Circulating oxidized LDL forms complexes with β2-glycoprotein I: implication as an atherogenic autoantigen

Abstract

␤ 2 -glycoprotein I ( ␤ 2 -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 ␤ 2 -GPI specifically binds to Cu 2 ؉ -oxidized LDL (oxLDL) and that the ␤ 2 -GPI ligands are -carboxylated 7-ketocholesteryl esters. In the present study, we demonstrate that oxLDL forms stable and nondissociable complexes with ␤ 2 -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 ␤ 2 -GPI ligands was necessary for ␤ 2 -GPI binding. The ligand-mediated noncovalent interaction of ␤ 2 -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 ␤ 2 -GPI-oxLDL complexes were frequently detected in sera from patients with APS and/or systemic lupus erythematodes. Both the presence of ␤ 2 -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 ␤ 2 -GPI or LDL. Thus, the ␤ 2 -GPI-oxLDL complexes acting as an autoantigen are closely associated with autoimmune-mediated atherogene-

Adrenomedullin 2 Improves Early Obesity-Induced Adipose Insulin Resistance by Inhibiting the Class II MHC in Adipocytes

“…MHCII is believed to present exogenous antigens, but nearly 20-30% of antigens presented by APCs in a MHCII-dependent manner are self-antigens (38). Previous results showed that in atherosclerosis heat shock protein 60, oxidized LDL and b2-glycoprotein I act as self-antigens (39)(40)(41). During the onset of adipose expansion in obesity, oxidative stress and endoplasmic reticulum stress induce the generation of lipid-binding protein, oxidative modified protein, and misfolded protein, which might be the self-antigen to MHCII.…”

Freqüência de síndrome metabólica em pacientes com nefrite lúpica

“…(37) , a incidência de IAM não-fatal foi dez vezes maior do que a esperada de acordo com a escala de Framingham, a de morte por DAC foi 17 vezes maior e a de acidente vascular encefálico teve aumento próximo de oito vezes. Com efeito, outros autores têm evidenciado novos fatores diretamente relacionados à inflamação sistêmica e possivelmente implicados no mecanismo de aterogênese acelerada, como a ativação do sistema complemento, inibição da lipoproteína lipase pela IL-6 (8) , anticorpos anti-HDL e anti-Ox LDL (10) , além da presença dos anticorpos antifosfolipídicos, que foram associados à reatividade cruzada com anti-HDL e anti-ApoA1, anti-OxLDL e à formação de complexos β2GP1-OxLDL (11,40,41) . Outros trabalhos estabeleceram relações entre doença cardiovascular e manifestações de atividade de doença, como pericardite (41) , vasculite digital (6) , aumento da VHS e da PCR (4) e leucopenia ou com escores mais elevados de SLICC (42) .…”

Antiphospholipid Syndrome - An Evolving Story of a Multisystemic Disease

“…The role that apoptosis plays in the exposure of these phospholipids on the cell surface and the subsequent interaction with  2 GPI has been proposed as a possible mechanism for the production of pathogenic aPL in APS patients [30]. An interesting pathogenic role for oxidized low-density lipoprotein (ox-LDL)/ 2 GPI complexes bound by aPL in the initiation and progression of atherogenesis has been described [31,32].…”