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)

It is widely hypothesized that autoantibodies directly contribute to the prothrombotic state in the antiphospholipid syndrome (APS). The discovery that antiphospholipid autoantibodies are specific for phospholipid-binding plasma proteins (beta2-glycoprotein I, prothrombin, etc.) has allowed a much more precise investigation of the interactions of autoantibodies and antigens, and the effects of these interaction on hemostasis. Recent studies suggest that two types of interactions may be important in the pathophysiology of APS: (1) antibody cross-linking of membrane bound antigens may alter the kinetics of phospholipid-dependent reactions; and (2) antibody cross-linking of antigens bound to cell surface receptors may trigger signal transduction and cellular activation. In light of these findings, previous reports implicating various mechanisms of autoantibody-mediated thrombosis are being re-evaluated.
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PMID:Mechanisms of autoantibody-mediated thrombosis. 981 87

Atherosclerosis is a multifactorial disease that involves the arterial system. Recent data suggest that immune and autoimmune factors play a dominant role in mediating the progression of atherosclerosis. Among these factors, humoral response to modified forms of LDL and heat-shock proteins has been shown to be influential. The antiphospholipid syndrome (APS) entails clinical manifestations that result from a hypercoagulable state. Antibodies to phospholipids and to beta2-glycoprotein I have been suggested to confer the tendency to thrombosis. In a set of recent studies, we have been able to show that generation of antiphospholipid antibodies in mice is associated with enhanced atherosclerosis. These findings imply that APS and atherosclerosis may share a common etiologic background, which may have direct implications for the management of both conditions.
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PMID:Atherosclerosis and the antiphospholipid syndrome: a link unravelled? 981 92

Antiphospholipid syndrome is characterized by a prothrombotic state and the presence of beta2-glycoprotein I (beta2-GPI)-dependent antiphospholipid antibodies. The feasibility of a B cell tolerance-based approach for specific reduction of anti-beta2-GPI antibodies was investigated. Anti-beta2-GPI antibodies isolated from a patient with antiphospholipid syndrome were used to screen peptide libraries expressed in phage, resulting in the identification of a phage that specifically bound anti-beta2-GPI antibodies. The phage-displayed peptide was identified and chemically optimized to generate a synthetic 14-mer peptide with an internal thioether linkage (LJP 685) that retained the binding profile of the original phage. LJP 685 was conjugated to a defined, non-immunogenic organic platform to generate a tetravalent presentation of LJP 685 for use as a toleragen. Tetravalent LJP 685 induced a dose-dependent reduction in antibody levels in mice previously immunized and boosted with LJP 685 coupled to the carrier keyhole limpet hemocyanin. These experiments support the technical feasibility of a tolerance-based approach for reducing anti-beta2-GPI antibodies in vivo.
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PMID:A chemically defined, toleragen-based approach for targeting anti-beta2-glycoprotein I antibodies. 981 97

Oral tolerance was induced in BALB/c mice by feeding low dose beta2-glycoprotein I (beta2GPI). The beta2GPI-fed mice did not develop serologic and clinical markers of experimental antiphospholipid syndrome (APS) upon immunization with the autoantigen. The treated group was characterized by low titers of serum anti-beta2GPI and anticardiolipin Abs in the serum, lack of fetal resorptions, low incidence of thrombocytopenia, and normal aPTT (activated partial thromboplastin time) values. Beta2GPI given orally before priming with beta2GPI resulted in complete prevention of experimental APS development; beta2GPI given at an early stage of the disease reduced clinical manifestations. However, administration of beta2GPI 70 days postimmunization had a less significant effect on disease expression. Tolerized mice exhibited a diminished T lymphocyte proliferation response to beta2GPI in comparison with beta2GPI-immunized mice fed with OVA. When nontolerant beta2GPI-primed T lymphocytes were mixed with T lymphocytes derived from tolerized mice, a significant inhibition of proliferation upon exposure to beta2GPI was observed. The induction of suppression was beta2GPI specific and driven, as well as TGF-beta mediated. The beta2GPI-specific response of T lymphocytes from the beta2GPI-fed mice was reversed by anti-TGF-beta Abs. The tolerance was adoptively transferred by CD8+ T cells from the tolerized mice into naive mice. Those CD8+ cells were MHC class I restricted, found to secrete TGF-beta, and had no cytolytic activity. Oral administration of beta2GPI suppressed priming of CTLs in the recipient mice. In sum, beta2GPI-induced oral tolerance has an immunomodulatory effect in experimental APS, demonstrating the importance of beta2GPI in the pathogenesis of the disease.
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PMID:Oral tolerance to low dose beta 2-glycoprotein I: immunomodulation of experimental antiphospholipid syndrome. 982 May 3

