Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis.

[inclusion body myositis]

We investigated the molecular mechanisms involved in the pathogenesis of three inflammatory myopathies , dermatomyositis (DM ), polymyositis (PM ) and inclusion body myositis (IBM ). We performed microarray experiments (†) using microdissected pathological muscle fibres from 15 patients with these disorders and five controls . Differentially expressed candidate genes were validated by immunohistochemistry on muscle biopsies , and the altered pathways were analysed in human myotube cultures . Up-regulation of genes involved in viral and nucleic acid recognition were found in the three myopathies but not in controls . In DM , retinoic acid-inducible gene 1 (RIG-I , DDX 58 ) and the novel antiviral factor DDX 60 , which promotes RIG-I -mediated signalling , were significantly up-regulated , followed by IFIH 1 (MDA 5 ) and TLR 3 . Immunohistochemistry confirmed over-expression of RIG-I in pathological muscle fibres in 5 /5 DM , 0 /5 PM and 0 /5 IBM patients , and in 0 /5 controls . Stimulation of human myotubes with a ligand of RIG-I produced a significant secretion of interferon-β (IFN β ; p < 0 .05 ) and up-regulation of class I MHC , RIG-I and TLR 3 (p < 0 .05 ) by IFN β-dependent and TLR 3 -independent mechanisms . RIG-I -mediated innate immunity , triggered by a viral or damage signal , plays a significant role in the pathogenesis of DM , but not in that of PM or IBM .