title: Clonal B cells in patients with hepatitis C virus-associated mixed cryoglobulinemia contain an expanded anergic CD21low B-cell subset.
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 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.
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Edgar D
authors.initials: ED
authors.lastname: Charles
authors.forename: Claudia
authors.initials: C
authors.lastname: Brunetti
authors.forename: Svetlana
authors.initials: S
authors.lastname: Marukian
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Ritola
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Talal
authors.forename: Kristen
authors.initials: K
authors.lastname: Marks
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Dustin
mesh_terms: D000328:Adult; D017209:Apoptosis; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D039521:CD11c Antigen / Q000378:metabolism; D017635:Clonal Anergy; D003449:Cryoglobulinemia / Q000209:etiology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D007156:Immunologic Memory; D053662:Interleukin-4 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D017464:Receptors, Complement 3d / Q000378:metabolism; D011961:Receptors, Fc / Q000378:metabolism; D012217:Rheumatoid Factor / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
chemical_list: D039521:CD11c Antigen; C423544:FCRL4 protein, human; C504000:IL4R protein, human; D007075:Immunoglobulin M; D053662:Interleukin-4 Receptor alpha Subunit; D017464:Receptors, Complement 3d; D011961:Receptors, Fc; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D012217:Rheumatoid Factor