Altered RIG‐I/DDX58‐mediated innate immunity in dermatomyositis

Abstract

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, DDX58) and the novel antiviral factor DDX60, which promotes RIG-I-mediated signalling, were significantly up-regulated, followed by IFIH1 (MDA5) and TLR3. 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 (IFNβ; p < 0.05) and up-regulation of class I MHC, RIG-I and TLR3 (p < 0.05) by IFNβ-dependent and TLR3-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.

Treatment of Juvenile Dermatomyositis: An Update

“…+ T lymphocytes and plasmacytoid dendritic cells, into muscle tissue [15][16][17]. Type 1 interferons produced by dendritic cells, in turn, stimulate the production of pro-inflammatory cytokines and enhance the expression or HLA class I and class II molecules [17].…”

The Spectrum of Inflammatory Myopathies: Dermatomyositis, Polymyositis, Necrotizing Myositis, and Inclusion-Body Myositis

“…The infl ammatory infi ltrates consist of B cells, CD4+ cells, and plasmacytoid-dendritic cells [ 2 ]. Innate immunity also plays a role based on increased expression of type I interferon-inducible proteins in the perifascicular regions [ 26 ]; this effect may have a role in enhancing local infl ammation after the primary complement-mediated ischemic damage has taken place [ 27 ] (Fig. 6.5 ).…”

“…There is also B-cell activation, most prominent in IBM [ 43 ], as supported by B-cell and plasma cell infi ltrates and the presence of autoantibodies against nuclear antigens, initially reported 15 years ago [ 44 ], and recently identifi ed as being against 5′-nucleotidase 1A [ 21 , 22 ]. The role of innate immunity in infl ammation and perifascicular atrophy appears secondary to hypoxic and ischemic damage sensed by the retinoic acid-inducible gene-1 (Rig-1) signaling, which in turn leads to auto-amplifi cation of the local infl ammation via β-interferon [ 27 ] What triggers disease remains unknown. Genetic risk factors regulating immune responses against undefi ned environmental agents have been proposed [ 8 ].…”

Vascular changes and perifascicular muscle fiber damage in dermatomyositis: another question of the chicken or the egg that is on our mind

“…Several IFN type 1 signature genes are overexpressed specifically in the perifascicular areas of DM tissues, as is the associated factor retinoic acid-inducible gene-1 (RIG-1). Interestingly, RIG-1 was found absent from the affected muscle fibers of polymyositis and sporadic inclusion body myositis tissues (10). In a subgroup of DM patients, usually presenting an amyopathic phenotype with interstitial lung disease, autoantibodies can be detected that recognize IFN-induced with helicase C domain protein 1 (IFIH1), one of the RIG-I-like receptors (11,12).…”

“…Viperin, another IFN-induced anti-viral protein and a modulator of mitochondrial and endoplasmic reticulum (ER) stress, is upregulated in DM (10). Viperin thus represents a link between inflammatory and ER stress response pathways, the latter being significantly elevated in muscle tissue of patients with polymyositis and DM alike (15).…”