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

Yan Ye, Zechuan Chen, Shan Jiang, Fengyun Jia, Teng Li, Xia Lu, Jing Xue, Xinyue Lian, Jiaqiang Ma, Pei Hao, Liangjing Lu, Shuang Ye, Nan Shen, Chunde Bao, Qiong Fu () and Xiaoming Zhang ()
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Yan Ye: Shanghai Jiaotong University School of Medicine
Zechuan Chen: Institut Pasteur of Shanghai, Chinese Academy of Sciences
Shan Jiang: Institut Pasteur of Shanghai, Chinese Academy of Sciences
Fengyun Jia: Institut Pasteur of Shanghai, Chinese Academy of Sciences
Teng Li: Institut Pasteur of Shanghai, Chinese Academy of Sciences
Xia Lu: Shanghai Jiaotong University School of Medicine
Jing Xue: the Second Affiliated Hospital of Zhejiang University School of Medicine
Xinyue Lian: Shanghai Jiaotong University School of Medicine
Jiaqiang Ma: Institut Pasteur of Shanghai, Chinese Academy of Sciences
Pei Hao: Institut Pasteur of Shanghai, Chinese Academy of Sciences
Liangjing Lu: Shanghai Jiaotong University School of Medicine
Shuang Ye: Shanghai Jiaotong University School of Medicine
Nan Shen: Shanghai Jiaotong University School of Medicine
Chunde Bao: Shanghai Jiaotong University School of Medicine
Qiong Fu: Shanghai Jiaotong University School of Medicine
Xiaoming Zhang: Institut Pasteur of Shanghai, Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34145-4

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