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

• Main Authors: Kazuko Kobayashi, Makoto Kishi, Tatsuya Atsumi, Maria L. Bertolaccini, Hirofumi Makino, Nobuo Sakairi, Itaru Yamamoto, Tatsuji Yasuda, Munther A. Khamashta, Graham R.V. Hughes, Takao Koike, Dennis R. Voelker, Eiji Matsuura
• Format: Article
• Language: English
• Published: Elsevier 2003-04-01
• Series: Journal of Lipid Research
• Subjects: antiphospholipid syndrome; arterial thrombosis; autoantibody
• Online Access: http://www.sciencedirect.com/science/article/pii/S0022227520311615

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 β2-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 β2-GPI-oxLDL complexes acting as an autoantigen are closely associated with autoimmune-mediated atherogenesis.