Understanding the role of anti-apolipoprotein A-I antibodies in atherosclerotic cardiovascular disease

The identification of autoantigens in atherosclerotic plaques has prompted investigation of the antibody-mediated pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Detailed characterization of the antigen, epitope specificity, antibody subclass and receptor engagement will enhance the understanding of ASCVD and guide therapeutic development. One target of IgG antibody induction in patients is apolipoprotein A-I (ApoA-I), the major protein of high density lipoprotein (HDL). Although anti-ApoA-I antibodies have been identified in mice and human subjects, the role of these antibodies have not been elucidated. Continued evaluation of the detailed antibody profile will improve our understanding of the immune responses associated with ASCVD. The longterm goal is to improve clinical risk stratification and identify novel therapeutic targets, which will reduce the burden of ASCVD in patients. To achieve this goal, the overall objectives of this proposal are to characterize the molecular components of the anti-ApoA-I antibody response in mice and patient serum samples and correlate their characteristics with cellular interactions, functional outcomes and atherosclerosis progression. The hypothesis is that anti-ApoA-I can exhibit a pro-inflammatory or anti-inflammatory effect depending on the specific antibody characteristics (i.e. antigen engagement, subclass, epitope specificity, Fc receptor interaction) leading to exacerbation or suppression from ASCVD. The rationale for this proposed research is that understanding one component of the immune response associated with ASCVD will promote improved patient outcomes through novel therapeutic strategies. Encouraged by strong preliminary data, this hypothesis will be tested through two specific aims: 1) Elucidate the molecular components and functional implications of antibodies targeting ApoA-I in mouse models of atherosclerosis; and 2) Delineate the association between antibody profiles and ASCVD events in a large community-based prospective patient cohort. In the first aim, immunomodulation strategies developed in the applicants’ laboratory will be used to achieve epitope-specific modulation of antibody responses in mice to investigate their role in disease through detailed characterization of the antibodies and epitopes and subsequent association with atherosclerosis progression. In the second aim, sera from patients in the Multi-Ethnic Study of Atherosclerosis (MESA) will be evaluated for antibody profiles and correlated with patient outcomes. The approach is innovative due to the utilization of novel immunomodulation approaches, which have not been employed in the context of ASCVD; and the strategy to obtain detailed antibody profiles in mice and patients for association studies with disease progression. The proposed research is significant because the outcomes of this research will improve our understanding of B cell mediated immune responses to ApoA-I to elucidate the role of antibodies on disease progression. These data will guide future efforts to improve risk stratification procedures in patients and will facilitate clinical translation of novel therapeutics to decrease the burden of ASCVD in patients.