Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02749 (beta2-glycoprotein I)
 836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the antiphospholipid syndrome (APS), pathogenic antiphospholipid antibodies (aPL) that cause thrombosis or pregnancy morbidity are characterized by binding to anionic phospholipids (PL) and beta2-glycoprotein I (beta(2)GPI). Sequence analysis of human monoclonal aPL has shown that high affinity for these antigens is associated with the presence of three particular amino acids: arginine (Arg), asparagine and lysine in the complementarity determining regions (CDRs) of their heavy and light chains. In vitro expression systems have been used to create variants of the antibodies in which these amino acids have been altered. In general, removal of Arg residues reduces affinity for anionic PL and beta(2)GPI. Arg at different positions in the sequence, however, have different effects on binding affinity and effects on binding are not always mirrored by effects on pathogenicity. This review will focus upon the sequence motifs that have been found to distinguish pathogenic from non-pathogenic aPL, and whether these or other properties may help to identify distinct pathogenic subsets of aPL. In particular, we will focus on our recent work in which we are trying to develop a better understanding of the molecular mechanisms involved in activation of target cells by pathogenic aPL. These studies, together with molecular models of antigen/antibody complexes, help us to understand exactly how pathogenic antibodies interact with antigens. Ultimately, this understanding may aid the design of more powerful diagnostic/prognostic assays and targeted therapeutic agents to block the pathogenic effects of these antibodies.
Lupus 2008 Oct
PMID:Examining the non-linear relationship between monoclonal antiphospholipid antibody sequence, structure and function. 1882 54

Lupus anticoagulants (LAC) consist of antiphospholipid antibodies, detected via their anticoagulant properties in vitro. Strong LAC relate to thromboembolic events, a hallmark of the antiphospholipid syndrome. We have analyzed whether detection of this syndrome would benefit from thrombin generation measurements. Therefore, calibrated automated thrombography was done in normal plasma (n = 30) and LAC patient plasma (n = 48 non-anticoagulated, n = 12 on oral anticoagulants), diluted 1:1 with a normal plasma pool. The anti-beta2-glycoprotein I monoclonal antibody 23H9, with known LAC properties, delayed the lag time and reduced the peak height during thrombin generation induction in normal plasma dose-dependently (0-150 microg/ml). At variance, LAC patient 1:1 plasma mixtures manifested variable lag time prolongations and/or peak height reductions. Coupling these two most informative thrombin generation parameters in a peak height/lag time ratio, and upon normalization versus the normal plasma pool, this ratio distributed normally and was reduced in the plasma mixtures, for 59/60 known LAC plasmas. The normalized peak height/lag time ratio correlated well with the normalized dilute prothrombin time, diluted Russell's viper venom time and silica clotting time, measured in 1:1 plasma mixtures (correlation coefficients 0.59-0.72). The anticoagulant effects of activated protein C (0-7.5 nM) or 23H9 (0-150 microg/ml), spiked in the 1:1 LAC plasma mixtures were reduced for the majority of patients, compatible with functional competition between patient LAC and activated protein C and LAC and 23H9, respectively. Hence, the normalized thrombin generation-derived peak height/lag time ratio identifies LAC in plasma with high sensitivity in a single assay, irrespective of the patient's treatment with oral anticoagulants.
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PMID:Laboratory detection of the antiphospholipid syndrome via calibrated automated thrombography. 1913 7

Thrombosis is a frequent finding in cancer patients, being referred to as a poor prognostic factor. The mechanisms underlying the thrombophilic state in malignancy are not well elucidated but involve a complex interaction between tumor and host cells as well as the hemostatic system. A number of studies have demonstrated the presence of antiphospholipid antibodies (aPL) in cancer patients, suggesting a potential role in tumor-associated thrombosis. A prospective analysis has been performed in a group of lung adenocarcinoma patients in respect to the presence of aPL and thrombotic manifestations. Lupus anticoagulant (LAC) was identified in 61 out of 105 patients and it correlated highly with thrombosis (22/61, LAC positive vs 2/44, LAC negative RR=7.93; p<0.001). On the other hand, patients that displayed IgM anti-beta2-glycoprotein I (abeta2GPI) (22/80) showed an unexpected decrease in thrombosis risk (2/22, with IgM abeta2GPI vs 18/58, without IgM abeta2GPI RR=0.29; p=0.04). Considerations on the mechanisms that link cancer, thrombosis and aPL are discussed in this article.
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PMID:Lung adenocarcinoma and antiphospholipid antibodies. 1918 19

