Clonal expansion and functional exhaustion of monoclonal marginal zone B cells in mixed cryoglobulinemia: The yin and yang of HCV-driven lymphoproliferation and autoimmunity

Monoclonal marginal zone (MZ) B cells expressing a VH1-69-encoded idiotype accumulate in HCV-associated mixed cryoglobulinemia (MC). These cells recognize the E2 protein of HCV and their massive clonal expansion reflects the propensity of MZ B cells to proliferate robustly upon antigenic stimulation by microorganisms, a property that makes them prone to neoplastic transformation. VH1-69+ B cells of MC patients are phenotypically heterogeneous and resemble either mature MZ B cells (IgM+CD27+CD21high) or the unusual CD21low B cells that accumulate in other immunological disorders such as common variable immunodeficiency (CVID) or HIV infection. The CD21low VH1-69+ B cells of MC patients, like those of CVID and HIV patients, are anergic to BCR and TLR9 stimulation and display deregulation of several anergy-related genes; proliferative anergy is also observed in CD21high MZ-like VH1-69+ B cells, that over-express the antiproliferative transcriptional repressor Stra13. Upon evolution to splenic marginal zone lymphoma, MZ-like VH1-69+ B cells down-regulate Stra13 and partially recover their capacity to proliferate in response to TLR9 ligation. Like yin and yang, robust clonal expansion and early proliferative anergy may be viewed as the opposite forces balancing the responses of human MZ B cells to chronic microbial stimuli. Disruption of this balance facilitates autoimmunity and lymphoproliferation.