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Abnormalities of the lipid profile partly explain the atherogenic tendency of systemic lupus erythematosus but the picture is unclear in thrombotic primary antiphospholipid syndrome (PAPS). Herein we compare the lipid profile, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (CHO), apolipoprotein A (ApoA-I), apolipoprotein B (ApoB), tryglicerides (TRY)), anti-lipoprotein antibodies, beta-2-glycoprotein I complexed to oxidized low-density lipoprotein (oxLDL-β2GPI) and C-reactive protein (CRP) from thrombotic PAPS (n=34), thrombotic patients with inherited thrombophilia (IT; n=36), subjects persistently positive for antiphospholipid antibodies (aPL, n=18) with no underlying autoimmune or non-autoimmune disorders and healthy controls (n=28) and determined the reciprocal effects of anti-lipoprotein antibodies, the lipid profile, oxLDL-β2GPI and CRP. Average concentrations of HDL (p<0.0001), LDL (p<0.0001), CHO (p=0.0002), ApoA-I (p=0.002) were lower in PAPS whereas average TRY was higher (p=0.01) than other groups. Moreover, the aPL and PAPS group showed higher levels of IgG anti-HDL (p=0.01) and IgG anti-ApoA-I (p<0.0001) whereas the PAPS group showed greater average oxLDL-β2GPI (p=0.001) and CRP (p=0.003). Within the PAPS group, IgG anti-HDL correlated negatively to HDL (p=0.004) and was an independent predictor of oxLDL-β2GPI (p=0.009). HDL and ApoA-I correlated negatively with CRP (p=0.001 and p=0.007, respectively). IgG anti-HDL may hamper the antioxidant and anti-inflammatory effect of HDL favoring low-grade inflammation and enhanced oxidation in thrombotic PAPS. [ABSTRACT FROM AUTHOR]

Since β2-glycoprotein I (β2GPI) was described as the major antigenic target for antiphospholipid antibodies, many studies have focused their attention to the physiological role of β2GPI and anti-β2GPI antibodies on autoimmune-mediated thrombosis. Studies reporting the physiological role of β2GPI have been numerous, but the exact mechanism of action(s) has yet to be completely determined. β2GPI's epitopes for anti-β2GPI autoantibodies have been characterized, however, not all of the heterogeneous anti-β2GPI antibodies are pathogenic. The pathophysiologic role of β2GPI has been reported in the fields of coagulation, fibrinolysis, angiogenesis, and atherosclerosis. Our understanding of the impact of β2GPI, its metabolites and autoantibodies to β2GPI on these physiological functions may contribute to the development of better therapeutic strategies to treat and prevent autoimmune-mediated atherothrombotic vascular disease. [ABSTRACT FROM AUTHOR]

Helicobacter pylori (H. pylori) is a predominant pathogen that causes not only gastroduodenal diseases but also extra-alimentary tract diseases. In this study, we demonstrated that H. pylori infection promoted atherogenesis in heterozygous apoe+/- ldlr+/- mice. The male mice were fed with high fat diet from the age of 6 weeks. At the age of 16 weeks, development of atherosclerotic lesions was observed in the H. pylori-infected mice, and it seemed to be associated with an elevation of Th1-immune response against H. pylori origin-heat shock protein 60 (Hp-HSP60) and an increment of transendothelial migration of T cells. Subcutaneous immunisation with Hp-HSP60 or H. pylori eradication with antibiotics significantly reduced the progression of atherosclerosis, accompanied by a decline of Th1 differentiation and reduction of their chemotaxis beyond the endothelium. Thus, oral infection with H. pylori accelerates atherosclerosis in mice and the active immunisation with Hp-HSP60 or the eradication of H. pylori with antibiotics can moderate/prevent cellular immunity, resulting in a reduction of atherosclerosis. [ABSTRACT FROM AUTHOR]