Although there has been recent emphasis on autoantibodies to epitopes on beta-2-glycoprotein I and prothrombin in the pathogenesis of antiphospholipid syndrome (APS), antibodies other than those directed toward epitopes on phospholipid binding proteins are present. These include those reactive with antigens on platelet membrane glycoproteins, and with vascular endothelial cell membrane. As the pathogenesis of the thrombotic manifestations of APS remains unexplained, further characterization of these antibodies may be informative. We have confirmed anti-endothelial cell binding to a range of cell membrane antigens in systemic lupus erythematosus (SLE) and primary APS. Furthermore, differences in both the pattern of antibody binding and band intensity between human umbilical vein (HUVEC) and human microvascular endothelial cells (HMEC-1) were demonstrated. Of 17 primary APS sera, antibody binding to HUVEC cell membranes was found in nine and to HMEC-1 membranes in seven. Binding at 72-79 kD was confined to HUVEC. In 32 SLE sera, binding to HUVEC and HMEC-1 membranes was detected in 17 and 22 respectively, binding at 135-155 kD being confined to HMEC-1. These results are consistent with the phenotypic variation in endothelial cells of different origins and confirm the frequent presence of autoantibodies reactive with vascular endothelium in both SLE and PAPS. Whether these antibodies could be involved in the pathogenesis of thrombosis, through induction of endothelial cell apoptosis or damage, remains to be determined.
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PMID:Anti-endothelial cell antibodies in primary antiphospholipid syndrome and SLE: patterns of reactivity with membrane antigens on microvascular and umbilical venous cell membranes. 982 13

Anticoagulant activity is present in non-immunoglobulin (IgG) fractions from plasma of patients with antiphospholipid syndrome (APS). Plasma from six patients with primary or secondary APS was passed through a protein A sepharose 4B column. Anticoagulant activity in IgG samples and non-IgG samples was determined by both dilute aPTT based clotting assay and by dilute PT based clotting assay. Thrombin generation was determined by prothrombinase complex assay in the presence of IgG sample or non-IgG sample. Anticoagulant activity was detected in the IgG samples with the dilute aPTT based clotting assay and in non-IgG samples with the dilute PT based clotting assay. The activity was not detected in IgG samples with the dilute PT clotting assay. Forty percent of total thrombin generation was inhibited in the presence of non-IgG samples although thrombin generation was not inhibited in the presence of IgG samples and beta2-glycoprotein I. The anticoagulant activity detected by dilute PT based clotting assay and prothrombinase complex assay was non-IgG, phospholipid-Ca++-dependent and beta2-glycoprotein I-independent. The role of non-IgG anticoagulants should be determined as well as the role of LA Igs antibodies in the mechanisms of thrombosis.
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PMID:Anticoagulant activity in non-immunoglobulin fraction from plasma of patients with antiphospholipid syndrome. 983 16

