Vascular injury derived apoptotic exosome-like vesicles trigger autoimmunity

• Published in: Journal of translational autoimmunity (Online) 2024-12, Vol.9, p.100250, Article 100250
• Main Authors: Juillard, Sandrine, Karakeussian-Rimbaud, Annie, Normand, Marie-Hélène, Turgeon, Julie, Veilleux-Trinh, Charlotte, C. Robitaille, Alexa, Rauch, Joyce, Chruscinski, Andrzej, Grandvaux, Nathalie, Boilard, Éric, Hébert, Marie-Josée, Dieudé, Mélanie
• Format: Article
• Language: English
• Subjects: Anti-LG3; ApoExos; Autoantibodies; Research paper; Systemic lupus erythematosus (SLE); Toll-like receptors (TLR)
• ISSN: 2589-9090; 2589-9090
• DOI: 10.1016/j.jtauto.2024.100250

According to a central tenet of classical immune theory, a healthy immune system must avoid self-reactive lymphocyte clones but we now know that B cells repertoire exhibit some level of autoreactivity. These autoreactive B cells are thought to rely on self-ligands for their clonal selection and survival. Here, we confirm that healthy mice exhibit self-reactive B cell clones that can be stimulated in vitro by agonists of toll-like receptor (TLR) 1/2, TLR4, TLR7 and TLR9 to secrete anti-LG3/perlecan. LG3/perlecan is an antigen packaged in exosome-like structures released by apoptotic endothelial cells (ApoExos) upon vascular injury. We demonstrate that the injection of ApoExos in healthy animals activates the IL-23/IL-17 pro-inflammatory and autoimmune axis, and produces several autoantibodies, including anti-LG3 autoantibodies and hallmark autoantibodies found in systemic lupus erythematosus. We also identify γδT cells as key mediators of the maturation of ApoExos-induced autoantibodies in healthy mice. Altogether we show that ApoExos released by apoptotic endothelial cells display immune-mediating functions that can stimulate the B cells in the normal repertoire to produce autoantibodies. Our work also identifies TLR activation and γδT cells as important modulators of the humoral autoimmune response induced by ApoExos.