Abstract Text: Extracellular-vesicles (EVs) have been implicated in autoimmune disease pathogenesis. Plasma-derived DNA containing EVs have been shown to induce STING-mediated proinflammatory responses in dermatomyositis (DM), but their protein content is not well characterized. We collected EVs from plasma of 16 DM patients and 5 controls. Protein profile was generated by mass spectrometry and differentially expressed proteins were assessed. Findings were used to train a machine learning model (random forest), which achieved 90% accuracy with AUC = 0.92 in correctly predicting disease state. Sixty-seven proteins were uniquely detected in the patient cohort. Thirty-five proteins were significantly differentially expressed, of which 13 were upregulated and 22 downregulated. Over representation analysis found the unique and upregulated proteins enriched for myeloid mediated immunity, glutathione metabolism, nucleic acid synthesis and vesicle transport pathways. EVs were enriched with USP15, TMED2, STK4, ABCC1, PDMS14 and MMP8, all of which participate in induction of innate inflammatory cascades. Downregulated proteins were enriched for the classical and lectin complement pathways. The diminution of complement components in vesicles may reflect its abundance in target tissues but may also reflect host inability to circulate these molecules to damaged tissue, which in a chronic stage of disease may have a protective role. Finally, surfactant protein B was expressed almost exclusively in patients with lung disease, rendering it a possible marker for pulmonary involvement. Taken together, proteins carried by EVs appear to be markers of DM, particularly pulmonary manifestations, and may have a role in inflammation in these patients and may indicate potential therapeutic targets.
