is part of the TransQST collection.
2018-10-29 | E-GEOD-96851 | biostudies-arrayexpress
Project description:Hepatitis B virus (HBV)-associated acute liver failure (ALF) is a dramatic clinical syndrome due to a sudden loss of hepatic cells leading to multiorgan failure. The mechanisms whereby HBV induces ALF are unknown. We used gene expression profiling to establish a molecular definition of hepatitis B virus (HBV)-associated ALF. Two patients who underwent liver transplantation for HBV-associated ALF were studied. Gene expression profiling was performed on 8 liver specimens obtained from the two patients with ALF (4 samples per liver) and individual liver specimens from 8 liver donors and normal livers from 11 patients who underwent resection for angioma. Statistical analyses were used to identify the signature genes of HBV-associated ALF. Multivariate permutation analysis identified 1,368 transcripts that were differentially expressed in ALF; 709 were up-regulated and 659 down-regulated. The most represented up-regulated transcripts were those involved in the immune response, whereas the most abundant down-regulated transcripts were those involved in metabolism and hepatic synthesis. ALF was characterized by overriding B-cell signature comprising genes related to mature B cells and plasma cells with abundant polyclonal expression of immunoglobulin genes. By contrast, there was a limited T-cell signature and up-regulation of several inhibitors of T-cell activation. Immunohistochemical analysis confirmed the prominent B-cell signature showing diffuse liver infiltration by plasma blasts and plasma cells with strong cytoplasmic staining for IgM and IgG, associated with a significant deposition of complement factors. Using phage display technology, we demonstrated that the molecular target of the massive intrahepatic antibody response is the hepatitis B core antigen (HBcAg). These data suggest that the humoral immunity may exert a primary role in the pathogenesis of HBV-associated ALF. Liver samples were obtained from explanted livers of two patients with HBV-associated ALF (4 samples per liver), 8 normal liver donors and 11 patients who underwent resection for angioma. Gene expression profiling was used to establish a molecular definition of ALF. Patient data derived from associated publication Table S2. This dataset is part of the TransQST collection.
2010-04-26 | E-GEOD-14668 | biostudies-arrayexpress
Project description:Hepatitis B virus (HBV)-associated acute liver failure (ALF) is a dramatic clinical syndrome due to a sudden loss of hepatic cells leading to multiorgan failure. The mechanisms whereby HBV induces ALF are unknown. We used gene expression profiling to establish a molecular definition of hepatitis B virus (HBV)-associated ALF. Two patients who underwent liver transplantation for HBV-associated ALF were studied. Gene expression profiling was performed on 8 liver specimens obtained from the two patients with ALF (4 samples per liver) and individual liver specimens from 8 liver donors and normal livers from 11 patients who underwent resection for angioma. Statistical analyses were used to identify the signature genes of HBV-associated ALF. Multivariate permutation analysis identified 1,368 transcripts that were differentially expressed in ALF; 709 were up-regulated and 659 down-regulated. The most represented up-regulated transcripts were those involved in the immune response, whereas the most abundant down-regulated transcripts were those involved in metabolism and hepatic synthesis. ALF was characterized by overriding B-cell signature comprising genes related to mature B cells and plasma cells with abundant polyclonal expression of immunoglobulin genes. By contrast, there was a limited T-cell signature and up-regulation of several inhibitors of T-cell activation. Immunohistochemical analysis confirmed the prominent B-cell signature showing diffuse liver infiltration by plasma blasts and plasma cells with strong cytoplasmic staining for IgM and IgG, associated with a significant deposition of complement factors. Using phage display technology, we demonstrated that the molecular target of the massive intrahepatic antibody response is the hepatitis B core antigen (HBcAg). These data suggest that the humoral immunity may exert a primary role in the pathogenesis of HBV-associated ALF.
