Single-cell profiling reveals distinct adaptive immune hallmarks in MDA5+ dermatomyositis with therapeutic implications

Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5(+) DM) is an autoimmune condition associated with rapidly progressive interstitial lung disease and high mortality. The aetiology and pathogenesis of MDA5(+) DM are still largely unknown. Here we describe the immune signatures of MDA5(+) DM via single-cell RNA sequencing, flow cytometry and multiplex immunohistochemistry in peripheral B and T cells and in affected lung tissue samples from one patient. We find strong peripheral antibody-secreting cell and CD8(+) T cell responses as cellular immune hallmarks, and over-stimulated type I interferon signaling and associated metabolic reprogramming as molecular immune signature in MDA5(+) DM. High frequency of circulating ISG15(+) CD8(+) T cells at baseline predicts poor one-year survival in MDA5(+) DM patients. In affected lungs, we find profuse immune cells infiltration, which likely contributes to the pro-fibrotic response via type I interferon production. The importance of type I interferons in MDA5(+) DM pathology is further emphasized by our observation in a retrospective cohort of MDA5(+) DM patients that combined calcineurin and Janus kinase inhibitor therapy show superior efficacy to calcineurin inhibitor monotherapy. In summary, this study reveals key immune-pathogenic features of MDA5(+) DM and provides a potential basis for future tailored therapies.