Submitted July 17, 2007
Accepted October 12, 2007
Clonal expansion of IgM+CD27+ B cells in HCV-associated mixed cryoglobulinemia
Edgar D. Charles, Rashidah M. Green, Svetlana Marukian, Andrew H. Talal, Gerond V. Lake-Bakaar, Ira M. Jacobson, Charles M Rice, and Lynn B. Dustin*
Center for the Study of Hepatitis C, The Rockefeller University, New York, NY, United States
Dept. of Medicine, Div. of Gastroenterology and Hepatology, Weill Medical College of Cornell University, New York, NY, United States
* Corresponding author; email: dustinl{at}rockefeller.edu.
Hepatitis C virus (HCV) is associated with B cell lymphoproliferative disorders such as mixed cryoglobulinemia (MC) and B cell non-Hodgkin lymphoma (B-NHL). The pathogenesis of these disorders remains unclear, and it has been proposed that HCV drives the proliferation of B cells. Here we demonstrate that certain HCV+MC+ subjects have clonal expansions of IgM+
+IgDlow/negCD21lowCD27+ B cells. Using RT-PCR to amplify Ig from these singly-sorted cells, we show that these predominantly rheumatoid 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 notion that specific antigenic stimulation leads to B cell proliferation in HCV MC and that chronic B cell stimulation may set the stage for malignant transformation and the development of B-NHL. The finding that these hypermutated, marginal zone-like IgM+CD27+ B cells are clonally expanded in certain subjects with MC offers insight into mechanisms of HCV-associated MC and B cell malignancy. This study was registered at www.clinicaltrials.gov as #NCT00219999.
