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)

Autoantibodies to beta2-glycoprotein I (beta2GPI) are believed to be the primary cause of coagulation abnormalities in patients with antiphospholipid syndrome (APS). Clinical features include a range of life-threatening thrombotic events and microangiopathies affecting multiple organ systems. Current standard of care relies on long-term, high-intensity anticoagulation and is associated with a high risk for serious bleeding events. The relation between autoantibodies and the pathophysiology of APS is not clearly understood, but numerous in vitro studies have characterized the effects of antiphospholipid autoantibodies on various components of the coagulation cascade, including tissue factor and the protein C pathway. The fine specificity of autoantibodies to beta2GPI is a subject of considerable debate; however, a body of evidence may offer resolution by integrating concepts of antibody affinity and assay sensitivity with carefully designed molecular studies. An investigational new therapy for APS is based on the approach that pathogenic antibodies may be reduced via depletion of circulating autoantibodies and induction of immune tolerance at the B-cell level. Preliminary results from a phase I/II clinical trial with LJP 1082, a B-cell toleragen, indicate the drug was well tolerated and may warrant further development for reduction of thrombotic events in patients with APS.
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PMID:Therapeutic potential of toleragens in the management of antiphospholipid syndrome. 1537 72

Antiphospholipid antibodies detected by lupus anticoagulant, anticardiolipin or anti-beta2 glycoprotein I assays were associated with fetal loss. Rather than being diagnostic tools only, antiphospholipid antibodies are thought to be pathogenic. The strongest demonstration of their pathogenic role lies in the ability to induce fetal resorptions--the experimental equivalents of the human fetal losses--when passively infused in pregnant naive animals. However, still debated is how the antibodies might induce the obstetrical manifestations. Thrombotic events at the placental levels might be related to endothelial cell activation, inhibition of protein C/S system and fibrinolysis as well as to Annexin V displacement. However, the thrombophilic state apparently cannot explain all the miscarriages and a direct antibody-mediated damage on the trophoblast has been suggested. During differentiation to syncytium, trophoblasts express cell membrane anionic phospholipids that can bind beta2 glycoprotein I, the main cationic phospholipid binding protein recognized by the antiphospholipid antibodies. Adhered beta2-glycoprotein I might be recognized by the antibodies that, once bound, strongly interfere with in vitro trophoblast cell maturation so resulting in a defective placentation. These mechanisms have been suggested to play a role in early fetal loss, while thrombotic events would be responsible for miscarriages late in the pregnancy.
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PMID:Antiphospholipid antibodies as cause of pregnancy loss. 1548 95

Thrombophilia can be defined as an increased tendency to thrombosis. There are several defined risk factors for thrombosis, and these are generally separated into acquired and congenital factors. Congenital risk factors include deficiencies or defects in natural anticoagulants, such as antithrombin, protein C and protein S, and genetic polymorphisms such as prothrombin G20210A and the cleavage-resistant factor mutation, factor V Leiden, which leads to a condition known as activated protein C resistance. Acquired risk factors include antiphospholipid antibodies, detected as lupus anticoagulants, and/or anticardiolipin or anti-beta2-glycoprotein I antibodies. Elevated homocysteine, immobility, increasing age, surgery, cancer, poor nutrition, pregnancy, high levels of clotting factors, and use of oral contraceptives and hormone replacement therapy comprise other risk factors. Each of these constitutes an element of increased risk, which is compounded when concomitant. There is ongoing debate regarding relative and compound risks, the value of laboratory screening, whom to screen for with these markers, and the form and duration of clinical management. This report briefly explores, from a scientist's perspective, some important issues that are sometimes overlooked.
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PMID:Diagnostic issues in thrombophilia: a laboratory scientist's view. 1570 70

The discovery that antiphospholipid antibodies recognize plasma proteins that bind to phospholipids rather than recognizing phospholipids themselves has been a major advance in research into antiphospholipid syndrome (APS). It is now established that beta2-glycoprotein I (beta2 GPI) is the most important antigen for antiphospholipid antibodies. However, the possible pathologic mechanism is still much debated. This is mainly because not all patients with anti-beta2 GPI antibodies show clinical symptoms that are related to APS. Several reports indicate that anti-beta2 GPI antibodies with lupus anticoagulant (LA) activity are clinically of much importance. Most patients with LA caused by anti-beta2 GPI antibodies suffer from thrombosis as a result of recognition of the first domain of beta2 GPI by these antibodies. In the search for a pathologic mechanism that might explain the high occurrence of thrombosis in patients with anti-domain I antibodies (LA-causing anti-beta2 GPI antibodies), it was found that these antibodies show increased resistance to the anticoagulant activity of annexin A5. We have shown that the same population of antibodies also displays increased resistance to activated protein C. Owing to the diversity of clinical symptoms related to APS, it is likely that other pathologic mechanisms also contribute to the occurrence of APS-related symptoms.
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PMID:Mechanisms of disease: antiphospholipid antibodies-from clinical association to pathologic mechanism. 1828 65

