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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 V(H)1-69 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 CD21(low) memory B-cell subset in HIV(+) patients. Moreover, HCV(+)MC(+) patients' clonal peripheral B cells are enriched with CD21(low), CD11c(+), FCRL4(high), IL-4R(low) memory B cells. In contrast to the functional, rheumatoid factor-secreting CD27(+)CD21(high) subset, the CD27(+)CD21(low) 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.

Original publication

DOI

10.1182/blood-2010-10-312942

Type

Journal article

Journal

Blood

Publication Date

05/2011

Volume

117

Pages

5425 - 5437

Addresses

Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.

Keywords

B-Lymphocyte Subsets, Humans, Hepatitis C, Chronic, Cryoglobulinemia, Immunoglobulin M, Antigens, CD11c, Receptors, Complement 3d, Antigens, CD27, Receptors, Fc, Rheumatoid Factor, Gene Expression Profiling, Lymphocyte Activation, Apoptosis, Clonal Anergy, Immunologic Memory, Adult, Middle Aged, Female, Male, Interleukin-4 Receptor alpha Subunit