Aberrant activation of the type I interferon system may contribute to the pathogenesis of anti‐melanoma differentiation‐associated gene 5 dermatomyositis

Summary Background Anti‐melanoma differentiation‐associated gene 5 ( MDA 5) dermatomyositis ( DM ) is a distinctive subtype of DM that carries a significant risk of interstitial lung disease ( ILD ). The mechanisms remain elusive. Objectives To explore the role of the type I interferon ( IFN ) system in the pathogenesis of anti‐ MDA 5 DM . Methods Twenty patients with anti‐ MDA 5 DM were studied and compared with patients with anti‐aminoacyl‐ tRNA synthetase ( ARS ) DM ( n = 10) and autoantibody‐negative patients with DM ( n = 20). The levels of inflammatory cytokines, B‐cell‐activating factor ( BAFF ) and Krebs von den Lungen ( KL )‐6 in blood were tested by enzyme‐linked immunosorbent assay and multiplex assays. Expressions of transcripts for IFN ‐associated sensors and type I IFN ‐inducible genes in peripheral blood mononuclear cells ( PBMC s) were detected by real‐time polymerase chain reaction. Expressions of the signal transducer and activator of transcription ( STAT )1, interferon‐stimulated gene ( ISG )15 and MxA proteins in skin lesions were analysed by immunohistochemistry. Results Plasma IFN ‐α levels were significantly increased in patients with anti‐ MDA 5 DM . PBMC s from patients with anti‐ MDA 5 DM showed significant upregulation of the TLR 3 , TLR 7 , IFIH 1 and DDX 58 genes, as well as serial IFN ‐inducible genes. Skin biopsies from patients with anti‐ MDA 5 DM were characterized by strong expression of the STAT 1, ISG 15 and MxA proteins. In the patients with anti‐ MDA 5 DM and ILD with high IFN ‐α production, there was a positive quantitative correlation between IFN ‐α and BAFF ( r s = 0·63, P = 0·044). In addition, the higher levels of BAFF paralleled the higher concentrations of KL ‐6 ( r s = 0·86, P = 0·0012). Conclusions Our data confirm the aberrant activation of the type I IFN system in anti‐ MDA 5 DM . Overproduction of IFN ‐α linked with BAFF may be implicated in the development of ILD .