Atherosclerosis is an inflammatory disease, leading to the formation of pro-inflammatory and pro-oxidative lipids that generate an immune response. Several antigens have been shown to activate the immune response and affect the development of atherogenesis. Systemic lupus erythematosus is an autoimmune and inflammatory disease strongly associated with premature development of atherosclerotic plaques. Modulation of the immune system could represent a useful approach to prevent and/or treat atherosclerosis. A vaccination-based approach might be a useful, effective tool in the modern arsenal of cardiovascular therapies and could be used on a large scale at a low cost. In non-systemic lupus erythematosus populations, vaccines against oxidized low-density lipoprotein, beta-2-glycoprotein I, heat shock proteins, lipoproteins, cholesterol, molecules involved in cholesterol metabolism, and other molecules (CD99, vascular endothelial growth factor-receptor, and interleukin-2) have been tested, with promising results. However, there are no studies of vaccination against atherosclerosis in systemic lupus erythematosus.
Lupus 2009 Nov
PMID:Vaccination, atherosclerosis and systemic lupus erythematosus. 1988 May 70

beta2-glycoprotein I is the best-characterized antigenic target for antiphospholipid autoantibodies. We synthesized a tetrameric conjugate of the domain 1 of beta2-glycoprotein I (LJP 993) aimed at developing the conjugate as a Toleragen to suppress antiphospholipid syndrome. The present studies focused on determining the stability, tissue distribution, plasma concentration-time profile and excretion of the LJP 993 in mice. The stability of LJP 993 in mouse plasma was quantitatively evaluated using strong cation-exchange high performance liquid chromatography. ( 125)I-labeled LJP 993 was intravenously injected to mice, and levels of (125)I-labeled LJP 993 in plasma, tissues, urine and feces were determined at known intervals. Incubation of LJP 993 with mouse serum at 37 degrees C for 8 h resulted in a decrease by 34% of LJP 993 concentration. No degradation fragment was observed during the incubation. After a single intravenous administration of (125)I-LJP 993 (0.5 and 5 mg/kg) to mice, both C(max) and area-under-curve values increased in a dose-proportional manner, and blood radioactivity disappeared in a bi-exponential manner with the distribution half-lives equal to 1.7 min, and the elimination half-lives 188 and 281 min, respectively. The (125)I-LJP 993 was moderately distributed into organs and tissues with the exception that brain level of ( 125)I-LJP 993 was negligible. The major sites of (125)I-LJP 993 uptake were the kidney (at 30 min post dosing), and kidney, lung, liver, heart, spleen, skin, muscle and fat tissues (at 4 h post dosing). Cumulative urinary and fecal radioactivity for 0-48 h post dosing accounted for 44.7% and 4.2% of the administered dose, respectively, with the fast rate of urinal excretion occurring within the first 8 h. In summary, LJP 993 was fairly stable in mouse plasma. After administration to mice, (125)I-LJP 993 was taken up mainly by kidney and then distributed extensively to tissues except brain. Both C(max) and area-under-curve values increased in a dose-proportional manner. It was predominantly excreted in the urine with an elimination half-life longer than 3 h. Kidney is a major route to excrete the tetrameric conjugate.
Lupus 2010 Feb
PMID:Pharmacokinetics of LJP 993, a tetrameric conjugate of domain 1 of beta2-glycoprotein I for antiphospholipid syndrome. 1991 73

Lupus anticoagulants (LACs) are associated with thromboembolic complications (TECs). LACs can be detected by their anticoagulant properties in thrombin generation assays, by the peak height (PH) and lag time (LT). To assess the thrombotic risk in LAC-positive patients, we have expressed the LAC activity quantitatively by PH/LT calibration curves, constructed for mixtures of monoclonal antibodies against beta2-glycoprotein I (beta2GPI) and prothrombin, spiked in normal plasma. PH/LT was determined in LAC patients, with (n = 38) and without (n = 21) TECs and converted into arbitrary LAC units. LAC titers ranged from 0 to 200 AU/mL, with 5 of 59 patients being negative. In the positive LAC titer population (54 of 59), LAC and anti-beta2GPI immunoglobulin G (IgG) titers correlated with TECs, with odds ratios of 3.54 (95% CI, 1.0-1.7) and 10.0 (95% CI, 1.98-50.6), respectively. In patients with single or combined low titers, useful predictions on thrombosis could be made only after additional measurements of soluble P-selectin and factor VII. This layered strategy yielded positive and negative predictive values, sensitivity, and specificity values approximately 90% in this subgroup. Hence, LAC and anti-beta2GPI IgG titers, when combined with selected markers of the hypercoagulable state, allow a relevant thrombotic risk assessment in nearly all patients with LACs.
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PMID:Thrombotic risk assessment in the antiphospholipid syndrome requires more than the quantification of lupus anticoagulants. 1996 29

