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
Department of Cell Chemistry, Okayama University Graduate School of Medicine and Dentistry, Japan.
J Lipid Res. 2003 Apr;44(4):716-26. doi: 10.1194/jlr.M200329-JLR200. Epub 2003 Jan 16.
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.
β2-糖蛋白I（β2-GPI）是抗磷脂综合征（APS）患者体内抗磷脂抗体（aPL）的主要抗原。我们最近报道（《脂质研究杂志》，42: 697，2001；《脂质研究杂志》，43: 1486，2002）β2-GPI能特异性结合铜离子氧化的低密度脂蛋白（oxLDL），且β2-GPI的配体是ω-羧化的7-酮胆固醇酯。在本研究中，我们证明oxLDL在血清中与β2-GPI形成稳定且不可解离的复合物，并且该复合物的高血清水平与APS中的动脉血栓形成相关。胆固醇7位的共轭酮功能以及β2-GPI配体的ω-羧基功能对于β2-GPI的结合是必需的。在中性pH条件下，β2-GPI与oxLDL的配体介导的非共价相互作用在体外会发生温度和时间依赖性转变，形成更稳定但易于解离的复合物。相比之下，在APS和/或系统性红斑狼疮患者的血清中经常检测到稳定且不可解离的β2-GPI - oxLDL复合物。β2-GPI - oxLDL复合物的存在以及识别这些复合物的IgG抗体都与动脉血栓形成密切相关。此外，这些相同的抗体与含有β2-GPI或LDL的IgG免疫复合物相关。因此，作为自身抗原的β2-GPI - oxLDL复合物与自身免疫介导的动脉粥样硬化密切相关。