Autoimmune vascular inflammation and oxidative stress (lipid peroxidation) are common in systemic autoimmune diseases and contribute to the oxidative modification of low-density lipoprotein (oxLDL) and oxLDL/β2GP1 complex formation. Circulating 0xLDL/β2GP1 complexes have been detected in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). The presence of antibodies to oxLDL/β2GP1 complexes indicates that these complexes are immunogenic, and the coexistence of complexes and antibodies has pointed to an active proatherogenic role in the development of autoimmune vascular complications. Immunohistochemical staining of atherosclerotic lesions suggest that these complexes are formed in the arterial wall and released into circulation. The in vitro macrophage uptake of oxLDL/β2GP1 complexes was significantly increased in the presence of antiphospholipid antibodies, either β2GP1-dependent anticardiolipin or anti-β2GP1 antibodies, suggesting that macrophage Fcy receptors are involved in lipid intracellular influx and foam cell formation. These findingγs provide an explanation for the accelerated development of atherosclerosis seen in SLE and APS. The presence of circulating oxLDL/ β2GP1 complexes and IgG antibodies to these complexes indicate significant vascular injury and oxidative stress as well as an active role in autoimmune-mediated atherothrombosis. [ABSTRACT FROM AUTHOR]

Several interpretations have been made regarding the specificity of antiphospholipid antibodies and antibodies against oxidized low-density lipoprotein (oxLDL), but these are still controversial. In the present study, we delineated specificity of these two types of antibodies and analyzed their regulatory effect on oxLDL and/or β2-glycoprotein I (β2GPI) binding to macrophages. Scavenger receptormediated binding of oxLDL (or its β2GPI complexes) to macrophages was observed and the binding was partly prevented by β2GPI. The IgG monoclonal anti-β2GPI antibody (WB-CAL-1), which was derived from NZW X BXSB F1 mouse (a model of antiphospholipid syndrome), significantly increased the oxLDL/β2GPI binding to macrophages. In contrast, IgM anti-oxLDL natural antibody, EO6 (derived from apoe-/- mouse), prevented the binding. Different antigenic specificity of these antibodies to oxLDL and its β2GPI complexes was also confirmed in TLC-ligand blot and ELISA. Thus, IgG anti-β2GPI autoantibodies contribute to lipid metabolism (housekeeping of oxLDL by macrophages) whereas IgM natural anti-oxLDL antibodies may protect against atherogenesis. In addition, in vitro data suggest that relatively high dose of intravenous immunoglobulin preparations (mainly contain IgG anti-oxLDL antibodies) might also prevent atherogenesis by inhibiting the oxLDL binding to macrophages. [ABSTRACT FROM AUTHOR]

