Apolipoprotein B100 autoimmunity and atherosclerosis – disease mechanisms and therapeutic potential

Abstract

Purpose of reviewAdaptive immune responses have been shown to play an important role in the atherosclerotic disease process and both pathogenic and protective immunity has been identified. Apolipoprotein (apo) B100 appears to be a key antigen and novel therapies modulating immune responses against apo B100 have shown promising results in experimental models. This review will discuss recent developments in the mechanistic understanding of apo B100 autoimmunity and approaches taken to use this knowledge for development of novel therapies. Recent findingsIt has recently been shown that not only apo B100 modified by oxidation but also nonmodified apo B100 is targeted by autoimmune responses. This implies that a corresponding set of regulatory T cells with the same antigen specificity must exist and that these cells under normal circumstances are able to prevent autoimmunity against LDL. Recent studies also suggest that the athero-protective effect of apo B100 peptide immunization acts by reenforcing the activity of such cells. SummaryThese novel findings suggest that aggravation of plaque inflammation may occur as result of a local loss of tolerance against LDL in the plaque due to insufficient activity of regulatory T cells. Restoration of lost tolerance represents an interesting novel approach for treatment of cardiovascular disease.

Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine

“…Similar data have been reported by others with MDA-LDL and with other oxidation-specifi c models leading to elevated Ab titers to epitopes of OxLDL ( 10,11 ). These studies led us and others ( 5,(12)(13)(14) to propose the concept that a vaccine to OSEs of OxLDL could be developed to limit atherogenesis. Assuming the safety of such an approach, it would have the advantage of wide applicability and a relatively cost-effi cient approach.…”

“…Further, because the IK17 Fab lacks the Fc effector portion of Abs, this strongly suggests that IK17's binding and blocking ability alone is suffi cient to provide atheroprotection. In the current work, antisera from MAA-immunized mice were the most effective in inhibiting macrophage ( 3,14,40,41,47,48 ). We emphasize that our approach is quite different in that the principle of the immunization strategy here is to generate an active humoral and cellular response to OSEs (e.g., to haptens of proteins generated by adduct formation between products of lipid peroxidation and various proteins, including apoB of OxLDL).…”

Circulating CD40 + and CD86 + B Cell Subsets Demonstrate Opposing Associations With Risk of Stroke

“…16,17 This notion is also supported by findings of protective effects of antibodies against LDL phospholipid and apolipoprotein B antigens in experimental models of atherosclerosis as well as by clinical studies demonstrating inverse associations between autoantibodies against LDL antigens and the severity of carotid and coronary disease. [18][19][20] However, this view has been challenged by more recent studies that found reduced atherosclerosis in hypercholesterolemic mice after B cell depletion by CD20 antibody treatment. 21,22 The reasons for these discrepant observations remain to be fully clarified.…”

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

“…However, such immunizations increase both IgG1 from B-2 cells and IgM from B-1 cells, the latter resulting from an induced Th2 response with IL-5 release, which is a known B-1 cell stimulant (71). Subsequent studies have shown that elevations of titers of OSE Abs in murine models, whether by immunization, passive infusions, or adenoviral-mediated expression, can inhibit atherogenesis (7,86,90,91). This includes use of fragment, antigen-binding (Fab) or even single-chain variable fragment (scFv) anti-oxLDL Ab fragments that have no effector functions (92), demonstrating the inherent ability of such OSE Abs to inhibit foam cell formation.…”