Abstract 025: Anti-Apolipoprotein A-I Antibody Profiles Predict Cardiovascular Disease Outcomes in Patients and in a Mouse Model of Atherosclerosis

Abstract

Apolipoprotein A-I (ApoA-I) is the target of antibody induction in patients suffering from chronic inflammation associated with obesity, autoimmunity and cardiovascular disease (CVD). Anti-ApoA-I antibodies are considered serum markers for CVD, but the exact immunologic stimuli and role of these antibodies in disease progression are poorly understood. Our efforts in characterizing the anti-ApoA-I antibody profiles in 375 patients with coronary artery disease resulted in a hazard ratio of 1.52 (95% CI: 1.03-2.18; p = 0.02) when adjusted for 12 traditional markers of cardiovascular disease. We then aimed to recapitulate these findings in mice using an immunostimulatory liposomal formulation decorated with peptides derived from ApoA-I to induce epitope-specific antibody responses in mice. Intriguingly, acute inflammation associated with adjuvant exposure and high fat diet alone induced an anti-ApoA-I antibody response in mice. Immunization shifted the antibody profile to a pro-atherogenic phenotype, which accelerated atherosclerosis as measured by en face lesion area. Protective antibody profiles were also observed in mice, which recapitulate the phenotype observed in patients protected from major adverse cardiovascular events. Comparison of mice exhibiting a pro-atherogenic antibody profile with mice exhibiting an anti-inflammatory antibody profile result in lesion areas of 20% and 5% ( p = 0.005), respectively. Continued evaluation of the immunologic mechanisms that lead to pro-atherogenic and anti-atherogenic antibody responses and the immunologic sequelae associated with specific antibody profiles will promote novel therapeutic strategies and guide interventions to improve patient outcomes.