title: Dysfunctional B-cell activation in cirrhosis resulting from hepatitis C infection associated with disappearance of CD27-positive B-cell population.
abstract: Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma (HCC). Both advanced solid tumors and HCV have previously been associated with memory B-cell dysfunction. In this study, we sought to dissect the effect of viral infection, cirrhosis, and liver cancer on memory B-cell frequency and function in the spectrum of HCV disease. Peripheral blood from healthy donors, HCV-infected patients with F1-F2 liver fibrosis, HCV-infected patients with cirrhosis, patients with HCV-related HCC, and non-HCV-infected cirrhotics were assessed for B-cell phenotype by flow cytometry. Isolated B cells were stimulated with anti-cluster of differentiation (CD)40 antibodies and Toll-like receptor (TLR)9 agonist for assessment of costimulation marker expression, cytokine production, immunoglobulin (Ig) production, and CD4(+) T-cell allostimulatory capacity. CD27(+) memory B cells and, more specifically, CD27(+) IgM(+) B cells were markedly less frequent in cirrhotic patients independent of HCV infection. Circulating B cells in cirrhotics were hyporesponsive to CD40/TLR9 activation, as characterized by CD70 up-regulation, tumor necrosis factor beta secretion, IgG production, and T-cell allostimulation. Last, blockade of TLR4 and TLR9 signaling abrogated the activation of healthy donor B cells by cirrhotic plasma, suggesting a role for bacterial translocation in driving B-cell changes in cirrhosis.
  
  
  CONCLUSIONS
  Profound abnormalities in B-cell phenotype and function occur in cirrhosis independent of HCV infection. These B-cell defects may explain, in part, the vaccine hyporesponsiveness and susceptibility to bacterial infection in this population.
authors.affiliation: Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Doi
authors.forename: Tara K
authors.initials: TK
authors.lastname: Iyer
authors.forename: Erica
authors.initials: E
authors.lastname: Carpenter
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Kyong-Mi
authors.initials: KM
authors.lastname: Chang
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.forename: David E
authors.initials: DE
authors.lastname: Kaplan
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D053282:CD27 Ligand / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006526:Hepatitis C / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism*
chemical_list: D053282:CD27 Ligand; D019013:CD40 Antigens; D016207:Cytokines; D007074:Immunoglobulin G; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7