Cofactor dependence and isotype distribution of anticardiolipin antibodies in viral infections.
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BACKGROUND: Antibodies to cardiolipin (aCLs) are often detected in patients with autoimmune disorders or infectious diseases. OBJECTIVE: To investigate the distribution of aCL isotypes and requirement of protein cofactor in viral infections in order to establish the importance, if any, of these antibodies in these infectious diseases. PATIENTS AND METHODS: The isotype distribution of aCLs in the sera from 160 patients with infection caused by HIV-1 (n=40), hepatitis A virus (n=40), hepatitis B virus (n=40), or hepatitis C virus (n=40) was studied by standardised enzyme linked immunosorbent assay (ELISA) in the presence and absence of protein cofactor (mainly beta2-glycoprotein I). Serum samples from healthy volunteers and patients with syphilis and antiphospholipid syndrome were also included and served as negative and positive control groups respectively. RESULTS: The prevalence of one or more aCL isotypes in serum of patients with HIV-1, hepatitis A virus, hepatitis B virus, or hepatitis C virus infection was 47%, 92%, 42%, and 17% respectively (principally IgM and/or IgA). Most of these antibodies were mainly cofactor independent. CONCLUSIONS: The presence of aCLs in viral infections is principally cofactor independent, suggesting that cofactor dependence of the aCLs should be assessed to distinguish subjects most likely to suffer from clinical symptoms observed in the presence of these antibodies. (+info)
Identification of an Fc gamma receptor-independent mechanism by which intravenous immunoglobulin ameliorates antiphospholipid antibody-induced thrombogenic phenotype.
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OBJECTIVE: Patients with the antiphospholipid antibody syndrome (APS) often experience recurrent arterial and venous thrombosis and pregnancy losses. Intravenous immunoglobulin (IVIG) therapy has prevented pregnancy loss in some women with APS and has reversed fetal resorption rates in murine models of pregnancy loss. Although the basis for these effects is unknown, effector mechanisms of pathogenic antibodies often involve receptors for IgG (Fc gamma receptors [Fc gammaR]). We examined the potential mechanisms of action of WIG in an in vivo murine model of antiphospholipid antibody (aPL)-induced thrombosis and endothelial cell activation. METHODS: Mice infused with IgG containing human anticardiolipin antibodies (aCL) were treated with IVIG (36 microg i.v.), saline, or ovalbumin. Surgically induced thrombus formation and in vivo leukocyte adhesion to endothelial cells were measured. Circulating levels of aCL were measured by enzyme-linked immunosorbent assay. To determine whether Fc gammaR are required for the effects of IVIG, we treated mice deficient in stimulatory Fc gammaR. To examine the effects of IVIG on endogenously generated antibody, we treated mice immunized with beta2-glycoprotein I (beta2GPI). RESULTS: IVIG treatment inhibited aPL-induced endothelial cell activation and enhancement of thrombosis in mice passively infused with human aPL-containing IgG, and this was associated with a decrease in aPL levels. Similarly, IVIG lowered aPL levels and inhibited thrombogenesis in mice immunized with beta2GPI. The thrombophilic effects of aPL were evident in Fc gammaR-deficient mice. CONCLUSION: Treatment with IVIG inhibits the thrombogenic effects of aPL in vivo and reduces the levels of aCL in the circulation. Blockade of stimulatory Fc gammaR on inflammatory cells is not necessary for this effect. The mechanism of action of IVIG is more likely saturation of the IgG transport receptor, leading to accelerated catabolism of pathogenic aPL. These results have implications in the management of thrombosis in APS and may have applications for pregnant patients with a history of APS. (+info)
A specific ligand for beta(2)-glycoprotein I mediates autoantibody-dependent uptake of oxidized low density lipoprotein by macrophages.
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beta(2)-Glycoprotein I (beta(2)-GPI) is a major antigen for antiphospholipid antibodies (Abs) present in patients with the antiphospholipid syndrome (APS). We previously reported that beta(2)-GPI specifically binds to oxidized low density lipoprotein (oxLDL), but not to native low density lipoprotein (LDL). In the present study, a ligand specific for beta(2)-GPI, oxLig-1, was purified from the extracted lipids of oxLDL. The structure of oxLig-1 was shown to be identical to that of synthesized 7-ketocholesteryl-9-carboxynonanoate by mass spectroscopy and nuclear magnetic resonance analyses. Both purified and synthesized oxLig-1 were recognized by beta(2)-GPI and subsequently by anti-beta(2)-GPI auto-Abs, either in enzyme-linked immunosorbent assay (ELISA) or in ligand blot analysis. Binding of liposomes containing oxLig-1 (oxLig-1-liposomes) to mouse macrophages, J774A.1 cells, was relatively low, as compared with that of phosphatidylserine (PS)-liposomes. In contrast, binding of oxLig-1-liposomes was enhanced more than 10-fold in the presence of both beta(2)-GPI and an anti-beta(2)-GPI auto-Ab (WB-CAL-1), derived from (NZW x BXSB) F1 mouse, an animal APS model. Anti-beta(2)-GPI auto-Abs derived from APS patients with episodes of arterial thrombosis were detected in ELISA, using a solid phase oxLig-1 complexed with beta(2)-GPI. We suggest that autoimmune atherogenesis linked to beta(2)-GPI interaction with oxLDL and Abs may be present in APS. (+info)
Anticardiolipin and anti-beta(2) glycoprotein I antibodies in sera of 61 apparently healthy children at regular preventive visits.
