Charakterisierung des miRNA- und Protein-Cargos von kleinen extrazellulären Vesikeln aus Plasma von Patienten mit Hereditärem Angioödem

Introduction: Hereditary angioedema (HAE) causes swelling attacks of subcutaneous tissue or mucosa. It is unclear why disease burden and attack frequencies vary among patients. Small extracellular vesicles (sEVs) may influence pathogenesis, but sEV constellation and function in HAE are unknown. This is the first pilot study investigating sEVs as disease modulators in HAE.

Material and methods: sEVs were isolated from citrate plasma from 11 HAE patients and healthy donors (HD) by (ultra)centrifugation, filtration, and size exclusion chromatography. sEVs were characterized by western blot, transmission electron microscopy and nanoparticle tracking. sEV surface proteins were analyzed by bead-based flow cytometry. Their miRNA cargo was sequenced and used to predict sEV-based pathomechanisms in silico. All sEV readouts were analyzed for HAE-related changes and associations with clinical parameters.

Results: sEV levels were elevated in HAE patients compared to HD. HAE patients had lower levels of sEVs carrying CD8, CD209, CD81, CD24 and CD44, indicating a redistribution of sEV subpopulations. sEV miRNA profiling revealed 84 HAE-exclusive and 30 HAE-upregulated candidates, predicted to be involved in disease-relevant pathways, with AGO2, VEGF, RGS5, MTA1, and IFG1 as core hubs. 12 and 36 sEV miRNAs were restricted to patients with absent or present swelling attacks during prophylactic therapy, respectively.

Discussion: As a basis for new diagnostic and therapeutic approaches, our data sheds light on the sEV composition and role in HAE pathophysiology. sEVs, via surface proteins and miRNAs, contribute to HAE pathogenesis and a differential disease burden. They emerged as relevant disease modulators and we are conducting further studies to reveal underlying mechanisms.

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