Circulating oxidized LDL forms complexes with beta2-glycoprotein I: implication as an atherogenic autoantigen.
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.
Kobayashi
Kazuko
K
Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Japan.
Kishi
Makoto
M
Atsumi
Tatsuya
T
Bertolaccini
Maria L
ML
Makino
Hirofumi
H
Sakairi
Nobuo
N
Yamamoto
Itaru
I
Yasuda
Tatsuji
T
Khamashta
Munther A
MA
Hughes
Graham R V
GR
Koike
Takao
T
Voelker
Dennis R
DR
Matsuura
Eiji
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D016736:Antiphospholipid Syndrome / Q000097:blood; D001161:Arteriosclerosis / Q000209:etiology / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000097:blood*; D003300:Copper / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000097:blood* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000097:blood; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D013927:Thrombosis / Q000209:etiology; D053482:beta 2-Glycoprotein I
D001323:Autoantibodies; D001324:Autoantigens; D006023:Glycoproteins; D007074:Immunoglobulin G; D008077:Lipoproteins, LDL; D053482:beta 2-Glycoprotein I; C099252:oxidized low density lipoprotein; D003300:Copper