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 V(H)1-69-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. V(H)1-69(+) B cells of MC patients are phenotypically heterogeneous and resemble either mature MZ B cells (IgM(+)CD27(+)CD21(high)) or the unusual CD21(low) B cells that accumulate in other immunological disorders such as common variable immunodeficiency (CVID) or HIV infection. The CD21(low) V(H)1-69(+) 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 CD21(high) MZ-like V(H)1-69(+) B cells, that over-express the antiproliferative transcriptional repressor Stra13. Upon evolution to splenic marginal zone lymphoma, MZ-like V(H)1-69(+) 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.

Indications for biotherapy in systemic vasculitides.

Biotherapy now holds a specific place in the therapeutic armamentarium for systemic vasculitides. Such therapy includes cytokines, such as (pegylated) alpha-interferon for hepatitis B virus-related polyarteritis nodosa and hepatitis C virus-related cryoglobulinemic vasculitis, and polyvalent immunoglobulin (IVIg), with well-defined indications and pending positive results. More specifically targeted monoclonal antibodies include antitumor necrosis factor-alpha or anti-CD20 for antineutrophil cytoplasmic antibody-associated vasculitides or anti-interleukin-5 and anti-IgE for Churg-Strauss syndrome. However, the exact indications of these latter new agents, as well as their optimal dosage and duration, are not defined. Therefore, they are prescribed mainly for patients with disease refractory to conventional therapy, in whom results are promising. Results of international ongoing trials will determine whether the agents may also have a place as first-line treatment.