New proteomic biomarkers identified in plasma extracellular vesicles in sarcoidosis: a case-control matched study

Background: Sarcoidosis is a heterogeneous disease with unknown mechanisms, nonspecific therapies, and multiple etiologies. The role of blood extracellular vesicles (EVs) in the diagnosis and pathogenesis of sarcoidosis remains obscure. AIMS. This study aims to test the hypothesis that the EV proteins in the blood can serve as phenotypic biomarkers of sarcoidosis. Methods: We combined EV proteomics with machine learning algorithms to identify and prioritize biomarkers, enrich their functions, and cluster networks in case-control matched ACCESS patients. Results: In total, 278 plasma EV proteins were significantly upregulated or downregulated in 40 sarcoidosis patients compared with 40 matched healthy controls. We identified 97 proteins that could serve as biomarkers with an AUC > 0.75. Of these, the AUC was > 0.90 for 13 proteins. 62 differentially expressed EV proteins strongly correlated with 20 clinical variables of severity, chest X-ray findings, and/or laboratory results. Functional annotation and network analysis suggest that these differentially expressed proteins regulate endocytosis, host responses to external stimuli, and transcription processes. Moreover, the top three ranked pathways were clathrin-mediated endocytosis, Hsp90 chaperone cycle, and spliceosome. Conclusions: This study demonstrates that plasma EV proteins can serve as biomarkers of various clinical phenotypes of the disease.