Role of matrix metalloproteinases, proinflammatory cytokines, and oxidative stress-derived molecules in hepatitis C virus-associated mixed cryoglobulinemia vasculitis neuropathy.

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 stress-derived 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-1beta 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.