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Specificity of an anti-capsid antibody associated with Hepatitis B Virus-related acute liver failure.

ABSTRACT: Previously, the livers of patients suffering from acute liver failure (ALF), a potentially fatal syndrome arising from infection by Hepatitis B Virus (HBV), were found to contain massive amounts of an antibody specific for the core antigen (HBcAg) capsid. We have used cryo-electron microscopy and molecular modeling to define its epitope. HBV capsids are icosahedral shells with 25Å-long dimeric spikes, each a 4-helix bundle, protruding from the contiguous "floor". Of the anti-HBcAg antibodies previously characterized, most bind around the spike tip while one binds to the floor. The ALF-associated antibody binds tangentially to a novel site on the side of the spike. This epitope is conformational. The Fab binds with high affinity to its principal determinants but has lower affinities for quasi-equivalent variants. The highest occupancy site is on one side of a spike, with no detectable binding to the corresponding site on the other side. Binding of one Fab per dimer was also observed by analytical ultracentrifugation. The Fab did not bind to the e-antigen dimer, a non-assembling variant of capsid protein. These findings support the propositions that antibodies with particular specificities may correlate with different clinical expressions of HBV infection and that antibodies directed to particular HBcAg epitopes may be involved in ALF pathogenesis.

SUBMITTER: Wu W

PROVIDER: S-EPMC3525778 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Specificity of an anti-capsid antibody associated with Hepatitis B Virus-related acute liver failure.

Wu Weimin W Chen Zhaochun Z Cheng Naiqian N Watts Norman R NR Stahl Stephen J SJ Farci Patrizia P Purcell Robert H RH Wingfield Paul T PT Steven Alasdair C AC

Journal of structural biology 20121016 1

Previously, the livers of patients suffering from acute liver failure (ALF), a potentially fatal syndrome arising from infection by Hepatitis B Virus (HBV), were found to contain massive amounts of an antibody specific for the core antigen (HBcAg) capsid. We have used cryo-electron microscopy and molecular modeling to define its epitope. HBV capsids are icosahedral shells with 25Å-long dimeric spikes, each a 4-helix bundle, protruding from the contiguous "floor". Of the anti-HBcAg antibodies pre ...[more]

PMID: 23079477

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Project description:BACKGROUND:Infection is common in acute-on-chronic liver failure (ACLF), which may worsen the clinical condition and prognosis. However, the characteristics of infection and its influence on prognosis in hepatitis B virus related ACLF (HBV-ACLF) as defined by the European Association for the Study of the Liver (EASL) have not been clarified. We aimed to investigate the characteristics of infection and its influence on mortality in patients with HBV-ACLF defined by EASL in China. METHODS:We performed a retrospective cohort study in patients with HBV-ACLF defined by EASL in a single center from January 2015 to December 2017. These patients were divided into two groups with and without infection. The incidence, sites of infection, isolated strains, and risk factors associated with mortality were evaluated. RESULTS:A total of 289 patients were included, among them 185 (64.0%) were diagnosed with an infection. The most common type of infection was pneumonia (55.7%), followed by spontaneous bacterial peritonitis (47.6%) and others. The gram-negative bacteria were the most frequent (58.3%). Patients with one, two, and three or more infection sites had a gradually increasing incidence of sepsis (P?<?0.01), septic shock (P?<?0.001), and ACLF-3 (P?<?0.05). Also, patients with infection isolated one, two, and three or more strains showed a growing incidence of sepsis (P?<?0.01) and septic shock (P?<?0.001). Patients with infection showed a significantly higher 28-day mortality than those without (P?<?0.01), especially in patients with ACLF-3. Infection was identified as an independent risk factor for 28-day mortality in all HBV-ACLF patients. Pneumonia and sepsis were identified as independent predictors of 28-day mortality for patients with infection. CONCLUSIONS:Infection is associated with severe clinical course and high mortality in HBV-ACLF defined by EASL. The increased number of infection sites or isolated strains was associated with the occurrence of sepsis and septic shock. Pneumonia and sepsis were independent predictors for mortality in HBV-ACLF patients with infection.

Project description:Purpose: Neutrophils and cytokines play a major role in the pathogenesis of acute-on-chronic liver failure (ACLF). We aimed to determine whether chemokine (CXC) ligand 1 (CXCL1), a key marker of neutrophil recruitment and activation, could predict the severity and prognosis of hepatitis B virus-related ACLF (HBV-ACLF). Methods: Hospitalized patients with HBV-ACLF were enrolled in a prospective study and stratified as survivors (alive at 28 days) and nonsurvivors (deceased at 28 days). Serum CXCL1 levels were measured in healthy controls, patients with chronic HBV, patients with HBV-related compensated cirrhosis, and patients with HBV-ACLF. Univariate and multivariable logistic analyses, Pearson correlation analysis, area under the receiver operating characteristic curve (AUROC), and Z tests were used to evaluate the performance of CXCL1 as a marker in HBV-ACLF. Results: Patients with HBV-ACLF had significantly higher serum levels of CXCL1 and neutrophil count than healthy controls and patients with chronic HBV or HBV-related compensated cirrhosis (P < 0.01, respectively). Among patients with HBV-ACLF, survivors had lower serum CXCL1 levels and neutrophil count than those of nonsurvivors (P < 0.001, P < 0.05, respectively). Serum CXCL1 level was positively correlated with neutrophil count (r = 0.256, P = 0.001), ACLF grade (r = 0.295, P < 0.001) and organ failure, including coagulation (r = 0.21, P = 0.005) and brain failure (r = 0.198, P = 0.008). Multivariable logistic analyses showed serum CXCL1 [OR (95% CI) = 1.017 (1.009-1.025), P < 0.001] was an independent risk factor for 28-day mortality in HBV-ACLF. Meanwhile, the AUROC analysis demonstrated that serum CXCL1 [0.741 (0.669-0.804)] might be a reliable prognostic biomarker for patients with HBV-ACLF. Conclusions: Overall, serum CXCL1 can serve as a biomarker indicating the severity of disease and prognosis for patients with HBV-ACLF. CXCL1 might also be a therapeutic target in this disease.

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Specificity of an anti-capsid antibody associated with Hepatitis B Virus-related acute liver failure.

Publications

Specificity of an anti-capsid antibody associated with Hepatitis B Virus-related acute liver failure.

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