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Journal of Lipid Research, Vol. 44, 716-726, April 2003
Copyright © 2003 by Lipid Research, Inc.
Circulating oxidized LDL forms complexes with ß2-glycoprotein I
: implication as an atherogenic autoantigen
* Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
Department of Immunochemistry, Faculty of Pharmaceutical Science, Okayama University, Okayama 700-8530, Japan
** Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
Lupus Research Unit, The Rayne Institute, St. Thomas' Hospital London, SE1 7EH, UK
Division of Bioscience, Graduate School of Environment Earth Science, Hokkaido University, Sapporo 060-0810, Japan
*** Program in Cell Biology, Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206
1 To whom correspondence should be addressed. e-mail: eijimatu{at}md.okayama-u.ac.jp
ß2-glycoprotein I (ß2-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 ß2-GPI specifically binds to Cu2+-oxidized LDL (oxLDL) and that the ß2-GPI ligands are 
-carboxylated 7-ketocholesteryl esters. In the present study, we demonstrate that oxLDL forms stable and nondissociable complexes with ß2-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 -carboxyl function of the ß2-GPI ligands was necessary for ß2-GPI binding. The ligand-mediated noncovalent interaction of ß2-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 ß2-GPI-oxLDL complexes were frequently detected in sera from patients with APS and/or systemic lupus erythematodes. Both the presence of ß2-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 ß2-GPI or LDL.
Thus, the ß2-GPI-oxLDL complexes acting as an autoantigen are closely associated with autoimmune-mediated atherogenesis.
Abbreviations: Ab, antibody; APS, antiphospholipid syndrome; ß2-GPI, ß2-glycoprotein I; oxLDL, oxidized LDL; PL, phospholipid
Supplementary key words antiphospholipid syndrome • arterial thrombosis • autoantibody
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