22PProteomic profiling in juvenile dermatomyositis toward the elucidation of protein signatures correlating with severity of myopathology

Juvenile dermatomyositis (JDM) is an idiopathic, pediatric-onset inflammatory myopathy, primarily manifested via muscle inflammation and skin rash. Specific biological processes such as the interferon signaling pathway are known to play a role in the disease, but the precise molecular pathology is still incompletely understood. With muscle biopsies being invasive, molecular studies to understand protein dysregulations driving disease onset and severity of muscle pathology are limited. Here, we used a myopathological scoring system enabling to systematically stratify JDM patients into severity groups. Untargeted proteomics on muscle tissue was applied to measure protein levels and assess the differential abundance in each group and in healthy controls and to identify biological processes correlating with the severity of myopathology, and thus disease activity. Our analyses revealed a number of differentially abundant proteins that positively correlated with disease severity. Notably, interferon-induced GTP-binding protein Mx1 (MX1) consistently emerged as the most statistically significant protein. upregulated proteins were predominantly associated with immune system functions, while downregulated proteins were linked to mitochondrial processes. Clustering of proteins based on their expression identified four distinct protein groups with unique expression patterns across controls and severity groups. Each expression pattern cluster was enriched for specific biological processes or cellular components relevant to JDM pathology. Immunofluorescence imaging validated proteomics results and confirmed the increase in MX1 and a role of periostin in fibrotic remodeling. Our combined findings provide critical insights into the molecular mechanisms driving disease onset and severity in muscle tissue, advancing our understanding of JDM's underlying pathophysiology.