Background: Anti-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.

Objectives: In this study, we aimed to explore the role of type I interferon (IFN) system in the pathogenesis of anti-MDA5 DM.

Methods: 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.

Results: 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.

Conclusions: 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.

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. Rheumatology 2010;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 rheumatism 2009;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 Rheumatism 1986;29(11):1365–1370.

Acknowledgements: The authors are grateful to Wangdong Xu for his help with statistical analysis

Disclosure of Interest: None declared

DOI: 10.1136/annrheumdis-2018-eular.5363