Elsevier

Autoimmunity Reviews

Volume 7, Issue 1, November 2007, Pages 52-58
Autoimmunity Reviews

OxLDL/β2GPI–anti-oxLDL/β2GPI complex and atherosclerosis in SLE patients

https://doi.org/10.1016/j.autrev.2007.06.003Get rights and content

Abstract

It has been demonstrated that atherosclerosis (ATS) is enhanced in autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE). The reason for this accelerated process is still debatable and, although traditional risk factors are more prevalent in SLE patients than in general population, they do not seem to fully explain the enhanced risk.

ATS has the characteristics of an autoimmune chronic disease, involving both the innate and the adaptive immunity. Moreover, it satisfies the four criteria defining an autoimmune disease, proposed by Witebsky and Rose.

It has been shown that some autoantibodies, including anti-oxLDL, anti-β2GPI, anti-HSP60/65, and more recently anti-oxLDL/β2GPI, play a key role in the pathogenesis of ATS. However the role of these autoantibodies in accelerated ATS in SLE patients is still controversial. In fact, some of them seem to be proatherogenic and other protective; moreover, it has been demonstrated that induced oral tolerance has a protective role against ATS.

We have recently observed that the levels of oxLDL/β2GPI antigenic complexes and their antibodies were higher in patients with SLE than in healthy subjects, but we did not find a clear association between oxLDL/β2GPI complexes and IgG or IgM anti-oxLDL/β2GPI autoantibodies and subclinical ATS in SLE patients.

Many other studies are required to explain the role of autoantibodies in the pathogenesis of ATS in SLE patients, because the characteristics of SLE seem to mask their effects for atherogenesis.

Introduction

SLE is a prototypic autoimmune systemic disease which can affect different organ systems, including kidney, joint, serosal tissues, skin, and central and peripheral nervous system and it is caused by genetic, immunological, hormonal and viral factors, but its etiology is not clear. Patients affected by SLE are characterized by the presence of a great variety of autoantibodies directed to different autoantigens associated with disturbed apoptosis [1].

Recently, a clear association between SLE and cardiovascular disease (CVD) has been shown [2], [3], [4], [5]. Early autopsy and angiographic studies demonstrated a high prevalence of atherosclerotic lesions in SLE [6], [7]. Subclinical atherosclerosis (ATS), represented by intima/media thickness (IMT), was also more frequent in SLE than in healthy controls [8].

ATS is the most common cause of cardiovascular failure, myocardial infarction and death, in industrialized countries. Today it is clear that not only traditional risk factors for ATS (i.e. age, sex, cholesterol, blood pressure, cigarettes smoking), but also infectious [9], like mycobacterium infection, inflammatory and autoimmune factors [9], such as cytokines chemokines and T and B cells, are involved in its pathogenesis. Actually, ATS fulfils the four criteria proposed by Witebsky and Rose to define a condition as an autoimmune in nature [9], and there are many evidence that it can be an autoimmune disease [9].

The aim of this review is to evaluate the possible proatherogenic or protective role of some autoantigens and their autoantibodies in SLE patients.

Section snippets

Innate and adaptive immunity in atherosclerosis

Both innate immunity, including phagocytic leukocytes, complement and proinflammatory cytokines, and adaptive immunity, with T cells, antibodies and immunoregulatory cytokines, are involved in the pathogenesis and progression of ATS [10].

The first immunologic defensive line is the innate immunity, of which mononuclear phagocyte lineage is the most important cell type [10]. It recognizes primitive organisms foreign to the mammalian and is mobilized very quickly, in minutes to hours, by the

Atherosclerosis and activation of the adaptive immunity

Both microbial products correlated with cardiovascular disease and nonlipid mediators implicated in vascular disease can determine cytokine gene expression [11]. Atherogenic stimuli cause production of cytokines, that augment the expression of the genes for leukocyte adhesion molecules. These molecules in early atherogenesis include vascular cell adhesion molecule-1 (VCAM-1) and E- and P-selectin [11]. Also lipid components of modified lipoproteins can induce adhesion molecules [12].

Major autoantigen–autoantibody systems involved in atherosclerosis

The immune system plays a key role in the pathogenesis of ATS [10], by involving effectors of both the innate and the adaptive immunity as demonstrated by the observation of monocytes/macrophages transformed in lipid loaded foam cells, dendritic cells, natural killer cells, mast cells and immunoglobulins within the plaque [9], [10].

Natural antibodies exhibit a remarkably conserved repertoire that includes a broad specificity for self-antigens. The self-antigens do not cause an immune reaction,

OxLDL/β2GPI complexes and anti-oxLDL/β2GPI

Lipid peroxidation resulting in oxLDL production is a common occurrence in patients with systemic autoimmune diseases as well as in chronic inflammatory (non-autoimmune) disorders and certain systemic infections. OxLDL, but not native LDL, bind to β2GPI to form oxLDL/β2GPI complexes [35]. In 2001 Liu et al. [36] reported that 7-ketocholesteryl-9-carboxinonanoate, so-called oxLig-1, is the major ligand of oxLDL for β2GPI; in 2002 the same group [37] demonstrated that ω-carboxilated

Conclusions

Today, ATS is considered in part to be a chronic autoimmune disease, because it involves the components of both innate and adaptive immunity [8]. It is enhanced in many autoimmune diseases, such as SLE, for traditional and nontraditional risk factors, such as age, blood pressure and cigarette smoking. SLE is a prototypic autoimmune disease, involving many organ systems; but its characteristics can mask the pathogenic role of some of the autoantibodies in the development of ATS. In fact, there

Take-home messages

  • Atherosclerosis (ATS) is considered a chronic autoimmune disease in which autoantibodies like anti-oxLDL, anti-β2GPI, anti-HSP60/65, and more recently anti-oxLDL/β2GPI complex play a pathogenetic role.

  • ATS is enhanced in systemic lupus erythematosus (SLE) as well as other autoimmune rheumatic diseases; however the role of proatherogenic autoantibodies in SLE patients is still controversial.

  • Circulating levels of oxLDL/β2GPI complex and respective antibodies are higher in SLE patients than in

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