Affiliation:
1. Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, Rockefeller University, New York, NY;
2. Department of Medicine, Division of Gastroenterology and Hepatology, Weill Medical College of Cornell University, New York, NY; and
3. University of Bari, Bari, Italy
Abstract
Abstract
Hepatitis C virus (HCV) is associated with the B-cell lymphoproliferative disorders mixed cryoglobulinemia (MC) and non-Hodgkin lymphoma. We have previously reported that HCV+MC+ patients have clonal expansions of hypermutated, rheumatoid factor–bearing marginal zone-like IgM+CD27+ peripheral B cells using the VH1-69 gene. Here we coupled transcriptional profiling with immunophenotypic and functional studies to ascertain these cells' role in MC pathogenesis. Despite their fundamental role in MC disease, these B cells have overall transcriptional features of anergy and apoptosis instead of neoplastic transformation. Highly up-regulated genes include SOX5, CD11C, galectin-1, and FGR, similar to a previously described FCRL4+ memory B-cell subset and to an “exhausted,” anergic CD21low memory B-cell subset in HIV+ patients. Moreover, HCV+MC+ patients' clonal peripheral B cells are enriched with CD21low, CD11c+, FCRL4high, IL-4Rlow memory B cells. In contrast to the functional, rheumatoid factor–secreting CD27+CD21high subset, the CD27+CD21low subpopulation exhibits decreased calcium mobilization and does not efficiently differentiate into rheumatoid factor–secreting plasmablasts, suggesting that a large proportion of HCV+MC+ patients' clonally expanded peripheral B cells is prone to anergy and/or apoptosis. Down-regulation of multiple activation pathways may represent a homeostatic mechanism attenuating otherwise uncontrolled stimulation of circulating HCV-containing immune complexes. This study was registered at www.clinicaltrials.gov as #NCT00435201.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Cited by
167 articles.
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