Oxidative stress and LDL modification (oxLDL) are early pro-atherogenic events. OxLDL binds β2GPI producing immunogenic oxLDL/β2GPI complexes. Antibodies to these complexes have been associated with arterial thrombosis in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Circulating oxLDL/β2GPI complexes, IgG and IgM antibodies to these complexes were measured by ELISA in 30 SLE patients asymptomatic for cardiovascular disease (mean age 31 years) and 27 age/sex matched healthy controls. Carotid intima-media thickness (IMT) was measured by ultrasound in all patients and controls. Forty-seven percent of SLE presented plaques (median IMT of 0.65 ± 0.12 mm) while only 7% of the controls had plaques (median IMT of 0.50 ± 0.04 mm, P < 0.001). Median optical density (OD450 nm) for oxLDL/β2GPI complexes in SLE was 0.244 ± 0.07, higher than controls (0.174 ± 0.09, P < 0.001). Median OD for IgG anti-oxLDL/β2GPI antibodies was also higher in SLE (0.297 ± 0.26) compared to controls (0.194 ± 0.07, P < 0.001) while the median OD for IgM antibodies in SLE (0.444 ± 0.46) was not different than controls (0.326 ± 0.22, P < 0.267). There was no correlation between IMT and oxLDL/β2GPI complexes, IgG or IgM antibodies, possibly reflecting the complex interrelationship between these serologic elements and tissue factors in the arterial wall. These results support the hypothesis that oxLDL/β2GPI complexes and IgG (not IgM) anti-oxLDL/β2GPI antibodies contribute to the development of autoimmune-mediated atherosclerosis [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate a possible association between lymphocyte subsets and intima media thickness (IMT) of carotid arteries in primary antiphospholipid syndrome (PAPS). We used a cross-sectional study on PAPS patients (n = 18) and healthy controls (n = 16). IgG anti-cardiolipin antibody (aCL), IgG anti-β2glycoprotein-I (anti-β2GPI), IgG anti-β2glycoprotein-I complexed to oxidized low-density lipoprotein (oxLDL) and to a specific oxidized moiety of LDL (oxLig1), and β2GPI-oxLDL were measured by ELISA. Lymphocyte immunophenotyping was performed using pairs of monoclonal antibodies directly labelled with fluorescein isothiocyanate, or phycoerythrin or phycoerythrin-Texas-red-X. Intima media thickness (IMT) of carotid arteries was determined by high-resolution sonography. Total peripheral blood lymphocytes did not differ between PAPS and controls. Memory CD4+/CD45RO + T cells were lower in PAPS than controls (P = 0.0007) as well as CD16+ 56+ natural killer cells (P = 0.02). In PAPS memory T CD45RO + cells positively correlated with IgG anti-β2GPI-oxLig1 (P = 0.002) and to IMT of carotid arteries (common carotid P = 0.02, bifurcation P = 0.007). Naïve CD4+/CD45RA+ T cells inversely correlated with β2GPI-oxLDL (P = 0.009). The relation between IgG anti-β2GPI-oxLig1 and IMT of carotid arteries with memory CD45RO + T lymphocytes suggests a role for the latter in PAPS related atherogenesis. [ABSTRACT FROM AUTHOR]

β2-glycoprotein I (β2GPI) is a major antigenic target for antiphospholipid antibodies. Oxidized low-density lipoprotein (oxLDL) is the principal lipoprotein found in atherosclerotic lesions, and it colocalizes with β2GPI and immunoreactive lymphocytes. oxLDL/β2GPI complexes appeared in the blood circulation of patients with diseases, such as systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), systemic sclerosis, diabetes mellitus and chronic renal diseases. Thus, the complexes may be associated with systemic and chronic inflammation of the vasculature. IgG anti-oxLDL/β2GPI complexes autoantibodies and their immune complexes were detected only in SLE/APS patients and in its animal model and were strongly associated with arterial thrombosis. The oxLDL/β2GPI complexes were internalized by macrophages via IgG anti-β2GPI antibody-mediated phagocytosis. In contrast, IgM anti-oxLDL antibodies derived from hyperlipidemic mice reduced the incidence of atherosclerosis. The distribution patterns of IgG and IgM anti-oxLDL antibodies in patients suggest the different roles of these antibodies. [ABSTRACT FROM AUTHOR]

β2-Glycoprotein I (β2-GPI) is a major antigen for anticardiolipin antibodies (aCL, Abs) present in patients with antiphospholipid syndrome (APS). We recently reported that oxidized LDL (oxLDL) is subsequently targeted by β2-GPI and anti-β2-GPI auto-Abs and that ω-carboxyl variants of 7-ketocholesteryl esters, such as 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and 7-ketocholesteryl-12-carboxy (keto) octadodecanoate (oxLig-2), are ligands for β2-GPI (J Lipid Res 2001; 42: 697; J Lipid Res 2002; 43: 1486). These β2-GPI ligands provide an electrostatic interaction between oxLDL and β2-GPI followed by forming stable complexes (such as Schiff base adducts). The ω-carboxyl function in these ligands is responsible for β2-GPI binding to oxLDL and the oxLDL-β2-GPI complexes are anti-β2-GPI auto-Ab-dependently taken up by macrophages (i.e., by phagocytosis). Our recent observations are consistent with the evidence that β2-GPI co-localizes with lymphocytes and mononuclear cells in human athero-plaques. Thus, autoimmune thrombogenesis (atherogenesis) is linked to interaction of anti-β2-GPI Abs with the β2-GPI-oxLDL complexes. We propose an alternative idea, that an immune response against the β2-GPI-oxLDL complexes may be involved in mechanisms in the development of atherosclerosis, which has been explained by the theory of 'the response to injury'. [ABSTRACT FROM AUTHOR]