2010-04-26 | GSE14668 | GEO
Project description:Background and Aims: Chronic HBV infection is a major cause of liver disease and cancer. Virus-host interactions and the pathogenesis of virus-induced liver disease are only partially understood. Hypoxia has been shown to play a major role in disease biology and carcinogenesis and HBV replicates a naturally hypoxic organ. In this study we aimed to investigate the role of liver hypoxia for HBV infection. Methods: Using cell culture, animal models and human tissues we investigated the impact of hyproxia on the HBV life cycle. Results: Establishing liver cell-based model systems that mimic hepatic oxygen, we uncover a major role of hypoxia in regulating HBV transcription. Hypoxia-inducible factors (HIFs) perturb HBV replication and expression in cell-based and animal models. Conservation of hypoxia responsive elements in the viral basal core promoter uncover an essential role for HIFs in regulating the hepadnaviridae family of hepatotropic viruses. Conclusions: Identifying a role for this conserved oxygen sensors in regulating HBV replication provides a new understanding of virus-host interactions and liver disease biology, improve state-of-the-art HBV model systems and unravels new opportunities for therapeutic targeting of chronic hepatitis B.
2023-07-20 | PXD020086 | Pride
Project description: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.
| S-EPMC6275524 | biostudies-literature
Project description:Hepatitis B virus (HBV)-associated acute on chronic liver failure (HBV-ACLF), characterized by an acute deterioration of liver function in the patients with chronic hepatitis B (CHB), is lack of predicting biomarkers for prognosis. To explore potential biomarkers of HBV-ACLF for clinical applications, immuno-depletion of high-abundance plasma proteins followed by iTRAQ-based quantitative proteomic approach was employed to analyze plasma samples from 20 healthy control people, 20 CHB patients and 20 HBV-ACLF patients, respectively. As a result, a total of 427 proteins were identified and quantified from these samples, and 42 proteins were differentially expressed in HBV-ACLF patients as compared to both CHB patients and healthy controls. According to bioinformatics analysis results, 6 proteins related to immune response (MMR), inflammatory response (OPN, HPX), blood coagulation (ATIII) and lipid metabolism (APO-CII, GP73) were selected as biomarker candidates. Further ELISA analysis confirmed the significant up-regulation of GP73, MMR, OPN and down-regulation of ATIII, HPX, APO-CII in HBV-ACLF plasma samples (p<0.01). Moreover, receiver operating characteristic (ROC) curve analysis revealed high diagnostic value of these candidates in assessing HBV-ACLF. In conclusion, present quantitative proteomic study identified 6 novel HBV-ACLF biomarker candidates and might provide fundamental information for development of HBV-ACLF biomarker.
2018-10-23 | PXD007975 | Pride
Project description:To investigate the role of viral and host factors in HDV-associated HCC we carried out an integrated clinicopathological and gene expression study of tissue specimens and laser microdissected hepatocytes obtained at the time of liver transplantation from livers with HDV-HCC, HDV-cirrhosis without HCC, HCV-HCC and HBV-HCC. References to GSM series of HDV and HBV livers, already deposited in GEO, are included in this series. Part of data of HCV livers are a re-analysis of GSE series GSE69715 and GSE78737, the re-analyzed GSM is indicated in the 'description' column and with a link at the bottom of the page.
2018-04-09 | GSE107170 | GEO
Project description:The liver has inherent regenerative capacity via mitotic division of mature hepatocytes. However, if the hepatic loss is massive or mature hepatocyte proliferation is impaired by chronic liver injury, HSPC are activated to support liver regeneration. Access to liver tissue from 4 patients who underwent liver transplantation for hepatitis B virus (HBV)- associated acute liver failure (ALF) provided us with the opportunity to investigate the molecular mechanisms of liver regeneration in humans by means of gene expression profiling and immunohistochemistry (IHC). Gene expression profiling of 17 liver specimens from the 4 ALF cases and individual liver specimens from 10 liver donors documented a distinct gene signature for ALF. However, unsupervised multidimensional scaling and hierarchical clustering identified two-well defined clusters that segregated according to the histopathological severity, i.e. massive hepatic necrosis (MHN; 2 patients) and submassive hepatic necrosis (SHN; 2 patients). We found that ALF is characterized by a strong hepatic stem/progenitor cell (HSPC) gene signature, as also confirmed by IHC, along with ductular reaction, both of which are more prominent in MHN. Interestingly, no evidence of further lineage differentiation was seen in MHN, whereas in SHN we detected cells with hepatocyte-like morphology. Strikingly, ALF was associated with a strong tumorigenesis gene signature. MHN had the greatest upregulation of cancer stem cell genes (EpCAM, CK19 and CK7), whereas the most upregulated genes in SHN were related to cellular growth and proliferation (AKR1B10, NQO1, RRM2, SFN, TOP2A, CCNB1, CDC20, ANLN and KI67). The extent of liver necrosis correlated with an overriding fibrogenesis gene signature, reflecting the wound healing process. Conclusion: Our data provide evidence of marked HSPC cell activation and fibrogenesis in HBV-associated ALF, which positively correlate with the extent of liver necrosis. Moreover, we detected a strong tumorigenesis gene signature in ALF, which underlines the relationship between liver regeneration and liver cancer. Liver samples were obtained from explanted liver of four patients with HBV-associated acute liver failure (4-5 samples per liver) and 10 individual normal liver donors and gene expression profiling was used to establish a molecular definition of this disease. This dataset is part of the TransQST collection.
