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

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

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159 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)716-726
Number of pages11
JournalJournal of Lipid Research
Volume44
Issue number4
DOIs
Publication statusPublished - Apr 2003

Keywords

  • Antiphospholipid syndrome
  • Arterial thrombosis
  • Autoantibody

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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    Kobayashi, K., Kishi, M., Atsumi, T., Bertolaccini, M. L., Makino, H., Sakairi, N., Yamamoto, I., Yasuda, T., Khamashta, M. A., Hughes, G. R. V., Koike, T., Voelker, D. R., & Matsuura, E. (2003). Circulating oxidized LDL forms complexes with β 2-glycoprotein I: Implication as an atherogenic autoantigen. Journal of Lipid Research, 44(4), 716-726. https://doi.org/10.1194/jlr.M200329-JLR200