Pathogenesis of Anti-melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis: A Concise Review With an Emphasis on Type I Interferon System

Abstract

Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (MDA5+ DM) is typically characterized by cutaneous manifestations, amyopathic or hypomyopathic muscle involvement, and a high incidence of rapid progressive interstitial lung disease (RP-ILD). However, the exact etiology and pathogenesis of this condition has yet to be fully elucidated. Melanoma differentiation-associated gene 5 (MDA5), as the autoantigen target, is a member of the retinoic acid-inducible gene-I (RIG-I) family. The MDA5 protein can function as a cytosolic sensor that recognizes viral double-strand RNA and then triggers the transcription of genes encoding type I interferon (IFN). Therefore, it was presumed that viruses might trigger the overproduction of type I IFN, thus contributing to the development of MDA5+ DM. Emerging evidence provides further support to this hypothesis: the increased serum IFNα level was detected in the patients with MDA5+ DM, and the type I IFN gene signature was upregulated in both the peripheral blood mononuclear cells (PBMCs) and the skin tissues from these patients. In particular, RNA sequencing revealed the over-expression of the type I IFN genes in blood vessels from MDA5+ DM patients. In addition, Janus kinase (JAK) inhibitors achieved the promising therapeutic effects in cases with interstitial lung disease (ILD) associated with MDA5+ DM. In this review, we discuss the role of the type I IFN system in the pathogenesis of MDA5+ DM.

Identification of Biomarkers Associated With CD4+ T-Cell Infiltration With Gene Coexpression Network in Dermatomyositis

“…ISG15 is widely considered to be a regulatory gene in DM and may regulate the pathogenesis of DM by driving injury mechanisms of myofibers and capillary DM ( 81 ). IFIH1 is also named melanoma differentiation–associated gene 5 ( MAD5 ), and the IFIH1 protein encoded by this gene acts as a cytoplasmic sensor that recognizes viral double-stranded RNA and then triggers transcription of genes encoding type I interferons ( 24 ). The IFIH1 protein is considered a specific autoantigen target of DM, and the anti-MDA5 antibody is highly expressed in DM ( 82 , 83 ).…”

“…It is speculated that the virus may trigger the overproduction of IFN-I, thereby promoting the development of anti-MDA5–associated DM. Patients with anti-MDA5–associated DM have unique cutaneous manifestations and an increased risk of rapidly progressive interstitial lung disease (RP-ILD), leading to high mortality ( 24 ). The biological pathways of ISG15 and IFIH1 include T-cell activation, antigen processing, complement activation, etc.…”

“…Weighted gene coexpression network analysis (WGCNA) is a powerful tool for the identification of biologically relevant associations between phenotypes and gene modules ( 22 ). It has been extensively utilized for the recognition of new biomarkers and therapeutic targets for diverse diseases at the transcriptional level ( 23 , 24 ). Cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) is a deconvolution algorithm to analyze gene expression data of different immune cells ( 25 ).…”

Anti-MDA5 Antibody Linking COVID-19, Type I Interferon, and Autoimmunity: A Case Report and Systematic Literature Review

“…Finally, a high type I IFN signature might have a pathogenic role in vasculopathy and interstitial lung damage, which are prominent features of DM (46). If compared with other inflammatory myopathies, anti-MDA5 syndrome shows an even stronger type I IFN signature (46)(47)(48). Increased levels of MDA5 expression are found in peripheral mononucleated blood cells of patients with anti-MDA5 syndrome (47), and a possible role for type I IFN in the pathogenesis of the disease has been recently proposed (48).…”

“…If compared with other inflammatory myopathies, anti-MDA5 syndrome shows an even stronger type I IFN signature (46)(47)(48). Increased levels of MDA5 expression are found in peripheral mononucleated blood cells of patients with anti-MDA5 syndrome (47), and a possible role for type I IFN in the pathogenesis of the disease has been recently proposed (48). Furthermore, a peculiar population of autoreactive B cells has been recently described in a cohort of patients with severe anti-MDA5 syndrome.…”