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), triglycerides (TRY)), anti-lipoprotein antibodies, beta-2-glycoprotein I complexed to oxidized low-density lipoprotein (oxLDL-ss(2)GPI) 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-ss(2)GPI 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-ss(2)GPI (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-ss2GPI (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.
Lupus 2010 May
PMID:High-density lipoprotein inversely relates to its specific autoantibody favoring oxidation in thrombotic primary antiphospholipid syndrome. 2006 10

Antiphospholipid syndrome (APS) is defined as a combination of antiphospholipid antibodies, arterial and/or venous thrombosis, and, in women, recurrent fetal loss. The mechanisms underlying this prothrombotic tendency are unclear. Here we determined plasma levels of the angiogenic growth factors vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and stromal cell-derived factor-1 (SDF-1) in 34 patients with APS (median age 40 years) compared with 180 healthy controls and with 80 age-matched deep-venous thrombosis patients in whom the diagnosis of APS had been excluded. All of the patients met updated APS criteria and two-thirds of them were triply positive for antiphospholipid antibodies (lupus anticoagulant, anti-beta2-glycoprotein I and anti-cardiolipin antibodies). Angiogenic cytokines were quantified at least 6 months after an acute thrombotic event. VEGF levels were similar in the patients and controls, but were significantly higher in the patients with arterial thrombosis than in the patients with venous thrombosis. Plasma levels of SDF-1 and PlGF were significantly elevated in the patients, regardless of the arterial/venous nature of the thrombosis. Together, these results suggest that APS is associated with an angiogenic process, but that the angiogenic signal differs between patients with arterial and venous thrombosis. Lupus (2010) 19, 837-843.
Lupus 2010 Jun
PMID:Arterial and venous thrombosis is associated with different angiogenic cytokine patterns in patients with antiphospholipid syndrome. 2013 49

Antiphospholipid syndrome (APS) represents one of the most common acquired causes of thrombophilia and recurrent miscarriages. The only treatment of proven benefit is anticoagulation, often required at high intensity and life-long duration. This therapy can be associated with side effects such as bleeding and is not always effective. Hence, there remains a need for safer, targeted and ideally more effective therapies. Antiphospholipid antibodies (aPL) are pathogenic and promote thrombosis. Independent groups, including our own, have show that the major epitopes that pathogenic aPL targets lie within domain I of the protein beta2-glycoprotein I (beta2GPI). This review focuses on the evidence presented thus far which characterizes the immunodominant epitopes within domain I, demonstrating that the epitope is a conformational one centred around residues R39-G43 and also involving other residues within domain I, such as residues D8 and D9. The hypothesis is proposed that a recombinant domain I molecule, and a recombinant mutant domain I with enhanced aPL binding properties, may be used as an inhibitor of aPL binding and thus inhibit aPL-induced pathogenicity. In vivo proof-of-concept studies within the murine femoral vein injury model are presented supporting this hypothesis, and the rationale as well as potential benefits and problems of employing such an approach to treat APS are discussed.
Lupus 2010 Apr
PMID:Domain I of beta2-glycoprotein I: its role as an epitope and the potential to be developed as a specific target for the treatment of the antiphospholipid syndrome. 2035 77

Lupus anticoagulants (LAC) are antibodies which are detected by a prolongation of phospholipid-dependent coagulation assays, and are associated with thrombotic events and pregnancy complications in patients with the antiphospholipid syndrome. The antiphospholipid syndrome is defined by arterial or venous thrombosis and/or pregnancy morbidity and by laboratory diagnosis of antiphospholipid antibodies. The laboratory diagnosis is based on LAC and/or anticardiolipin and/or anti-beta2-glycoprotein I antibodies present in plasma, on two or more occasions at least 12 weeks apart. ALthough the presence of LAC correlates best with thrombosis, the Laboratory testing of LAC is not well standardized. In this article, the Laboratory evaluation of LAC will be explained, including the different tests that are recommended by the Israeli Sub-committee of Thrombosis and Hemostasis Laboratories, the possibility to evaluate LAC in patients treated with antithrombotic therapy, and how to report and interpret the results.
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PMID:[Laboratory evaluation of lupus anticoagulant in Israel]. 2094 71


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