Summary

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.

Overall design

We performed single cell RNA-seq (scRNA-seq) on 4 healthy donors, 5 IIM disease controls, 7 active MDA5+ DM patients, 3 paired MDA5+ DM patients in remission and 1 end-stage MDA5+ DM patient who underwent lung transplantation. For scRNA-seq, after stringent computational quality control, 111,200 high-quality B and T cells from peripheral blood were obtained. This study reveals key immune-pathogenic features of MDA5+ DM and provides a potential basis for future tailored therapies.

Contributors

Yan Ye†, Zechuan Chen†, Shan Jiang†, Qiong Fu✉️, Xiaoming Zhang✉️

Contact

fuqiong@renji.com (Qiong Fu), xmzhang@ips.ac.cn (Xiaoming Zhang)