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OBJECTIVES: To determine anticardiolipin (aCL) and anti-beta(2) glycoprotein I antibodies (anti-beta(2)GPI) in apparently healthy children and express the cut-off levels in concentrations of monoclonal antibodies, and to compare the mean values and frequencies of aCL and anti-beta(2)GPI in children with those in blood donors. METHODS: Blood samples were collected from 29 preschool children and 32 adolescents during their routine preventive follow-up visits. The control group consisted of 52 blood donors. aCL and anti-beta(2)GPI were assayed by an ELISA method. Two monoclonal beta(2)GPI-dependent aCL (HCAL and EY2C9) were used as calibrators. RESULTS: The estimated cut-off values for immunoglobulin G (IgG) and immunoglobulin M (IgM) aCL, expressed in concentrations of monoclonal antibodies and standardized international units (GPL/MPL units), were 13.9 ng/ml (7.6 GPL) and 33.1 ng/ml (3.3 MPL) for preschool children, 13.5 ng/ml (7.2 GPL) and 36.9 ng/ml (4.0 MPL) for adolescents, and 14.4 ng/ml (8.0 GPL) and 42.6 ng/ml (5.1 MPL) for blood donors. No statistically significant differences in the mean values for IgG and IgM aCL were found between the age groups. The mean value of IgA aCL was significantly higher in blood donors than in preschool children and adolescents (P<0.037 and P<0.025 respectively). Seven (11.4%) of 61 apparently healthy children had low positive values for aCL (IgG for all seven). The estimated cut-off values for IgG and IgM anti-beta(2)GPI were 4.2 and 13.1 ng/ml respectively for preschool children, 3.2 and 13.1 ng/ml for adolescents, and 2.9 and 20.5 ng/ml for blood donors. The mean value for IgG anti-beta(2)GPI was found to be higher in preschool children than in adolescents and blood donors (P<0.0001 and P<0.0001). The mean values for IgM and IgA anti-beta(2)GPI were higher in blood donors than in preschool children (IgM, P<0.007; IgA, P<0.0001) and adolescents (IgM, P<0.01; IgA, P<0.0001). Four (6.6%) of 61 apparently healthy children had positive values for anti-beta(2)GPI (two for IgG and two for IgA). CONCLUSIONS: This is the first report in which the cut-off values for aCL and anti-beta(2)GPI in children are expressed in concentrations of monoclonal antibodies. Low titres of aCL, which were identified frequently in apparently healthy children, were hypothesized to be the result of previous infections. The high mean value of IgG anti-beta(2)GPI observed in preschool children was an unexpected result of the study and might indicate a default response to nutritional exposure to beta(2)GPI in this age group. (+info)
Association between the prevalence of antibodies to beta(2)-glycoprotein I, prothrombin, protein C, protein S, and annexin V in patients with systemic lupus erythematosus and thrombotic and thrombocytopenic complications.
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BACKGROUND: Anti-phospholipid (aPL) antibodies (Abs) frequently found in the plasma of patients with systemic lupus erythematosus (SLE) have been associated with thrombotic complications. Our aim was to clarify the roles in thrombosis of aPL Abs that react with complexes of phospholipids and plasma proteins such as beta(2)-glycoprotein I (beta(2)-GPI), prothrombin, protein C, protein S, and annexin V. METHODS: We determined the prevalence of aPL Abs to various phospholipid-binding plasma proteins in SLE patients with arterial thrombosis (30 cases), venous thrombosis (19 cases), thrombocytopenia (14 cases), fetal loss (14 cases), and patients without complications (91 cases). The aPL Abs were measured by an ELISA system in which human plasma proteins (beta(2)-GPI, prothrombin, protein C, protein S, and annexin V) were immobilized on gamma-irradiated or plain polystyrene plates. RESULTS: All types of aPL Abs were frequently observed in the patients with SLE when gamma-irradiated polystyrene plates were used (51 of 168 cases positive for anti-beta(2)-GPI, 94 of 168 cases positive for anti-prothrombin, 36 of 168 cases positive for anti-protein C, 47 of 168 cases positive for anti-protein S, and 50 of 168 cases positive for anti-annexin V), whereas no Abs to these plasma proteins were detected when plain polystyrene plates were used. Multivariate analysis confirmed that both anti-beta(2)-GPI and anti-prothrombin Abs were significant risk factors for arterial thrombosis [odds ratios (ORs), 8.8 and 14.5, respectively; 95% confidence intervals (CIs), 3.2-25 and 1.8-116, respectively] but not for venous thrombosis. The presence of anti-protein S Abs was a significant risk factor for venous thrombosis (OR, 30.4; CI, 3.3-281) but not for arterial thrombosis. The only significant risk factor for fetal loss was the presence of anti-annexin V Abs (OR, 5.9; CI, 1.4-14.8). CONCLUSIONS: Patients with SLE frequently have some aPL Abs to beta(2)-GPI, prothrombin, protein C, protein S, and annexin V. Thrombotic complications in SLE may depend on the antigenic specificities of these Abs, alone or in combination. (+info)
Detection of 'antiphospholipid' antibodies: a single chromogenic assay of thrombin generation sensitively detects lupus anticoagulants, anticardiolipin antibodies, plus antibodies binding beta(2)-glycoprotein I and prothrombin.
