IMMUNOBIOLOGY Clonal expansion of immunoglobulin MCD27 B cells in HCV-associated mixed cryoglobulinemia

Hepatitis C virus (HCV) is associated with B-cell lymphoproliferative disor-ders such as mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). The pathogenesis of these dis-orders remains unclear, and it has been proposed that HCV drives the pro-liferation of B cells. Here we demon-strate that certain HCVMC subjects have clonal expansions of immuno-globulin M (IgM)IgDlow/CD21low CD27 B cells. Using RT-PCR to amplify Ig from these singly sorted cells, we show that these predominantly rheuma-toid factor-encoding VH1-69/JH4 and V3-20 gene segment-restricted cells have low to moderate levels of somatic hypermutations. Ig sequence analysis suggests that antigen selection drives the generation of mutated clones. These findings lend further support to the no-tion that specific antigenic stimulation leads to B-cell proliferation in HCV MC and that chronic B-cell stimulation may set the stage for malignant transforma-tion and the development of B-NHL. The finding that these hypermutated, mar-ginal zone-like IgMCD27 B cells are clonally expanded in certain subjects with MC offers insight into mechanisms of HCV-associated MC and B-cell malig-nancy. This study was registered at www.clinicaltrials.gov as NCT00219999