Examines the possible involvement of auto-antibodies against anti-beta2- glycoprotein in accelerated atherosclerosis. Serological reactivity of antiphospholipid antibodies and anti-beta2-glycoprotein I antibodies; Biological nature and antigenicity of beta2-glycoprotein I; Oxidative modification of low density lipoproteins.

Anticardiolipin antibodies (aCL) were found to recognize β2glycoprotein I (β2GPI) structure altered by its interaction with an oxygen modified solid phase surface by γ-ray radiation. Lupus anticoagulant (LA) has been reported to comprise anti prothrombin antibodies, anti factor X antibodies and anti β2GPI antibodies. The present study focuses on the possible association between antibodies against the altered β2GPI structure (anti β2GPI antibodies) and LA in patients with recurrent pregnancy loss. Moreover, the clinical significance of both subgroups of so-called antiphospholipid antibodies were investigated to cast light on the controversy of whether aCL and LA are risk factors for pregnancy losses.One hundred and ninety five women with a history of two or more unexplained consecutive miscarriages and 100 control pregnant women were tested. Lupus anticoagulant was detected by the dilute phospholipid activated partial thromboplastin time. Anti β2GPI antibodies were measured by the ELISA method using commercially oxygenated microtiter plates.Twenty two (11.3%) and 19 (9.7%) of the 195 recurrent aborters were, respectively, positive for LA and anti β2GPI antibodies. Seven (3.6%) of the aborters had both of them. None of the control pregnant women had LA. Three of the control pregnant women had anti β2GPI antibodies.Nine (40.9%) of 22 aborters with positive-LA had a history of miscarriages in the second trimester as compared to 8 (4.6%) of 173 aborters with negative-LA. (P = 0.000007, Odds ratio = 14.3). None of the 12 aborters with anti β2GPI antibodies but no LA had a history of second trimester-fetal loss.These results support the hypothesis that aCL and LA define two distinct but partly related populations and that aCL include two subtypes of antibodies, with and without LA activity. LA and anti β2GPI antibodies appear to be associated with pregnancy loss, with LA being linked not only to abortions in the first trimester but also to miscarriages in the second trimester. [ABSTRACT FROM PUBLISHER]

We investigated the clinical significance of IgG phospholipid-dependent anti-β2-glycoprotein I (β2-GPI) antibodies in patients with SLE. The study population consisted of 140 patients with SLE. Sera were examined for IgG phospholipid-dependent anti-β2-GPI antibodies by ELISA. IgG phospholipid-dependent anti-β2-GPI antibodies were detected in 21 of 140 patients (15%) and remained positive from 4 to 98 months. Significantly higher incidences of thrombosis, intrauterine fetal loss, thrombocytopenia, patients with antiphospholipid syndrome (APS), prolonged APTT, BFP-STS and hemolytic anemia were found in SLE patients with phospholipid-dependent anti-β2-GPI antibodies. Moreover, significantly lower incidences of malar rash and serositis were found in SLE patients with phospholipid-dependent anti-β2-GPI antibodies, and the majority of these patients satisfied four or five of the revised criteria items of the American Rheumatism Association. These differences were not observed when we compared clinical manifestations in anticardiolipin antibody-positive patients with those in antibody-negative patients by conventional ELISA. These results indicated that SLE patients with IgG phospholipid-dependent anti-β2-GPI antibodies show an unique form of SLE. [ABSTRACT FROM PUBLISHER]