2012-12-01 | E-GEOD-38941 | biostudies-arrayexpress
Project description:Background & Aims: Hepatitis B virus (HBV) infection is a major health burden worldwide and currently there is no cure. The persistence of HBV covalently closed circular DNA (cccDNA) is the major obstacle for antiviral treatment. HBV core protein (HBc) has merged as a promising antiviral target, as it plays important roles in critical steps of viral life cycle. However, whether HBc could regulate HBV cccDNA transcription remains to be illustrated. Methods: Synthesized HBV cccDNA and HBVcircle with or without HBc deficiency were transfected into hepatocytes. A recently reported Adeno-Associated Virus (AAV) mediated HBV cccDNA mouse model was employed. Two capsid assembly modulators (CAMs) were used. HBV replication markers were evaluated. Chromatin immunoprecipitation (ChIP) or ChIP sequencing assays were conducted with different transcription factors, histones and RNA polymerase 2. Results: In HBV cccDNA and HBVcircle transfection assays, lack of HBc showed no effect on transcription of HBV RNA as well as HBV surface antigen production. Reconstitution of HBc did not change cccDNA derived HBV markers. Similar results were obtained in vivo, from mouse cccDNA model. ChIP data revealed similar transcription regulation of HBc deficient cccDNA chromatin with wide type cccDNA. Furthermore, CAMs treatment could not alter cccDNA transcription. Conclusions: Our results indicate that HBc neither affects histone modifications and transcription factors binding of cccDNA, nor influences cccDNA transcription. Although CAMs could reduce HBc binding to cccDNA, it does not suppress cccDNA transcriptional activity. Thus, therapeutic targeting capsid or HBc is not sufficient to reduce cccDNA transcription.
2022-04-01 | GSE199653 | GEO
Project description:Hepatitis B virus (HBV) core protein (HBc) plays many roles in the HBV life cycle such as regulation of transcription, RNA encapsidation, reverse transcription and viral release. To accomplish these functions, HBc interacts with many host proteins and undergoes different posttranslational modifications (PTMs). One of the most common PTM is ubiquitination that was shown to change function, stability, and intracellular localization of different viral proteins, but the role of HBc ubiquitination in the HBV life cycle remains unknown. Here, we found that HBc protein is posttranslationally modified through K29-linked ubiquitination. We performed a series of co-immunoprecipitation experiments with wild type HBc, lysine to arginine HBc mutants and wild type ubiquitin, single lysine to arginine ubiquitin mutants or single ubiquitin-accepting lysine constructs. We observed that HBc protein could be modified by ubiquitination in transfected as well as infected hepatoma cells. In addition, ubiquitination predominantly occurred on HBc lysine 7 and the preferred ubiquitin chain linkage was through ubiquitin-K29. Mass spectrometry (MS) analyses detected UBR5 as a potential E3 ubiquitin ligase involved in K29-linked ubiquitination. These findings emphasize that ubiquitination of HBc may play an important role in HBV life cycle.
2020-12-01 | PXD021712 | Pride