Etiopathogenesis of mixed cryoglobulinemia (MC) syndrome. The figure summarizes the etiopathogenetic cascade of MC and other HCV-related disorders. This is probably a multifactorial and multistep process: the remote events include some infectious agents, mainly HCV, predisposing host factors, and possible unknown environmental/toxic triggers. Viral antigens (for example HCV core, envelop E2, NS3, NS4, NS5A proteins) may exert a chronic stimulus on the host immune- system through specific lymphocyte receptors, such as CD81 that may interact with the viral E2. Predisposing host factors may include particular HLA alleles, metabolic and hormonal conditions. The main consequence is a 'benign' B-cell proliferation with a variety of autoantibody production, among which rheumatoid factor (RF), and cryo- and non-cryoprecipitable immune-complexes (IC). These serological alterations may be correlated with different organ- and non-organ-specific autoimmune disorders, including the MC syndrome (or cryoglobulinemic vasculitis). Moreover, the activation of Bcl2 proto-oncogene, responsible for prolonged B-cell survival, may be a predisposing condition to other genetic aberrations, which may lead to frank B-cell lymphomas and other malignancies. The appearance of malignant neoplasias can be observed in a small but significant percentage of patients, usually as late complication. Both immunological and neoplastic disorders show a clinico-serological and pathological overlap. Often, autoimmune organ-specific manifestations may evolve to systemic conditions, and less frequently to malignancies. Conversely, it is not rare that patients with malignancies may develop one or more autoimmune manifestations. In this scenario, MC syndrome represents a crossing road between autoimmune and neoplastic disorders. (modified from [11, 12]: Ferri C et al, HCV-related autoimmune and neoplastic disorders: the HCV syndrome. Dig Liver Dis 2007, 39: S13–21; Ferri C et al, B-cells and mixed cryoglobulinemia. Autoimm Rev 2007, 7: 114–20.).