title: Hepatitis C virus drives the unconstrained monoclonal expansion of VH1-69-expressing memory B cells in type II cryoglobulinemia: a model of infection-driven lymphomagenesis.
abstract: Chronic hepatitis C virus infection causes B cell lymphoproliferative disorders that include type II mixed cryoglobulinemia and lymphoma. This virus drives the monoclonal expansion and, occasionally, the malignant transformation of B cells producing a polyreactive natural Ab commonly encoded by the V(H)1-69 variable gene. Owing to their property of producing natural Ab, these cells are reminiscent of murine B-1 and marginal zone B cells. We used anti-Id Abs to track the stages of differentiation and clonal expansion of V(H)1-69(+) cells in patients with type II mixed cryoglobulinemia. By immunophenotyping and cell size analysis, we could define three discrete stages of differentiation of V(H)1-69(+) B cells: naive (small, IgM(high)IgD(high)CD38(+)CD27(-)CD21(high)CD95(-)CD5(-)), "early memory" (medium-sized, IgM(high)IgD(low)CD38(-)CD27(+)CD21(low)CD95(+)CD5(+)), and "late memory" (large-sized, IgM(low)IgD(low-neg)CD38(-)CD27(low)CD21(low-neg)CD5(-)CD95(-)). The B cells expanded in cryoglobulinemia patients have a "memory" phenotype; this fact, together with the evidence for intraclonal variation, suggests that antigenic stimulation by hepatitis C virus causes the unconstrained expansion of activated V(H)1-69(+) B cells. In some cases, these cells replace the entire pool of circulating B cells, although the absolute B cell number remains within normal limits. Absolute monoclonal V(H)1-69(+) B lymphocytosis was seen in three patients with cryoglobulinemia and splenic lymphoma; in two of these patients, expanded cells carried trisomy 3q. The data presented here indicate that the hepatitis C virus-driven clonal expansion of memory B cells producing a V(H)1-69(+) natural Ab escapes control mechanisms and subverts B cell homeostasis. Genetic alterations may provide a further growth advantage leading to an overt lymphoproliferative disorder.
authors.affiliation: Department of Clinical Medicine, Division of Clinical Immunology, University of Rome La Sapienza, and Istituto Dermopatico dell'Immacolata, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Carbonari
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Caprini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Tedesco
authors.forename: Francesca
authors.initials: F
authors.lastname: Mazzetta
authors.forename: Valeria
authors.initials: V
authors.lastname: Tocco
authors.forename: Milvia
authors.initials: M
authors.lastname: Casato
authors.forename: Giandomenico
authors.initials: G
authors.lastname: Russo
authors.forename: Massimo
authors.initials: M
authors.lastname: Fiorilli
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D000911:Antibodies, Monoclonal / Q000097:blood; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002472:Cell Transformation, Viral / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D003449:Cryoglobulinemia / Q000145:classification / Q000276:immunology* / Q000821:virology; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis* / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell