Aggrecan and polymeric immunoglobulin receptor in extracellular vesicles of patients with seropositive rheumatoid arthritis

Background The presence or absence of autoantibodies distinguishes patients with rheumatoid arthritis (RA) as seropositive (SP) or seronegative (SN), with SP generally associated with poorer prognosis. Extracellular vesicles (EVs) are important mediators of intercellular communication and may contribute to RA pathogenesis by disseminating immunologically active molecules that promote systemic inflammation. However, the protein cargo of circulating EVs associated with RA seropositivity remains poorly characterized. Therefore, we aimed to identify EV-associated proteins linked to RA and seropositivity and evaluate their relationship with clinical features. Methods Blood-derived EVs were isolated from patients with SP and SN disease and from healthy donors (HD) and were characterized according to international guidelines. EV protein cargo was analyzed by liquid chromatography–tandem mass spectrometry (LC-MS/MS). Differentially enriched proteins were identified in patients, and their associations with serum autoantibody levels, circulating cytokines, and disease activity were assessed. Results A total of 358 proteins were identified in EVs, most of which have been previously reported in these structures. Several complement proteins, collagens, and immunoglobulins were lower in patients with RA than in HD. Notably, aggrecan (ACAN) and the polymeric immunoglobulin receptor (PIGR), not previously described in RA-derived EVs, were specifically enriched in SP patients compared with both patients with SN RA and HD. Their enrichment was significantly associated with autoantibody levels and disease activity. Conclusion Our findings identify ACAN and PIGR as novel EV-associated proteins linked to RA seropositivity. Their association with autoantibody levels and disease activity suggests that circulating EVs may reflect biological pathways connecting cartilage remodeling, mucosal immunity, and systemic autoimmunity, supporting their potential utility as biomarkers and contributors to disease pathogenesis.