Enhancing Understanding of the Heterogeneity of Antiphospholipid Syndrome: Implications of the Complement System and Advanced Glycation End-Product Receptor ; Mieux comprendre l’hétérogénéité du Syndrome des AntiphospholipidesImplication du Système du Complément et du Récepteur aux Produits de Glycation Avancés

Introduction: Thrombotic manifestations of Antiphospholipid Syndrome (APS) can affect various types of vessels with variable severity, ranging from isolated distal venous thrombosis to catastrophic presentations of thrombotic storm (CAPS). The determinants of this heterogeneity remain unknown. The aim of this thesis was to explore the mechanisms underlying the phenotypic variability of APS by identifying specific biomarkers and initiating the investigation of the role of the receptor for advanced glycation end products (RAGE) in the pathophysiology of APS.Methods: Serum, plasma, and clinical data were collected from APS patients during remission (Lille University Hospital). Circulating levels of interleukins (IL)-1β, 6, 8, 10, tumor necrosis factor-α, interferon-α and γ, vascular endothelial growth factor, intercellular adhesion molecule 1, E-selectin, and vascular cell adhesion molecule (VCAM)-1), complement activation products (C3a, C4a, sC5b-9, and Bb), soluble RAGE, and anti-RAGE antibodies (aRAGE) were measured using ELISA (commercial kits or home-made). Thrombin generation tests (TGT) were automated (CAT: Stago, Asnieres-sur-Seine, France).C57BL/6 WT or RAGE-/- mice received an intraperitoneal injection of total IgG isolated from APS patient serum or healthy controls (HC) ± followed by two injections of heme (D5 and D6). After euthanasia on D7, aortic and mesenteric rings were isolated for immediate analysis of endothelial function in an isolated organ chamber. Kidneys, lungs, and aortas were collected for histological analysis, gene expression (RT-qPCR), and protein expression (Western Blot, Immunofluorescence) of inflammatory markers, oxidative stress, complement activation, RAGE, and mitochondrial dysfunction.Results: Levels of IL-6, VCAM-1, C3a, C4a, sC5b-9, and Bb were significantly elevated in 98 APS patients compared to 25 HC. Cluster analysis identified 2 homogeneous APS subgroups: "inflammatory cluster" and "complement cluster". Elevated IL-6 was associated with diabetes, high body mass index, ...