Circulating oxidized LDL forms complexes with β2-glycoprotein I: implication as an atherogenic autoantigen

• DOI: 10.1194/jlr.m200329-jlr200
• Publication Date: 2003-03-31T19:11:36Z
• Authors: Kazuko Kobayashi; Makoto Kishi; Tatsuya Atsumi; Maria L. Bertolac...; Hirofumi Makino; Nobuo Sakairi; Itaru Yamamoto; Tatsuji Yasuda; Munther A. Khamashta; Graham R.V. Hughes; Takao Koike; Dennis R. Voelker; Eiji Matsuura
• Keywords: Adult; Male; Adolescent; Arteriosclerosis; Lipoproteins; 610; QD415-436; arterial thrombosis; Biochemistry; Autoantigens; LDL; 03 medical and health sciences; 0302 clinical medicine; Humans; Lupus Erythematosus, Systemic; Aged; Autoantibodies; Glycoproteins; Lupus Erythematosus; Systemic; Thrombosis; Hydrogen-Ion Concentration; Middle Aged; Antiphospholipid Syndrome; 3. Good health; Lipoproteins, LDL; beta 2-Glycoprotein I; Immunoglobulin G; Female; antiphospholipid syndrome; autoantibody; Copper; Protein Binding

Beta2-glycoprotein I (beta2-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 beta2-GPI specifically binds to Cu2+-oxidized LDL (oxLDL) and that the beta2-GPI ligands are omega-carboxylated 7-ketocholesteryl esters. In the present study, we demonstrate that oxLDL forms stable and nondissociable complexes with beta2-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 beta2-GPI ligands was necessary for beta2-GPI binding. The ligand-mediated noncovalent interaction of beta2-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 beta2-GPI-oxLDL complexes were frequently detected in sera from patients with APS and/or systemic lupus erythematodes. Both the presence of beta2-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 beta2-GPI or LDL. Thus, the beta2-GPI-oxLDL complexes acting as an autoantigen are closely associated with autoimmune-mediated atherogenesis.