Skewed B cells in chronic hepatitis C virus infection maintain their ability to respond to virus‐induced activation

Abstract

Chronic hepatitis C virus (HCV) infection is characterized by persistent B-cell activation, with enhanced differentiation and reduced proliferative ability. To assess the possible role of HCV in altering B-cell subset distribution, we examined ex vivo frequencies and B-cell inhibitory receptor expression in 37 chronic HCV-infected patients and 25 healthy donors (HD). In addition, we determined whether short-term exposure to culture-derived HCV (HCVcc) resulted in B-cell subset skewing and/or activation. There was a statistically significant increase in the frequencies of immature transitional, activated memory and tissue-like memory (TLM) B cells in HCV-infected patients compared with HD. We also found that the frequency of memory B cells correlated with serum HCV RNA levels. The proportion of B cells expressing the marker of exhaustion Fc receptor-like 4 (FcRL4) was generally low even though significantly higher in the patients' memory B-cell compartment compared with HD, and a positive correlation was found between the frequencies of the patients' TLM FcRL4+ B cells and serum alanine aminotransferase and histological activity index at liver biopsy. Exposure to cell-free HCVcc in vitro did not result in B-cell skewing but induced significant activation of naïve, TLM and resting memory B cells in HCV-infected patients but not in HD, in whom cell-associated virus was an absolute requirement for activation of memory B cells. These findings provide corroborative evidence in favour of significant B-cell subset skewing in chronic HCV infection and in addition show that expression of exhaustion markers in selected B-cell subsets does not impair virus-induced B-cell activation.

T-bet+ B cells are induced by human viral infections and dominate the HIV gp140 response

“…We also observed involvement of T-bet + B cells in the response to HIV infection, as T-bet was rapidly induced in B cells during the acute phase and T-bet We and others have previously demonstrated an expansion of CD21 -B cell subsets induced by Th1-type human infections, including HIV, malaria, and hepatitis C (30,31,34,35,(60)(61)(62)(63), and expansion of a clonal CD21 -subset has been described during hepatitis B-and hepatitis C-associated mixed cryoglobulinemia (64)(65)(66). Interestingly, maintenance of expanded CD21 -cells in each of these infections appears to be dependent upon pathogen load (34,35,60,(67)(68)(69).…”

HIV-associated memory B cell perturbations

“…While TLM are consistently found to be accumulated in HIV viremic patients [9, 16, 19-21, 72], whether this B cell subset is increased in HIV elite controllers is not clear [19, 21]. Aside from HIV infection, similar B cell subsets are expanded in many diseases with chronic inflammation, such as chronic HCV infection [74-76], chronic infection of plasmodium falciparum[77, 78], rheumatoid arthritis [79], and systemic lupus erythematosus [80]. …”

“…Although expressing inhibitory receptors, the antigen-specific responses are still maintained in this exhausted cell subset [16, 73, 76]. Moreover, reduced levels of the antigens are associated with reduced frequencies of TLM [9, 21, 76, 78]. Therefore, it is possible that the expansion of TLM is driven by the chronic antigen stimulation.…”

Atypical memory B cells in human chronic infectious diseases: An interim report

“…Recent studies have suggested that B cell populations similar to aMBCs are expanded in chronic HCV infections. Oliviero et al (48) observed an increase in aMBCs (characterized as CD10 − , CD19 + CD21 Lo , CD27 − ) in chronic HCV-infected individuals as compared to healthy controls and a correlation between the proportion of aMBCs that expressed FcRL4 and the degree of liver inflammation. In both cirrhotic and non-cirrhotic HCV infections, Doi et al (49) observed an expansion of aMBCs (CD19 + CD27 − CD21 − ) relative to healthy controls.…”