Antibodies against apoB100 peptide 210 inhibit atherosclerosis in apoE-/- mice

Abstract

Atherosclerotic plaques are characterized by an accumulation and subsequent oxidation of LDL, resulting in adaptive immune responses against formed or exposed neoepitopes of the LDL particle. Autoantibodies against native p210, the 3136–3155 amino acid sequence of the LDL protein apolipoprotein B-100 (apoB100) are common in humans and have been associated with less severe atherosclerosis and decreased risk for cardiovascular events in clinical studies. However, whether apoB100 native p210 autoantibodies play a functional role in atherosclerosis is not known. In the present study we immunized apoE-/- mice with p210-PADRE peptide to induce an antibody response against native p210. We also injected mice with murine monoclonal IgG against native p210. Control groups were immunized with PADRE peptide alone or with control murine monoclonal IgG. Immunization with p210-PADRE induced an IgG1 antibody response against p210 that was associated with reduced atherosclerotic plaque formation in the aorta and reduced MDA-LDL content in the lesions. Treatment with monoclonal p210 IgG produced a similar reduction in atherosclerosis as immunization with p210-PADRE. Our findings support an atheroprotective role of antibodies against the apoB100 native p210 and suggest that vaccines that induce the expression of native p210 IgG represent a potential therapeutic strategy for lowering cardiovascular risk.

Oxidized Lipids: Common Immunogenic Drivers of Non-Alcoholic Fatty Liver Disease and Atherosclerosis

“…More recently, a study revealed the protective function against the development of atherosclerotic plaques using autoantibodies against the ApoB100 peptide p210 in ApoE −/− mice, which was accomplished by injecting IgG2b against p210. These results in ApoE −/− mice support previous human studies, which showed an inverse association between apoB100 native p210 IgG and plaques in coronary or carotid arteries (142).…”

“…One of these peptides is the p210-PADRE, which has already been mentioned in the section on passive immunization. Besides direct infusion of IgG antibodies, ApoE −/− mice were immunized with the p210-PADRE peptide, which induced a specific IgG1 response against p210, thereby preventing MDA-LDL accumulation in lesions and reducing atherosclerotic plaque formation in the aorta ( 142 ). Moreover, immunization with OxLDL- and MDA-modified ApoB100 peptides were described to have an atheroprotective effect associated with an increase in IgG and IgM antibodies specific for the antigen used ( 142 , 147 ).…”

“…Besides direct infusion of IgG antibodies, ApoE −/− mice were immunized with the p210-PADRE peptide, which induced a specific IgG1 response against p210, thereby preventing MDA-LDL accumulation in lesions and reducing atherosclerotic plaque formation in the aorta ( 142 ). Moreover, immunization with OxLDL- and MDA-modified ApoB100 peptides were described to have an atheroprotective effect associated with an increase in IgG and IgM antibodies specific for the antigen used ( 142 , 147 ). Interestingly, two small immunogenic peptides, linear P1 and circular P2, were identified that immunologically mimic MDA-type epitopes ( 148 ).…”

High levels of autoantibodies against apoB100 p210 are associated with lower incidence of atrial fibrillation in women

“…Thus, a hypothesis is that infiltration or generation of oxidized LDL in the atrium results in increased inflammation in the atrial tissue. During LDL oxidation, reactive aldehydes are formed, and we have recently shown that a monoclonal antibody against p210 binds aldehyde‐modified LDL but not native LDL, indicating that p210 is exposed upon oxidation of LDL [29]. Thus, it is highly likely that at least part of the p210‐measured autoantibodies in the current study recognizes aldehyde‐modified LDL.…”

Anti-inflammatory and Immunomodulatory Therapies in Atherosclerosis

“…In addition to lipid-derived antigens, peptide-based vaccination strategies based on ApoB100-derived peptides, many of which are recognized by autoantibodies from sera of patients with coronary heart disease, have also shown promise in preclinical studies (Fredrikson et al 2003). Administration of several ApoB100 peptides, including P210, P45, P74, (Fredrikson et al 2003(Fredrikson et al , 2005(Fredrikson et al , 2008Dunér et al 2021), P2 (Chyu et al 2005), P3 (Tse et al 2013), P18 (Kimura et al 2018), P265 and P295 , has been shown to reduce lesion formation in murine atherosclerosis However, several challenges remain before the clinical implementation of inflammation-restraining tolerogenic T cell vaccine is possible. Given that the interaction of TCRs with their cognate peptide is dependent on the efficient presentation on MHC type II molecules, HLA types need to be matched.…”