Background/Purpose: MDA5 DM is a distinct subtype of DM that is characterized by high mortality due to rapid progressive interstitial lung disease (ILD). MDA5 is a cytosolic protein and a family of retinoic-acid inducible gene-I (RIG-I) like receptor, which functions as a virus RNA sensor and induces the production of type 1 interferons (IFN) and proinflammatory cytokines. This leads to the activation of the antigen-specific antiviral immune response. There is a hypothesis that pathogenic involvement of anti-MDA5 antibodies has been proposed. Recently, similarities have been noted between COVID-19 infection and MDA5 DM, which suggests shared underlying autoinflammatory mechanisms. In this study, we try to detect the critical factors in the pathogenesis of MDA5 DM by gene expression analysis of peripheral blood.

Methods: Total of 31 DM cases were investigated, including anti-aminoacyl-tRNA synthetase positive (ARS) DM (n=12), MDA5 DM (n=7, survivor=3) and others (n=12). Peripheral blood was drawn at baseline and 2 to 3 months after treatments. Total RNAs were then extracted with using PAXgene miRNA kit. After quantifying the expressions of transcripts by multiplex sequencing, hierarchical clustering analysis, enrichment analysis using gene ontology (GO) terms, single sample gene set enrichment analysis (ssGSEA) and weighted gene co-expression network analysis (WGCNA) were performed.

Results: The hierarchical clustering with expression profiles of peripheral blood at baseline showed major 3 clusters. Interestingly, ARS DM cases were segregated into right side of the 3rd cluster while MDA5 DM cases fell into 1st and 2nd clusters. ARS and MDA5 DM were clearly discriminated if differentially expressed genes (DEGs) between these subtypes of DM were analyzed. By GO enrichment analysis, the terms, such as related to “defense response to virus” including “type 1 IFN signaling pathway” were found in the DEGs. In the MDA5 DM cases, ssGSEA revealed that genes of “Fcγ receptor mediated phagocytosis pathway” was significantly enriched. Next, we also investigated the DEGs of peripheral blood at 2-3 months after treatment between survival and fatal cases in MDA5 DM. We found that suppressing RIG-I like receptor and type 1 and 2 IFN signaling were the keys for survival.

Conclusion: MDA5 is a key sensor of RNA viruses including coronavirus families and then activate antiviral gene transcription such as type 1 IFN genes, leading to establish an antiviral host response. As the pulmonary damage of COVID-19 is known to be difficult to distinguish from the ILD associated with anti-MDA5 DM, the life-threating ILD of MDA5 DM may be caused by the over-activation of RIG-I like receptor signaling via MDA5. The hypothesis is supported by our findings that the defining features of MDA5 DM are activation of “type 1 IFN pathways” and antigen-specific antiviral immune responses including “Fcγ receptor mediated phagocytosis pathway”. As the levels of anti-MDA5 antibodies reported to be important prognostic parameter, it may be involved in pathogenesis of MDA5 DM. As we found that suppression of type 1 and 2 IFN signaling were the keys for survival, it seems to be reasonable to use inhibitors of Janus Kinases (JAK) for treatment of MDA5 DM.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/detecting-the-critical-factors-in-the-pathogenesis-of-anti-melanoma-differentiation-associated-gene-5-positive-dermatomyositis-mda5-dm-by-gene-expression-analysis-of-peripheral-blood/