Accelerated Atherogenesis and Antiphospholipid Antibodies

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Atherosclerosis is a major health concern of worldwide importance. The causal relationship between atherosclerosis and cholesterol metabolism is well established. However, newer inflammatory and immunologic mechanisms are emerging as relevant factors for the initiation and progression of atherosclerotic lesions. In particular, the oxidation of low-density lipoprotein (LDL) has been identified as an early pro-atherogenic event that promotes the formation of macrophage derived foam cells [1–4]. The increased cardiovascular morbidity and mortality recently reported in patients with systemic autoimmune diseases is a likely consequence of the accelerated (or premature) development of atherosclerosis. These findings have suggested a contributing role of autoimmunity in the development of atherosclerosis. Antiphospholipid syndrome (APS) is characterized by venous and arterial thromboembolic complications associated with high serum levels of antiphospholipid antibodies. APS is frequently diagnosed in the context of an autoimmune disease [5, 6]. The exact mechanism(s) by which anticardiolipin (aCL), lupus anticoagulants (LA), and/or other antiphospholipid antibodies promote thrombosis is not completely understood. It is now widely agreed that β2-glycoprotein I (β2-GPI) plays a central role in APS, and more importantly, represents a major antigenic target for antiphospholipid antibodies [7–11]. Oxidized LDL (oxLDL) is the principal lipoprotein found in atherosclerotic lesions, and it co-localizes with β2-GPI and immunoreactive lymphocytes [12]. It was also reported that aCL antibodies from patients with systemic lupus erythematosus (SLE) cross-reacted with malondialdehyde (MDA) modified LDL [13], and that anti–β2-GPI antibodies were associated with arterial thrombosis [14, 15]. These findings further indicated the participation of antiphospholipid antibodies in atherogenesis. More recently, we have demonstrated that oxLDL binds to β2-GPI, and that these complexes (oxLDL/β2-GPI) can be found in the blood stream of patients with various autoimmune and chronic inflammatory diseases, such as SLE, APS, chronic renal disease, diabetes mellitus, as well as in some patients with “acute” myocardial infarction [16]. IgG antibodies to oxLDL/β2-GPI were detected only in SLE and APS patients and were strongly associated with arterial thrombosis. Further, immune complexes con-