Interaction between antiphospholipid antibodies, endothelial cell-derived extracellular vesicles and monocytes in antiphospholipid syndrome

• Applicant: Dr. Diana Maria Morales Prieto
• Subject Area: Gynaecology and Obstetrics
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468501728

Antiphospholipid syndrome (APS) is an autoimmune disease classically associated with occurrence of vascular thrombosis (vascular APS) and/or pregnancy morbidity (obstetric APS). A causative relationship between clinical manifestations and persistent presence of antiphospholipid antibodies (aPL) has been experimentally described. However, the heterogeneity of antiphospholipid antibody types and their effects reported in vitro suggests that vascular and obstetric APS may have additional specific pathogenic mechanisms. Several cell types including monocytes, endothelial and trophoblast cells are important players in APS, but their interaction in presence of vascular and obstetric aPL remains unclear. Besides the direct effects, indirect mechanisms such as intercellular communication via extracellular vesicles (EVs) may be also involved in the development of APS. In this research proposal, we suggest that IgG fractions isolated from the serum of patients with APS trigger secretion of specific endothelial-derived EVs (EDEVs). APS-EDEVs of APS variants (obstetric and vascular) differ in their specific features (amount, surface markers and content). These EDEVs may be internalized by monocytes and trophoblast cells triggering variable procoagulant effects and trophoblast dysfunction, which explain the different clinical manifestations of APS. In order to prove this hypothesis, we propose a panel of assays addressed to characterize EDEVs upon vascular- and obstetric-APS treatment (APS-EDEVs) in terms of morphology, concentration, size, surface markers and cargo. Mechanisms of uptake of APS-EDEVs, transfer of endothelial-specific miRNAs and the consequent effects on monocyte capability to induce clot activation will be described. Immune signals released by monocytes upon APS-EDEV treatment will be identified. Finally, the effects of these monocyte-derived signals on syncytiotrophoblast integrity and trophoblast functions will be investigated respectively in an organ-on-chip model of placenta barrier and a model of trophoblast-endothelial cell interaction. This project will contribute to understand the molecular mechanisms involved in APS, which may help to generate new strategies for treatment tools specifically directed for vascular or obstetric APS.

• DFG Programme: Research Grants
• International Connection: Colombia
• Partner Organisation: Universidad de Antioquia
• Co-Investigator: Professor Dr. Udo Markert
• Cooperation Partner: Professorin Angela Patricia Cadavid, Ph.D.