Single-cell sequencing reveals distinct peripheral immune responses in anti-MDA5 antibody positive dermatomyositis with rapidly progressive interstitial lung disease

Anti-melanoma differentiation-associated protein 5 antibody positive dermatomyositis (MDA5+ DM) is an autoimmune disease related to rapidly progressive interstitial lung disease (RPILD) with high mortality. However, the pathogenesis of MDA5+ DM with RPILD remains unclear. We aimed to explore the peripheral immune landscape of MDA5+ DM with RPILD using single-cell RNA sequencing (scRNA-seq). We performed scRNA-seq of peripheral blood mononuclear cells (PBMCs) from MDA5+ DM with RPILD (n = 4), MDA5+ DM with ILD (non-RPILD, n = 3), and healthy controls (HCs, n = 3). The proportion of CD14+ monocytes increased, but the proportion of natural killer cells, CD4+ T cells and CD8+ T cells decreased in MDA5+ DM with RPILD compared with HCs. Obvious antiviral response was the main feature of MDA5+ DM with RPILD, and the expression of several interferon-stimulated genes (ISGs) related to RIG-I pathway increased, including IRF7, DDX60, IFI27 and IFI6. However, this antiviral response was not significant in MDA5+ DM with ILD. In addition, multiple immune pathways were downregulated in MDA5+ DM with RPILD, including antigen processing and presentation, translation initiation, mRNA splicing, and activation of T and B cells. Cell communication analysis revealed that multiple signaling pathways, including MHC-I and MHC-II, were attenuated in MDA5+ DM with RPILD. Notably, MHC-II signaling was absent in CD4+ naïve T cells from MDA5+ DM with RPILD. This study demonstrates that antiviral response plays an important role in the pathogenesis of MDA5+ DM with RPILD, as well as changes in downstream immune pathways, providing potential therapeutic targets for future treatment.