Discovery of tissue-specific proteomic signatures in juvenile dermatomyositis highlights pathways reflecting persistent disease activity, clinical heterogeneity, and myositis-specific autoantibody subtype

TL;DR

This study identifies unique protein patterns in juvenile dermatomyositis patients, revealing immune and tissue-specific disease mechanisms linked to autoantibody subtypes.

Contribution

The study discovers proteomic signatures specific to tissues and autoantibody subtypes in juvenile dermatomyositis, offering new insights into disease mechanisms.

Findings

Persistent innate immune activation and redox signaling persist despite treatment in juvenile dermatomyositis.

Endothelial cell markers are overrepresented in disease activity and expressed in muscle and skin of JDM patients.

MSA subtypes correlate with distinct pathways, such as angiogenesis in NXP2+ and interferon signaling in MDA5+ cases.

Abstract

Juvenile dermatomyositis (JDM) is a heterogeneous autoimmune condition needing targeted treatment approaches and improved understanding of molecular mechanisms driving clinical phenotypes. We utilised exploratory proteomics from a longitudinal North American cohort of patients with new-onset JDM to identify biological pathways at disease onset and follow-up, tissue-specific disease activity, and myositis-specific autoantibody (MSA) status.

We measured 3072 plasma proteins (Olink panel) in 56 patients with JDM within 12 weeks of starting treatment (from the Childhood Arthritis and Rheumatology Research Alliance Registry and 3 additional sites) and 8 paediatric controls. Twenty-four patients with JDM who had 6-month follow-up samples were assessed. We identified differentially expressed proteins (DEPs) between groups by fitting linear mixed effects models and associated DEPs with validated disease activity measures. We assessed for cell/tissue specificity using the Human Protein Atlas and JDM muscle single nuclei and skin single-cell transcriptomic datasets. Differences within MSA subgroups were also analysed.

We uncovered persistent dysregulation of innate immune activation, cell death, and redox signalling at 6 months despite multidrug immunosuppression. By leveraging tissue and cell-specific proteomes, we identified overrepresentation of circulating endothelial proteins associated with disease activity and verified endothelial cell marker expression in JDM muscle and skin. We discovered pathways associated with MSA subtypes that reflect JDM phenotypes. NXP2+ JDM-associated proteins reflected angiogenesis and extracellular matrix remodelling and were expressed in endothelial cells and fibroblasts. MDA5+ JDM was associated with circulating type III interferon and surfactant proteins.

These proteomic findings will inform future biomarker and treatment development considering the unique tissue- and autoantibody-associated inflammation in JDM.

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