Background: Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM) a distinct subtype of dermatomyositis associated with rapidly progressive interstitial lung disease and high mortality. The aetiology and pathogenesis of MDA5+ DM are largely unknown which pose great difficulty to develop novel therapeutic options.

Objectives: To explore the immune landscape and identify disease-specific immune cells of the affected lungs from the MDA5+ DM patients who underwent lung transplantation.

Methods: Six lung tissues from end-stage MDA5+ DM patients were obtained and processed into single-cell suspensions. Cells were subjected to scRNA-seq, scBCR-seq and scTCR-seq using the 10x Genomics Chromium platform. For comparisons, twelve lung tissues from healthy individuals, eleven from the patients with idiopathic pulmonary fibrosis (IPF) and seven Covid19 patients were collected from public datasets (GSE136831, GSE159585).

Results: Compared with health individual and other lung diseases, we observed a decrease of alveolar epithelial cells with high infiltration of macrophages in the lungs of MDA5+ DM patients. A panel of pathways, including type I and II interferon responses, inflammatory response, apoptosis and reactive-oxygen-species-pathway were strongly elevated in the macrophages from MDA5+ DM patients. Furthermore, the proportion of CXCL10+ macrophage cluster was significantly increased and intensely interacted with T cells. scBCR-seq and scTCR-seq analyses revealed that B cells and T cells exhibited strong clonal expansions in the affected lungs of MDA5+ DM patients, indicating intensive cellular and humoral responses occurred in situ . We validated the abnormal activation of macrophages, T cells and B cells by mIHC. Finally, we found a potential link between overactivation of CXCL10+ macrophages and fibrosis.

Conclusion: The innate and adaptive immune systems were highly activated and dysregulated in the lungs of active MDA5+ DM patients. Targeting disease-specific immune cell types may provide new therapeutic opportunities for MDA5+ DM.

REFERENCES: NIL.

Acknowledgements: This study was supported by the National Key Research and Development Program of China (No. 2021YFE0200600).

Disclosure of Interests: None declared.