Oxidized Low-Density Lipoprotein/β2-Glycoprotein I Complexes and Autoantibodies to oxLig-1/β2-Glycoprotein I in Patients with Systemic Lupus Erythematosus and Antiphospholipid Syndrome

Oxidized low-density lipoprotein (oxLDL) interacts with β 2 -glycoprotein I (β 2 -GPI) via oxLDL-derived specific ligands (oxLig-1) forming complexes. The prevalence and significance of oxLDL/β 2 -GPI complexes and antibodies to oxLig-1/β 2 -GPI were evaluated in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). The oxLDL/β 2 -GPI complex was 69% positive (above mean + 3 SD of control subjects) in 97 consecutive patients with SLE, 62% in 40 patients with SLE with secondary APS, and 60% in 50 control patients with SLE without APS. IgG anti–oxLig-1/β 2 -GPI antibody was positive in 31 (32%) of 97 consecutive patients with SLE, in 26 (65%) of 40 patients with SLE with secondary APS, and in 6 (19%) of 32 control patients with SLE. Anti–oxLig1/β 2 -GPI antibodies were 93.7% specific with a positive predictive value of 90.0% for APS, better than anticardiolipin antibodies (80.0% specific, 71.4% predictive value). These results confirm that oxLDL/β 2 GPI complexes are common in SLE and suggest a possible immunogenic role in APS. In contrast, IgG anti–oxLig-1/β 2 -GPI antibodies not only are associated with but also are clinically useful risk factors for APS. Vascular thromboembolic events, pregnancy morbidity (miscarriages and fetal loss), and thrombocytopenia in association with the presence of elevated serum levels of antiphospholipid antibodies are common clinical features of the antiphospholipid syndrome (APS). APS is classified as primary if there is no coexisting autoimmune disease or secondary when present in the context of an autoimmune disorder. There is considerable evidence to suggest a pathogenic role of antiphospholipid antibodies in the development of these clinical features. 1-3 Antiphospholipid antibodies are a heterogeneous group of autoantibodies characterized by their reactivity to anionic phospholipids, phospholipid/protein complexes, and certain proteins presented on suitable surfaces in the absence of phospholipids, ie, activated cell membranes and oxygenated polystyrene. 4-6 Several plasma proteins that participate in coagulation and interact with anionic phospholipids have been reported to function as antiphospholipid cofactors, eg, β 2 -glycoprotein I (β 2 -GPI), prothrombin, protein C, protein S, and annexin V. β 2 -GPI is the most extensively studied of the cofactors and has been shown to be a relevant antigenic target for antiphospholipid antibodies. 7,8 β 2 -GPI is a 50-kd, single-chain polypeptide composed of 326 amino acid residues, arranged in 5 homologous repeats known as complement control protein domains. β 2 -GPI’s fifth domain contains a patch of positively charged amino acids that likely represents the binding region for phospholipids. 9-11