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

Research output: Contribution to journalArticle

155 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

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Autoantigens
Glycoproteins
Antiphospholipid Syndrome
Ligands
Thrombosis
oxidized low density lipoprotein
Immunoglobulin G
Serum
Lipids
Antiphospholipid Antibodies
Antigen-Antibody Complex
Ketones
LDL Lipoproteins
Atherosclerosis
Esters
Cholesterol
Antigens

Keywords

  • Antiphospholipid syndrome
  • Arterial thrombosis
  • Autoantibody

ASJC Scopus subject areas

  • Endocrinology

Cite this

Circulating oxidized LDL forms complexes with β 2-glycoprotein I : Implication as an atherogenic autoantigen. / Kobayashi, Kazuko; Kishi, Makoto; Atsumi, Tatsuya; Bertolaccini, Maria L.; Makino, Hirofumi; Sakairi, Nobuo; Yamamoto, Itaru; Yasuda, Tatsuji; Khamashta, Munther A.; Hughes, Graham R V; Koike, Takao; Voelker, Dennis R.; Matsuura, Eiji.

In: Journal of Lipid Research, Vol. 44, No. 4, 04.2003, p. 716-726.

Research output: Contribution to journalArticle

Kobayashi, K, Kishi, M, Atsumi, T, Bertolaccini, ML, Makino, H, Sakairi, N, Yamamoto, I, Yasuda, T, Khamashta, MA, Hughes, GRV, Koike, T, Voelker, DR & Matsuura, E 2003, 'Circulating oxidized LDL forms complexes with β 2-glycoprotein I: Implication as an atherogenic autoantigen', Journal of Lipid Research, vol. 44, no. 4, pp. 716-726. https://doi.org/10.1194/jlr.M200329-JLR200
Kobayashi, Kazuko ; Kishi, Makoto ; Atsumi, Tatsuya ; Bertolaccini, Maria L. ; Makino, Hirofumi ; Sakairi, Nobuo ; Yamamoto, Itaru ; Yasuda, Tatsuji ; Khamashta, Munther A. ; Hughes, Graham R V ; Koike, Takao ; Voelker, Dennis R. ; Matsuura, Eiji. / Circulating oxidized LDL forms complexes with β 2-glycoprotein I : Implication as an atherogenic autoantigen. In: Journal of Lipid Research. 2003 ; Vol. 44, No. 4. pp. 716-726.
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AU - Kishi, Makoto

AU - Atsumi, Tatsuya

AU - Bertolaccini, Maria L.

AU - Makino, Hirofumi

AU - Sakairi, Nobuo

AU - Yamamoto, Itaru

AU - Yasuda, Tatsuji

AU - Khamashta, Munther A.

AU - Hughes, Graham R V

AU - Koike, Takao

AU - Voelker, Dennis R.

AU - Matsuura, Eiji

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N2 - 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.

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