Hepatitis C Virus Infection, Mixed Cryoglobulinemia and BLyS Upregulation: Targeting the Infectious Trigger, the Autoimmune Response, or Both?

Mixed cryoglobulinemia syndrome (MCsn) is a systemic vasculitis prevalently mediated by immune complexes, i.e., mixed cryoglobulins, and characterized by non-neoplastic B-cell lymphoproliferation favouring the progression into frank B-cell non-Hodgkin lymphoma (NHL) in 5-10% of patients. The hepatitis C virus (HCV) infection is the etiologic agent in the large majority of MCsn cases and chronic antigenic stimulation by HCV is considered a key mechanism sustaining the proliferation of the RF-secreting B-cell clones. Besides chronic antigenic stimulation, cytokines and growth factors may also play a key role in sustaining B-cell overactivation. B-lymphocyte stimulator (BlyS) was recently described as a critical survival factor for B cells, promoting their activation and maturation. Abnormal production of BLyS alters immune tolerance by allowing the survival of autoreactive B cells, thus triggering autoimmune disorders. BLyS inhibits B-cell apoptosis, and B-cell apoptosis is implicated in the pathogenesis of MCsn, as well as of other autoimmune diseases. Both antiviral therapy and B- cell depletive therapy in MCsn may influence BlyS expression. Antiviral therapy, monotherapy against biologic targets downstream viral infection, or the combination of the two, should be optimized in the single patient and stage of the disease, based on disease pathobiology, efficacy and safety issues.