Enhanced TH1 cytokine production in hepatitis C virus-infected patients with mixed cryoglobulinemia: understanding the pathological issues

Abstract

Mixed cryoglobulinemia (MC) is a distinct syndrome clinically characterized by purpura, weakness, arthralgia, and involvement of one or more organ systems, including membranoproliferative glomerulonephritis, peripheral neuropathy, skin ulcers, liver damage and diffuse vasculitis. Cryoprecipitable immunocomplexes, namely mixed (IgG– IgM) cryoglobulins, are the serological hallmark of the disease: IgG is the autoantigen, IgM, with rheumatoid factor (RF) activity, the autoantibody. Mixed cryoglobulinemia is classified in type II and type III according to the presence of polyclonal or oligo-monoclonal IgMs. Because expansion of RF-producing B-cells is the underlying disorder of MC, this condition is considered a ‘benign’ B-cell lymphoproliferative disease (LPD) [1–3]. The mechanism(s) responsible for the lymphoproliferation surrounding MC remain unknown. Due to geographical heterogeneity in prevalence of MC in HCV-infected patients, it is conceivable that unknown genetic and/or environmental factors may influence the development of this syndrome [4]. Several data are consistent with the possibility that chronic stimulation of B-cells by viral epitopes could play an important role [5–7]. Furthermore, it is possible to hypothesize that some pathogenically important B-cell subpopulations may be selected because of persistent antigenic stimulation. In this context, analogies may exist between the mechanisms by which HCV leads to MC or other LPDs, and the pathogenetic mechanisms of Helicobacter pylori lymphomagenesis. The latter is in fact considered a multi-step process evolving from a physiological polyclonal immune response, to an oligoclonal and