OP0147 Aberrant activation of type i interferon system in anti-mda5 dermatomyositis patients
Authors: S. Zhang, B. Yan
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Anti-melanoma differentiation-associated gene 5 (MDA5) DM patients have an increased risk of interstitial lung disease (ILD), with a potentially fatal course.<sup>1</sup> Viral infection has been speculated to be the putative trigger for anti-MDA5 DM.<sup>2 3</sup> The molecular pathogenesis remains largely unknown. <h3>Objectives</h3> In this study, we aimed to explore the role of type I interferon (IFN) system in the pathogenesis of anti-MDA5 DM. <h3>Methods</h3> We 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. <h3>Results</h3> Anti-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. <h3>Conclusions</h3> Our 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. <h3>References</h3> [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. <h3>Acknowledgements</h3> The authors are grateful to Wangdong Xu for his help with statistical analysis <h3>Disclosure of Interest</h3> None declared