Antiphospholipid syndrome is considered to be associated with a hypercoagulable state that leads to stroke and other ischemic events, and is currently diagnosed based on the modified Sapporo criteria that was proposed in 2006. Antiphospholipid antibodies (aPL) comprise a heterogeneous group of autoantibodies. Among them, the level of beta2-glycoprotein I-dependent anticardiolipin antibody, lupus anticoagulant (LA), and IgG anticardiolipin antibody are commonly measured. Recently, phosphatidylserine dependent anti-prothrombin antibody has been suggested to be closely related to LA. aPL is an independent risk factor for a first-ever ischemic stroke, especially in young female patients. It is still debatable whether aPL is a marker for recurrent stroke risk. The precipitating factors for the occurrence of stroke are beta2-GPI-dependent aCL, aGPL, and aCL levels of greater than 40, and the simultaneous presence of LA. Several mechanisms are considered to be involved in the thrombotic process in patients with antiphospholipid antibodies. Activation of protein C is impaired in patients with aPL. Beta2-GPI has simultaneous procoagulant and anticoagulant effects. Cardiac valvular involvement, which could be the cause of cardiogenic embolism, is prevalent in patients with aCL. In addition, the presence of aPL is associated with the development of atherosclerosis. Recently, it has been proposed that endothelial cells, monocytes, and platelets were reported to be activated by beta2-GPI: further, p38 mitogen-activated protein kinase has been reported to be phosphorylated. Several therapeutic options are available for the prevention of ischemic stroke in patients with aPL. For cases of cryptogenic ischemic stroke and positive aPL antibodies, antiplatelet therapy is reasonable. Oral anticoagulation with a target international normalized ratio (INR) of 2 to 3 is reasonable for patients with ischemic stroke who meet the criteria for antiphospholipid syndrome with venous and arterial occlusive disease in multiple organs.
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PMID:[Ischemic stroke with antiphospholipid antibody]. 1897 2

The objective of this study was to clarify the roles of anti-phospholipid antibodies (aPLs) in the pathogenesis of acquired activated protein C resistance (APC-R) in patients with systemic lupus erythematosus (SLE). We examined several aPLs levels (lupus anticoagulant, anti-cardiolipin antibodies, anti-beta2-glycoprotein I antibodies, anti-protein C antibodies, and anti-protein S antibodies), the APC-R test, and the factor V Leiden test in 85 SLE patients. Acquired APC-R, which was not found in any patient with the factor V Leiden mutation, was present in 26 (30.6%) of 85 patients, and confirmed that acquired APC-R was a significant risk factor for thromboembolic complications [odd ratio (OR), 3.36; 95% confidence interval (CI), 1.24-9.11]. Multivariate logistic analysis revealed that both LA and anti-PS strongly associated with the presence of APC-R, and that the correlation between anti-PS and APC-R was much stronger (OR, 46.7; 95%CI, 6.99-311) than that between LA and APC-R (OR, 11.3; 95%CI, 2.26-57.0). Furthermore, the mean value of APC sensitivity ratios was significantly lower in SLE patients with anti-PS (mean +/- SD, 1.68 +/- 0.37, p < 0.0001) than in those without anti-PS (2.23 +/- 0.40). These results suggest that acquired APC-R is most strongly attributable to functional interference of the APC pathway by anti-PS, which contribute to risk of thromboembolic complications.
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PMID:Acquired activated protein C resistance is associated with IgG antibodies to protein S in patients with systemic lupus erythematosus. 1912 22

