Circulating oxidized LDL forms complexes with β ₂-glycoprotein I: Implication as an atherogenic autoantigen

β₂-glycoprotein I (β₂-GPI) is a major antigen for antiphospholipid antibodies (Abs, aPL) present in patients with antiphospholipid syndrome (APS). We recently reported (J. Lipid Res., 42: 697, 2001; J. Lipid Res., 43: 1486, 2002) that β2-GPI specifically binds to Cu²⁺-oxidized LDL (oxLDL) and that the β ₂-GPI ligands are ω-carboxylated 7-ketocholesteryl esters. In the present study, we demonstrate that oxLDL forms stable and nondissociable complexes with β₂-GPI in serum, and that high serum levels of the complexes are associated with arterial thrombosis in APS. A conjugated ketone function at the 7-position of cholesterol as well as the ω-carboxyl function of the β₂-GPI ligands was necessary for β₂-GPI binding. The ligand-mediated noncovalent interaction of β₂-GPI and oxLDL undergoes a temperature- and time-dependent conversion to much more stable but readily dissociable complexes in vitro at neutral pH. In contrast, stable and nondissociable β₂-GPI-oxLDL complexes were frequently detected in sera from patients with APS and/or systemic lupus erythematodes. Both the presence of β₂-GPI-oxLDL complexes and IgG Abs recognizing these complexes were strongly associated with arterial thrombosis. Further, these same Abs correlated with IgG immune complexes containing β₂-GPI or LDL. Thus, the β ₂-GPI-oxLDL complexes acting as an autoantigen are closely associated with autoimmune-mediated atherogenesis.