The presence of antiphospholipid antibodies (aPL) is strongly correlated with venous and arterial thrombosis, fetal loss and thrombocytopenia. This relation is called the antiphospholipid syndrome (APS). It is well recognized that thrombosis related aPL are not directed against phospholipids alone, but to phospholipid bound plasma proteins like beta2-glycoprotein I (beta2GPI). aPL that need beta2GPI for the binding to negatively charged phospholipids are called anti-beta2GPI-antibodies. Recently, a mutation in the gene encoding beta2GPI has been described, which results in an amino acid substitution Trp316 into Ser316. This Ser316-beta2GPI did not bind to negatively charged phospholipids. Because only phospholipid bound beta2GPI is recognized by human anti-beta2GPI-antibodies, it might be argued that individuals carrying the Trp316Ser mutation are protected against the development of anti-beta2GPI-antibodies. To investigate this hypothesis, the prevalence of the Trp316Ser mutation was measured in 170 systemic lupus erythematosus (SLE) patients and in 18 patients with the primary antiphospholipid syndrome (PAPS) and the mutation was correlated with the presence of anti-beta2GPI-antibodies. In the total patient group 1 homozygous patient and 21 heterozygous patients were found. The allele frequency of the mutation in SLE patients with anti-beta2GPI-antibodies (0.063) was comparable to that found in SLE patients without anti-beta2GPI-antibodies (0.062). These results indicate that the heterozygous presence of Trp316Ser mutation does not prevent an individual from developing anti-beta2GPI-antibodies. We showed that this can be explained by the concentration of Trp316-beta2GPI in heterozygous patients, which is far above the minimal beta2GPI level necessary for optimal phospholipid binding. In our single patient homozygous for the Trp316Ser mutation no binding beta2GPI to the phospholipid surface was detected and no anti-beta2GPI-antibodies were present in the plasma of this patient. In conclusion, heterozygous Trp316Ser beta2GPI persons are not protected against the development of anti-beta2GPI-antibodies. To confirm that homozygotes do not develop anti-beta2GPI-antibodies a very large population is needed, due to the relatively low prevalence of the mutation.
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PMID:The prevalence of a non-phospholipid-binding form of beta2-glycoprotein I in human plasma--consequences for the development of anti-beta2-glycoprotein I antibodies. 984 73

The aim of the present study was to evaluate the urea resistance and binding characteristics of anti-beta 2-glycoprotein I (anti-beta 2GPI) antibodies using standard anticardiolipin (aCL) and anti-beta 2GPI enzyme immunosorbent assays (ELISAs). Sera from patients with antiphospholipid syndrome (APS) (n = 22) and non-APS (n = 24), positive in a standard aCL ELISA, were tested in an anti-beta 2GPI ELISA performed in polystyrene-irradiated ELISA plates. Urea resistance aCL and anti-beta 2GPI ELISAs were performed by measuring the ability of antibodies to recognize antigen in the presence of 2 M urea. The serum dilution after urea treatment (D) expressed as a percentage of the serum dilution without urea treatment (D(o)) corresponding to the same optical density was defined as residual activity (RA = 100 D/D(o)). The higher the RA, the higher the resistance of the antibodies to urea. APS compared to non-APS sera had higher aCL binding (absorbance values ranging between 0.180 and 1.400; median, 0.717 vs 0.120-1.273; median, 0.250, respectively; P < 0.004). Six APS patients' sera had low aCL levels but they expressed RA > or = 30%. Anti-beta 2GPI antibodies were detected in 15 of 22 APS vs 3 of 24 non-APS patients (P < 0.03); RA > or = 30% was detected in 15 of 22 APS vs 1 of 23 non-APS patients (P < 0.004). Using a CL affinity column, antibodies were purified from three APS anti-beta 2GPI negative and three non-APS anti-beta 2GPI-positive patients and tested in a aCL ELISA, using highly purified bovine serum albumin (BSA) as a blocking agent (modified ELISA); reactivity was not detected in two APS and one non-APS sera. On the contrary, the reactivity of the purified antibodies was high when beta 2GPI was incubated with CL in the ELISA plates; thus some anti-beta 2GPI negative sera from APS patients recognized the CL/beta 2GPI complex, rather than CL or beta 2GPI alone. In conclusion, anti-beta 2GPI antibodies are common in the APS patients, but a number of such patients recognize the CL/beta 2GPI complex and not CL or beta 2GPI. Antibodies to either beta 2GPI or the CL/beta 2GPI complex derived from APS sera present a high resistance to urea. Anti-beta 2GPI antibodies of low urea resistance exist in a minority of non-APS patients with autoimmune disease.
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PMID:Antibodies to beta 2-glycoprotein-I: urea resistance, binding specificity, and association with thrombosis. 985 82

