title: 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.
authors.affiliation: Research Laboratories, Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Oliviero
authors.forename: S
authors.initials: S
authors.lastname: Mantovani
authors.forename: S
authors.initials: S
authors.lastname: Ludovisi
authors.forename: S
authors.initials: S
authors.lastname: Varchetta
authors.forename: D
authors.initials: D
authors.lastname: Mele
authors.forename: S
authors.initials: S
authors.lastname: Paolucci
authors.forename: F
authors.initials: F
authors.lastname: Baldanti
authors.forename: M U
authors.initials: MU
authors.lastname: Mondelli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000097:blood; D001402:B-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D008099:Liver / Q000473:pathology; D016131:Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D011961:Receptors, Fc / Q000032:analysis; D019562:Viral Load
chemical_list: C423544:FCRL4 protein, human; D012367:RNA, Viral; D011961:Receptors, Fc; D000410:Alanine Transaminase
keywords: B cells; FcRL4; activation; hepatitis C virus