Deciphering antibody-mediated atheroprotection to MDA-LDL

Abstract

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 05-11-2021Esta tesis tiene embargado el acceso al texto completo hasta el 05-05-2023Atherosclerosis is a chronic inflammatory disease of the arteries that underlies the majority of cardiovascular events. Both innate and adaptive arms of immunity are involved in atherosclerosis initiation and progression. Neo-antigens resulting from endogenous modification of self-components are believed to be the main trigger for the adaptive immune response in atherosclerosis. The most paradigmatic of such neo-antigens are oxidized forms of LDL, and particularly, MDA-LDL. Indeed, immunization of pro-atherogenic mice and rabbits with MDA-LDL is atheroprotective. However, the immune response to MDA-LDL and the mechanisms responsible for this atheroprotection are not well understood. In this thesis, we have assessed the role of germinal center-derived antibodies in atherosclerosis and in MDA-LDL-driven atheroprotection. We have found that immunization of mice with MDA-LDL gives rise to memory B cells, IgG1 switched plasma cells and anti-MDA-LDL antibodies. Additionally, we have found that a fraction of antibodies generated upon MDA-LDL immunization recognize epitopes unique to MDA-LDL neo-antigen. High-throughput single cell immunoglobulin sequencing has revealed that MDA-LDL immunoglobulin repertoire is characterized by highly mutated antibodies. Thus, our data suggest that MDA-LDL behaves as a T-dependent antigen. To analyze the role of germinal center-derived antibodies in atherosclerosis, we have generated a mouse model lacking germinal center-derived plasma cells by conditional deletion of Blimp1. We have found that Blimp1-deficient mice show altered germinal center dynamics. Furthermore, Blimp1-deficient pro-atherogenic chimeras show accelerated atherosclerosis, suggesting an atheroprotective role of germinal center-derived antibodies in atherosclerosis. Finally, we have found that MDA-LDL immunization does not promote atheroprotection in mice lacking Blimp1, therefore indicating that germinal center-derived antibodies are required for MDA-LDL-driven atheroprotection. These findings support the idea that MDA-LDL-based vaccines could potentially be used for the prevention or treatment of atherosclerosi