Dysfunctional B-cell activation in cirrhosis resulting from hepatitis C infection associated with disappearance of CD27-Positive B-cell population

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. Conclusion: 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. (HEPATOLOGY 2012)