Objective. Mixed cryoglobulinemia (MC) is a systemic vasculitis, usually associated with hepatitis C virus (HCV) infection. The molecular mechanisms responsible for HCV-associated MC (HCV-MC) vasculitis are largely unknown. This study was undertaken to assess the expression profile of selected genes involved in inflammatory vascular damage in patients with HCV-MC vasculitis, patients with polyarteritis nodosa (PAN), and patients with noninflammatory idiopathic neuropathy.
Methods. The quantitative expression levels of 42 selected genes involved in inflammatory vascular damage were assessed in nerve lesions of patients with HCV-MC vasculitis, PAN (rheumatic disease controls), and noninflammatory idiopathic neuropathy (noninflammatory neuropathy controls), using real-time reverse transcriptase-polymerase chain reaction. Genes were considered to be differentially expressed when there was a >2-fold difference in mean expression levels between groups and the P value was less than 0.05.
Results. Expression levels of 8 genes were significantly increased in HCV-MC patients versus control patients with noninflammatory idiopathic neuropathy, with the highest increase for metallothionein 1 H (MT1H), a hypoxic and oxidative stress protein. Compared with PAN patients, HCV-MC patients had higher expression levels of genes encoding oxidative stressderived molecules (MT1H, endothelial cell nitric oxide synthase 3, Hsp70, and Hsp90) and tissue plasminogen activator and lower expression levels of matrix metalloproteinase 7 (MMP-7). HCV-MC neuropathies were classified according to their morphologic pattern and the presence or absence of necrotizing arteritis. MMP-1, MMP-7, MMP-9, and interleukin-1 were up-regulated in patients with necrotizing arteritis.
Conclusion. This comprehensive molecular study of HCV-MC vasculitis provides strong evidence that MMPs, proinflammatory cytokines, and oxidative stress-derived molecules have a role in the pathogenesis of HCV-MC vasculitis neuropathy.
Mixed cryoglobulinemia (MC) is a systemic vasculitis that affects mainly the small and, less frequently, medium-sized vessels (1). MC is characterized by the proliferation of B cell clones, which produce pathogenetic IgM with rheumatoid factor activity. Clinical manifestations associated with MC range from the so-called "MC syndrome" (purpura, arthralgia, and asthenia) to more serious lesions with neurologic and renal involvement. Shortly after the discovery of hepatitis C virus (HCV) in 1989, evidence that Ͼ80% of cryoglobulinemia vasculitis cases were associated with HCV Dr. Saadoun's work was supported by the Agence Nationale de Recherche sur le Sida et les He ´patites.