OP0147 Aberrant activation of type i interferon system in anti-mda5 dermatomyositis patients

Abstract

BackgroundAnti-melanoma differentiation-associated gene 5 (MDA5) DM patients have an increased risk of interstitial lung disease (ILD), with a potentially fatal course.1 Viral infection has been speculated to be the putative trigger for anti-MDA5 DM.2 3 The molecular pathogenesis remains largely unknown.ObjectivesIn this study, we aimed to explore the role of type I interferon (IFN) system in the pathogenesis of anti-MDA5 DM.MethodsWe studied 20 anti-MDA5 DM patients and compared them with anti- aminoacyl-tRNA synthetase (ARS) DM patients (n=10) and seronegative DM patients (n=30). The levels of IL-1b, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, TNF-a, IFN-a, IFN-b, IFN-g, B cell activating factor (BAFF), Krebs von den Lungen-6 (KL-6) in blood were tested by enzyme-linked immunosorbent assay and multiplex assay. Expressions of mRNA for sensor molecules (TLR3, TLR4, TLR7, TLR9, MDA5, RIG-1) and type I IFN inducible genes (IRF7, STAT1, MxA, ISG15) in peripheral blood mononuclear cell (PBMC) were detected by real-time polymerase chain reaction analysis. Expressions of STAT1, MxA, ISG15 proteins in skin lesions from anti-MDA5 DM were analysed by immunohistochemistry technique.ResultsAnti-MDA5 DM patients had higher levels of plasma type I IFN (IFN-a, IFN-b), IL-6, IL-10 and TNF-a than seronegative-DM patients. In comparison to anti-ARS DM patients, IFN-a alone displayed heightened level in anti-MDA5 DM patients. Among these 3 subsets of patients, PBMC from anti-MDA5 DM patients have the significant upregulation of TLR3, TLR7, MDA5, RIG-1 sensors as well as IRF7, STAT1, MxA, ISG15 genes. And skin biopsies from anti-MDA5 DM patients were characterised by strong expression of STAT1, MxA, ISG15 proteins. Furthermore, overexpression of plasma BAFF was observed in anti-MDA5 DM patients. BAFF level was showed to be positively correlated with IFN-a level. Additionally, BAFF level, synergizing with IFN-a, was of great relevance to KL-6 in anti-MDA5 DM patients with higher plasma IFNa concentration.ConclusionsOur data suggest that aberrant activation of the type I IFN system associated with BAFF may be implicated in the pathogenesis of ILD in anti-MDA5 DM. The discovery may drive the development of new therapeutic strategies for the type of DM patients.References[1] Gono T, Kawaguchi Y, Satoh T, et al. Clinical manifestation and prognostic factor in anti-melanoma differentiation-associated gene 5 antibody-associated interstitial lung disease as a complication of dermatomyositis. Rheumatology2010;49(9):1713–9.[2] Sato S, Hoshino K, Satoh T, et al. RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: Association with rapidly progressive interstitial lung disease. Arthritis and rheumatism2009;60(7):2193–2200.[3] Christensen ML, Pachman LM, Schneiderman R, et al. Prevalence of Coxsackie B virus antibodies in patients with juvenile dermatomyositis. Arthritis and Rheumatism1986;29(11):1365–1370.AcknowledgementsThe authors are grateful to Wangdong ...

Mitochondrial morphology and MAVS‐IFN1 signaling pathway in muscles of anti‐MDA5 dermatomyositis

“…Allenbach et al also reported the expression of IFN‐stimulated genes was up‐regulated in muscle but significantly lower than classic DM patients, which further supported our foundings 1 . Conversely, the IFN1 signature levels in peripheral blood mononuclear cells were higher of anti‐MDA5 DM patients than that of antibody‐negative DM patients 24 . This discrepancy may be mainly due to differences in tissue or organ susceptibility to the attacks via anti‐MDA5 antibody regulated pathway.…”

“…IFN appears to play a key role in the pathogenesis of idiopathic inflammatory myopathies, especially in DM 23 . An up‐regulated IFN signature has been observed in skeletal muscle, skin samples, and peripheral blood mononuclear cells of anti‐MDA5 DM 1,24 . Our study showed the components of the IFN1 signaling pathway (MDA5, MAVS, IRF7, and ISG15), were overexpressed at the protein level, suggesting that the MAVS‐IFN1 pathway is broadly involved in the muscle pathology of anti‐MDA5 DM.…”

The Role of Toll-Like Receptors in Oncotherapy

“…In breast cancer, the activation of TLR3 promotes tumor cell death 18 . Specifically, type 1 interferon (IFN) induced by poly(I:C) activates apoptosis in multiple cancer models in mice and humans 19 . Specifically, apoptotic and necrotic cell death are induced by TLR3 stimulation in human colon and lung cancer 20 .…”