Hepatitis C virus drives the unconstrained monoclonal expansion of V H1-69-expressing memory B cells in type II cryoglobulinemia: A model of infection-driven lymphomagenesis

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 _H1-69 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_H1-69⁺ cells in patients with type II mixed cryoglobulinemia. By immunophenotyping and cell size analysis, we could define three discrete stages of differentiation of V_H1-69⁺ B cells: naive (small, IgM^highIgD^highCD38 ⁺CD27^-CD21^highCD95^-CD5^-), "early memory" (medium-sized, IgM^highIgD ^lowCD38^-CD27⁺CD21^lowCD95 ⁺CD5⁺), and "late memory" (large-sized, IgM ^lowIgD^low-neg CD38^-CD27^lowCD21 ^low-negCD5^-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_H1-69⁺ 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_H1-69⁺ 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_H1-69⁺ natural Ab escapes control mechanisms and subverts B cell homeostasis. Genetic alterations may provide a further growth advantage leading to an overt lymphoproliferative disorder.