Role of B-cell-attracting chemokine-1 in HCV-related cryoglobulinemic vasculitis

Abstract

B-cell-attracting chemokine-1 (BCA-1, CXCL13), also referred to as B-lymphocyte chemoattractant, is a major regulator of B-cell trafficking. Hepatitis C virus (HCV) infection is frequently associated with B-cell dysfunction and lymphoproliferative disorders. Mixed cryoglobulinemia (MC) is a chronic immune complex-mediated disease strictly related to HCV infection and is mainly characterized by oligoclonal/monoclonal B-cell expansions potentially capable of progressing to B-cell non-Hodgkin's lymphoma. In chronically HCV-infected patients with MC, circulating levels of BCA-1 were found to be higher than in healthy individuals. Interestingly, the highest BCA-1 levels strongly correlated with the active phase of cryoglobulinemic vasculitis. No direct relation was shown between BCA-1 levels and HCV circulating load, severity of liver disease, autoantibody production, cryoprotein levels, or complement consumption. Changes observed after B-cell depletion therapy suggest that B cells have little or no influence on BCA-1 transcription. Immunofluorescence demonstrated specific deposits of BCA-1 protein in the skin samples of patients with active cryoglobulinemic vasculitis, but not in those of MC patients with non-active vasculitis nor in those without MC. BCA-1 mRNA expression was confirmed in the skin of patients with deposits of BCA-1 immunoreactants. The elevated levels of circulating BCA-1 protein could be a cause of the impaired or altered trafficking of B cells in chronic HCV infection. BCA-1 is expressed at the site of cutaneous damage, where it may play a major role in the pathogenesis of skin manifestations in MC through a mechanism involving the chemoattraction of self-antigen-driven autoimmune B cells.