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

Abstract

Background Chronic hepatitis C virus infection is a leading cause of cirrhosis and hepatocellular carcinoma. Both advanced solid tumors and hepatitis C have previously been associated with memory B-cell dysfunction. In this study we sought to dissect the impact of viral infection, cirrhosis and liver cancer on memory B-cell frequency and function in the spectrum of HCV disease. Methods Peripheral blood from healthy donors, HCV-infected patients with F1–F2 liver fibrosis, HCV-infected patients with cirrhosis, patients with HCV-related hepatocellular carcinoma and non-HCV-infected cirrhotics were assessed for B-cell phenotype by flow cytometry. Isolated B-cells were stimulated with anti-CD40 antibodies and TLR9 agonist for assessment of costimulation marker expression, cytokine production, immunoglobulin production and CD4+ T-cell allostimulatory capacity. Results 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 upregulation, TNFβ secretion, IgG production and T-cell allostimulation. Lastly, blockade of TLR4 and TLR9 signaling abrogated the activation of normal 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 hepatitis C viral infection. These B-cell defects may explain in part the vaccine hyporesponsiveness and susceptibility to bacterial infection in this population.

Peripheral CD27−CD21− B-cells represent an exhausted lymphocyte population in hepatitis C cirrhosis

“…Among these explanations, activation-induced apoptosis has been contradicted by more recent data suggesting that B-cells in HCV-infected individuals are relatively resistant to apoptosis [11,12]. Rather than being expanded, we previously demonstrated that the circulating memory B-cell population disappears in cirrhotic but not non-cirrhotic HCV-infected patients [13]. The reduction in memory B-cells strongly correlated with multiple parameters of liver dysfunction and portal hypertension, also occurred in individuals with cirrhosis from other causes, and associated with a reduction in B-cell antigen-presenting cell function.…”

“…In our original cohort described in Doi et al [13], we described a collapse of the peripheral CD27 + B-cell subset associated with cirrhosis. In our expanded cohort (Fig.…”

Immunotherapy in the Treatment and Prevention of Infection in Acute-on-chronic Liver Failure

“…Depletion of B-cells, predominantly CD27 + -memory B-cells and hyporesponsiveness to TLR-activation has been observed in cirrhotic patients [38]. Also lymphopenia is commonly observed in cirrhosis and affects both T-helper and cytotoxic T cells, mainly affecting naive T cells [39,40].…”

MicroRNAs in Human Microbial Infections and Disease Outcomes

“…Moreover, no study has made an exhaustive analysis of miRNA expression patterns from peripheral blood cells. As (i) circulating peripheral blood cells including monocytes and lymphocytes have been previously involved in liver fibrogenesis [133][134][135], and (ii) treatment response has been significantly correlated with the proportion and activation state of regulatory T cells [136,137] and T helper cells [138][139][140], there is a need for a more exhaustive analysis of the miRNAs expressed in these cells in vivo and a further characterization of the molecular pathways involved.…”