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

beta(2)-glycoprotein I (beta(2)-GPI) is a major antigen for antiphospholipid antibodies (Abs, aPL) present in patients with antiphospholipid syndrome (APS). We recently reported (I. Lipid Res., 42: 697, 200 1; J Lipid Res., 43: 1486, 2002) that beta(2)-GPI specifically binds to Cu2+-oxidized LDL (oxLDL) and that the beta(2)-GPI ligands are omega-carboxylated 7-ketocholesteryl esters. In the present study, we demonstrate that oxLDL forms stable and nondissociable complexes with beta(2)-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 omega-carboxyl function of the beta(2)-GPI ligands was necessary for beta(2)-GPI binding. The ligand-mediated noncovalent interaction of beta(2)-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 beta(2)-GPI-oxLDL complexes were frequently detected in sera from patients with APS and/or systemic lupus erythematodes. Both the presence Of beta(2)-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 beta(2)-GPI or LDL.jlr Thus, the beta(2)-GPI-oxLDL complexes acting as an autoantigen are closely associated with autoimmune-mediated atherogenesis.