Cardiolipin binding of IgG-class anticardiolipin antibody (aCL) depends on the existence of β2-glycoprotein I (β2-GPI). We developed an EIA system that enables detection of antibodies against β2-GPI, without the presence of cardiolipin. This system involves use of irradiated polystyrene plates, in which oxygen atoms are introduced onto the surfaces of the plates. β2-GPI bound to the surface of these plates is assumed to undergo a conformational change that exposes normally cryptic epitopes. Anti-β2-GPI antibody measured using this EIA system showed good correlation with aCL measured by conventional EIA methods and may prove useful in evaluating the risk of thrombosis and monitoring the clinical course in patients with SLE. Utilizing this EIA system and β2-GPI-deleted mutants, we found that the fourth domain of β2-GPI is involved in expression of one of the cryptic epitopes recognized by aCL. We also found that oxidized LDL are sequentially targeted by β2-GPI and aCL. [ABSTRACT FROM PUBLISHER]

A case report of Klinefelter's syndrome is presented that shows features of systemic lupus erythematosus, arteriographically-proven peripheral artery occlusion with leg ulcers, multiple cerebral infarcts and persistent elevations of anticardiolipin antibodies. [ABSTRACT FROM PUBLISHER]

β2-Glycoprotein I (β2-GPI) is a major antigen for anticardiolipin antibodies (aCL) induced in patients with antiphospholipid syndrome and their antigenic epitopes are cryptic. The epitopes appear on the surface of β2-GPI molecule only when β2-GPI interacts with lipid membranes containing negatively charged phospholipids or polyoxygenated polystyrene surface. Our data also indicated that CuSO4-oxidized low density lipoproteins (oxLDL) are subsequently targeted by β2- GPI and aCL; however, malonedialdehyde (MDA)-modified LDL were recognized neither by β2- GPI nor aCL. β2-GPI binding to LDL was rapidly increased by incubation with CuSO4. Oxidation of lipoproteins was accompanied with the increment of thiobarbituric acid-reactive substances (TBARS) and denature of apolipoprotein. Ligands on LDL for β2-GPI seemed to be intermediate oxidative derivatives which were extractable into the chloroform phase by Bligh and Dyer's extraction, but not MDA. Further, immune responses against β2-GPI, as an anti-atherogenic protein, were demonstrated to induce atherogenic effect in in vitro oxLDL uptake by macrophages. [ABSTRACT FROM PUBLISHER]

The relationship between presence of anti-β2-glycoprotein I autoantibodies (aβ 2-GPI) and history of thrombosis is now widely known. However, differences in the methodology of aβ2-GPI detection have made the comparison of data from different laboratories extremely difficult. We discuss the significance of aβ2-GPI of the IgG, IgM and IgA isotypes, and our approach to developing an easier and more reproducible method for the detection of this autoantibody. In addition, we present data that shows that commercially available enzyme immunoassay plates differ regarding detectability of aβ 2-GPI. Since the clinical significance of this heterogeneity is presently unclear, the set-up of the detection systems and interpretation of data need great care. [ABSTRACT FROM PUBLISHER]

Anticardiolipin antibodies (aCL) found in sera from patients with antiphospholipid syndrome recognize a cryptic epitope that appears on the β2-glycoprotein I (β2-GPI) molecule when β2-GPI interacts with a lipid membrane composed of negatively charged phospholipid or when β2-GPI is adsorbed on a polyoxygenated polystyrene plate. A homology based model of β2-GPI was constructed based on the NMR coordinates of sushi domains of human factor H. The conformation was like a cylinder consisting of five domains, its IV and V domains being glued by electrostatic interaction. We used phage-displayed random peptide libraries to search the epitopes of human aCL. Structures similar to consensus sequences selected by a biopanning method was found on domain IV of β2-GPI. [ABSTRACT FROM PUBLISHER]