Antiphospholipid antibodies (aPL) are associated with vascular events, but the magnitude of this risk, alone, or in combination with other atherogenic and thrombophilic risk factors, remains unclear. A prospective cohort of 415 persons was studied for arterial and venous events (AE and VE) over a median time of 7.4 years. aPL and coagulation abnormalities were measured upon beginning of the study and annually for the first four years. Within the cohort, a nested case-control study was conducted to investigate the role of endothelial and inflammatory markers in predicting new vascular events. Forty-five individuals had new vascular events: 18 occurred during the first year of follow-up. The proportion of event-free survivors at eight years was 90% (95%CI = 87%, 94%) for aPL-negative and 72% (60%, 85%) for aPL-positive individuals, respectively. Predictors for new AE were previous AE (HR = 5.7 [2.7, 12.0]), diabetes (5.6 [2.4, 13.2]), aPL positivity (2.6 ([1.2, 5.9]), and age (1.04 [1.01, 1.07]). New VE were predicted by previous VE (6.1 [1.9, 19.9]), anti-beta2-glycoprotein I (abeta2GPI) positivity (5.8 [1.4, 24.1]), activated protein C resistance (APCR) (4.1 [1.1, 15.1]), and gender (3.7 [1.1, 12.9]). In the nested case-control study, similar predictors were observed for AE, while abnormal APCR (OR = 5.5 [1.1, 26.6]) and elevated von Willebrand factor (vWF) (OR = 5.0 [1.2, 19.8]) best predicted VE. We demonstrate that aPL independently predict new vascular events and discriminate between individuals with and without events in the first two years of follow-up, indicating that aPL are associated with a short-term risk of developing new and recurrent vascular events.
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PMID:Antiphospholipid antibodies predict imminent vascular events independently from other risk factors in a prospective cohort. 1913 95

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

Anti-phospholipid syndrome (APS) is defined based on both clinical findings (recurrent arterial and/or venous thrombosis and recurrent fetal loss) and laboratory evidence of persistent anti-phospholipid antibodies (anti-cardiolipin antibodies, anti-beta2 glycoprotein I antibodies, or LA activity). However, the precise mechanism responsible for arterial and/or venous thromboembolic complications in APS patients remains unclear. To clarify the association between the various types of anti phospholipid antibodies (aPLs) and thrombotic complications, we examined the prevalence of seven types of aPLs [anti-cardiolipin/beta2-glycoprotein I antibodies(anti-CL/beta2-GPI), anti-phosphatidylserine/prothrombin antibodies(anti-PS/PT), anti-beta2-glycoprotein I antibodies (anti-beta2-GPI), anti prothrombin antibodies (anti-PT), anti-protein C antibodies (anti-PC), anti-protein S antibodies(anti-PS), and annexin V antibodies(anti-AN)] in 168 patients with systemic lupus erythematosus (SLE). We confirmed that the presence of anti-CL/beta2-GPI, anti-PS/PT, and anti-beta2-GPI is closely related to arterial thrombosis, and that the presence of anti-protein S is closely related to venous thromboembolism. Furthermore, our in-vitro experiment suggests that anti-CL/beta2-GPI and anti-PS/PT may cooperate to promote platelet activation, and may be involved in the pathogenesis of arterial thrombosis. On the other hand, anti-protein S led to APC resistance, which may represent an important mechanism responsible for the development of venous thrombosis. Furthermore, our study showed that anti-CL/beta2-GPI causes a persistently high-level expression of tissue factor on monocytes, and this may increase the risk of atherosclerosis.
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PMID:[Advanced clinical laboratory studies in the graduate school of medicine--studies on pathogenic mechanisms of anti-phospholipid syndrome]. 1976 14

Different proteins, even without sequence similarity, still can contain similar surface regions involved in protein-protein interactions with common target. These regions can serve as structural determinants of cross-reactivity and molecular mimicry. Molecular mimicry, defined as the process in which structural properties of one molecule are simulated by the dissimilar molecules, is implicated in several biologically important processes, including autoimmune and allergic reactions, binding of some ligands to common receptor, and interactions in cell signaling. The problem of identification of the determinants of molecular mimicry is not completely solved at this time. We hypothesize that identification of structurally and chemically similar surface regions of two protein molecules capable of binding to the same target will allow us to identify sites involved in cross-reactivity including determinants of the molecular mimicry. We used a graph-theoretical approach in order to determine highly similar surface regions of two proteins with known three-dimensional structures. This approach uses a variation of Maximal Common Subgraph (MCS) isomorphism, where an association graph is constructed based on the surface-exposed residues of the two molecules and the matching regions are found based on the maximum cliques in the association graph. Testing the proposed method on the targets of autoantibody involved in antiphopholipid syndrome (APS)--beta2-GPI, PC, thrombin, factor IX, factor X, and plasmin allowed identifying potential epitopes for antibody that can inhibit coagulation proteases. Application of this method to the Activated Protein C and factor VII Gla-domains revealed surface regions involved in EPCR and plasma membrane binding, consistent with known experimental results. Analysis of major pollen allergen that can cause food allergies through cross-reactivity found known epitopes involved in cross-reactivity and also revealed additional surface regions that can complement the list of epitopes. Taken together, our results suggest that the proposed graph-theoretical approach can identify determinants of cross-reactivity and molecular mimicry.
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PMID:Graph-theoretical comparison of protein surfaces reveals potential determinants of cross-reactivity and the molecular mimicry. 1993 50


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