ANTI-ATHERO · Age-associated antigens in atherosclerosis immunity and immunotherapy

Cardiovascular disease remains the leading cause of mortality worldwide, with atherosclerosis (AT) as the primary underlying factor. Ageing is the strongest risk factor for both AT and CVD. Emerging evidence indicates that the B cell-mediated immune response plays a pivotal role in the development and progression of AT, although the nature of this response and its triggering antigens are poorly understood. In our prior research, we identified ALDH4A1 as novel AT antigen and showed that anti-ALDH4A1 A12 antibody is atheroprotective in mice. Our recent preliminary data show increased titers of anti-ALDH4A1 antibodies in aged mice as well as a rise in age-associated B cells in AT mice. These findings suggest a strong link between ageing, the B cell immune response, and AT. ANTI-ATHERO aims to functionally dissect the AT antibody response with the ultimate goal of identifying age-associated antigens that can serve as targets for specific immunotherapies. We will pursue the following aims: 1) characterize the early and aged B cell immune response in AT with time-stamping mouse models, 2) generate a single cell clonal atlas of time-stamped AT B cells and identify individual antibodies and antigens associated with the early and the aged AT antibody response, 3) translate our findings to human disease by mapping the B cell response in clinical AT and testing the identified antigens as markers of disease progression and, 4) evaluate the therapeutic potential of the identified antibodies and antigens through passive and active immunization strategies. We anticipate that the ANTI-ATHERO project will generate transformative insights into the interplay between ageing, the immune system, and AT. Our findings have the potential to significantly advance not only cardiovascular research but also contribute to a broader understanding of other age-related diseases and autoimmune disorders.