Type I interferon–inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis

Abstract

Objective. To apply gene expression profiling to the study of peripheral blood mononuclear cells from patients with inflammatory myopathies, in order to provide insight into disease pathogenesis and identify potential biomarkers associated with disease activity.Methods. We used Affymetrix whole-genome microarrays to measure the expression of ϳ38,500 genes in 65 blood and 15 muscle samples from 44 patients with dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), myasthenia gravis, or genetically determined myopathies and from 12 healthy volunteers.In 9 patients, 2 samples were obtained at different time points, when disease was either active or improving, and these paired blood samples were also compared. Bioinformatics techniques were used to identify genes with significant differential expression among diagnostic categories and in relation to disease activity. We corroborated the microarray data with quantitative real-time reverse transcriptase-polymerase chain reaction.Results. Most patients with active DM or PM, but not patients with IBM, had significant and high upregulation of the type I interferon-␣/␤ (IFN␣/␤)-inducible genes in blood. Furthermore, the upregulation of these genes correlated with disease activity in DM and PM, with down-regulation occurring when disease was controlled with treatment.Conclusion. DM and PM are diseases characterized by the systemic overexpression of IFN␣/␤-inducible genes. The magnitude of the overexpression of these genes is higher in DM and correlates with disease activity in both disorders. Although PM and IBM have been modeled as having similar immunologic processes occurring within muscle, there are substantial differences in the expression of IFN␣/␤-inducible genes in blood in these diseases.Dermatomyositis (DM) is an autoimmune inflammatory myopathy characterized clinically by subacute or chronic progressive proximal muscle weakness and characteristic skin changes. Although DM has been modeled as a disease attributable to an antibodydirected attack against endothelial antigens and resulting ischemia of muscle (1), no well-characterized pathogenic antibodies or endothelial antigens have been identified (2).

The role of interleukin-17 in immune-mediated inflammatory myopathies and possible therapeutic implications

“…Microarray gene expression profiling has detected upregulation of genes for adhesion molecules, cytokines, MHC class I molecules, chemokines and immunoglobulins in the muscles of patients with inflammatory myopathies [4,[53][54][55][56].In particular, the interferons (IFNs)and IFN-inducible genes have been strongly implicated in the pathogenesis of myositis. The enhanced type I IFN gene signature has been associated with disease activity in both PM and DM [57].Additionally,immunostaining for type I IFN has been detected in DM in muscle fibres in areas showingperifascular atrophy, as well as in plasmacytoid dendritic cells and in the capillary endothelial cells [27,58]. In contrast,overexpression of the type IIIFN (IFN-ƴ)…”

Diversity of human skeletal muscle in health and disease: Contribution of proteomics

“…Recent microarray studies have pointed toward a mechanism of tissue injury associated with the overexpression of type 1 interferoninducible gene [123,124]. Interferon-stimulated gene 15 (ISG15) conjugated proteins in DM muscle with muscle perifascicular atrophy, were investigated by Salajeheh et al [123].…”

Relationship between disease activity and type 1 interferon- and other cytokine-inducible gene expression in blood in dermatomyositis and polymyositis

“…These studies have shown marked overexpression of type 1 IFN-inducible genes in DM but not PM or IBM muscle. 22 Marked overexpression of type 1 IFN-inducible genes has also been observed in the blood of patients with DM or PM, 23 and in patients with systemic lupus erythematosus (SLE). 24,25 A previous cross-sectional and paired-visit study of 28 patients with DM, PM and IBM showed that type 1 IFN-inducible genes were the highest differentially expressed genes in DM and PM blood samples compared with normal controls.…”