Antiphospholipid antibodies (aPL), anti-beta 2-glycoprotein I (anti-beta 2-GPI) and anti-oxidized-low-density lipoprotein (LDL) antibodies are all implicated in the pathogenesis of antiphospholipid syndrome. To investigate whether different autoantibodies or combinations thereof produced distinct effects related to their antigenic specificities, we examined the frequencies of antiphospholipid syndrome (APS)-related features in the presence of different antibodies [aPL, beta 2-GPI, anti-oxidized low density lipoprotein (LDL)] in 125 patients with APS. Median follow-up was 72 months: 58 patients were diagnosed as primary APS and 67 as APS plus systemic lupus erythematosus (SLE). Anticardiolipin antibodies (aCL), anti-beta 2-GPI and anti-oxidized LDL antibodies were determined by ELISA; lupus anticoagulant (LA) by standard coagulometric methods. Univariate analysis showed that patients positive for anti-beta 2-GPI had a higher risk of recurrent thrombotic events (OR = 3.64, 95% CI, p = 0.01) and pregnancy loss (OR = 2.99, 95% CI, p = 0.004). Patients positive for anti-oxidized LDL antibodies had a 2.24-fold increase in the risk of arterial thrombosis (2.24, 95% CI, p = 0.03) and lower risk of thrombocytopenia (OR = 0.41 95% CI, p = 0.04). Patients positive for aCL antibodies had a higher risk of pregnancy loss (OR = 4.62 95% CI, p = 0.001). When these data were tested by multivariate logistic regression, the association between anti-beta 2-GPI and pregnancy loss and the negative association between anti-oxidized LDL antibodies and thrombocytopenia disappeared.
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PMID:Antiphospholipid, anti-beta 2-glycoprotein-I and anti-oxidized-low-density-lipoprotein antibodies in antiphospholipid syndrome. 1002 16

Anti-beta2-glycoprotein I (beta2-GPI) antibodies behave as classical Lupus Anticoagulants (LA), as they inhibit phospholipid-dependent coagulation reactions and their activity disappears in the presence of excess exogenous phospholipids (PLs). We have recently shown that a certain amount of PLs in the dilute Russell Viper Venom Time (dRVVT) test system is required to express LA activity of anti beta2-GPI antibodies. We have now extended this observation to two other tests, i.e., Kaolin Clotting Time (KCT) in which PLs are not added, and Tissue Thromboplastin Inhibition test (TTI) in which PLs are extremely diluted. In fact, affinity-purified antibody preparations from 5 patients with antiphospholipid syndrome did not express or only weakly expressed anticoagulant activity in both tests; the mean ratios of coagulation times obtained with purified antibodies and that of control buffer were 1.11 and 1.0 for KCT and TTI, respectively. On the contrary, the mean ratios in dRVVT were 1.31 and 1.49 at a PLs dilution of 1:8 and 1:64, respectively. Therefore, the presence of LA activity due to autoantibodies to beta2-GPI is characterized by a positive dRVVT and negative or only weakly positive KCT and TTI.
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PMID:dRVVT is more sensitive than KCT or TTI for detecting lupus anticoagulant activity of anti-beta2-glycoprotein I autoantibodies. 1006 2


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