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The diagnosis of the antiphospholipid syndrome (APS) requires both a typical clinical event plus a persistently positive test in an assay for either anticardiolipin (aCL) antibodies or a lupus anticoagulant (LA). Enzyme linked immunosorbent assays (ELISA) specific for autoantibodies against beta(2)-glycoprotein I (beta(2)GPI) or prothrombin are also used, but none of the tests are adequately sensitive or specific. A chromogenic assay was developed that measures the effect of test antibody or plasma samples on in vitro thrombin formation. It is able to detect both LA and beta(2)GPI-dependent aCL antibodies and may have greater specificity for APS than currently available tests. Using this method various monoclonal antibodies (MoAbs) were examined, from mice immunized with beta(2)GPI, mice with a spontaneous animal model of APS, and from three humans with APS. Plasma and affinity purified antibodies from patients with APS and control groups were also examined. Thrombin inhibition was more sensitive to perturbation by MoAbs than a combination of tests for LA (P < 0.05) and at lower antibody concentrations (12.5 microg/ml versus 100 microg/ml). There was a significant correlation between inhibition of thrombin generation and the level of MoAb reactivity to beta(2)GPI (r = 0.90; P < 0.001) but not to CL (r = 0.06; P = 0.76). Plasma and affinity purified antibodies from patients with APS also inhibited thrombin generation, and significantly more so than patients with aPL from causes other than APS. APS patient samples showed thrombin inhibition in the presence of anti-beta(2)GPI or antiprothrombin antibodies. All MoAbs binding beta(2)GPI showed inhibition of thrombin generation, while MoAbs binding domain I of beta(2)GPI had more LA effect. (+info)
beta(2)-Glycoprotein 1-dependent anticardiolipin antibodies and risk of ischemic stroke and myocardial infarction: the honolulu heart program.
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BACKGROUND: It has been hypothesized that immunoreactivity to beta(2)-glycoprotein 1 (beta2GP1)-dependent anticardiolipin antibody (aCL), but not beta2GP1-independent aCL, is associated with increased risk of ischemic stroke and myocardial infarction (MI). METHODS: We performed a nested case-control study examining aCL as a risk factor for ischemic stroke and MI by using stored frozen sera obtained from subjects enrolled in the Honolulu Heart Program and followed for up for 20 years. We measured beta2GP1-dependent and beta2GP1-independent aCL and anti-beta2GP1 immunoreactivity in 259 men who developed an ischemic stroke, in 374 men who developed an MI, and in a control group of 1360 men who remained free of both conditions. RESULTS: Only beta2GP1-dependent aCL of the IgG class was significantly associated with both incident ischemic stroke and MI. This association was attenuated in the last 5 years of the 20-year follow-up. For stroke, the risk factor-adjusted relative odds for men with a positive versus a negative beta2GP1-dependent aCL of the IgG class were 2.2 (95% CI 1.5 to 3.4) at 15 years and 1.5 (95% CI 1.0 to 2.3) at 20 years. For MI, the adjusted relative odds were 1.8 (95% CI 1.2 to 2.6) at 15 years and 1.5 (95% CI 1.1 to 2.1) at 20 years. CONCLUSIONS: These data suggest that aCL IgG, particularly the beta2GP1-dependent variety, is an important predictor of future stroke and MI in men. (+info)
Prothrombotic disorders in children with moyamoya syndrome.
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BACKGROUND AND PURPOSE: Moyamoya syndrome is an uncommon chronic occlusive cerebrovascular disease in children. The origin of moyamoya syndrome remains undetermined. The role of the prothrombotic disorders contributing to its pathogenesis has not been completely elucidated. The purpose of this study was to determine the frequency of prothrombotic disorders in a pediatric population with moyamoya syndrome. METHODS: From May 1992 to April 2000, a prospective study of 10 consecutive children with moyamoya syndrome was carried out at a single center. Evaluation included the following assays: protein C, protein S, antithrombin, plasminogen, activated protein C resistance, factor V Leiden, and prothrombin gene mutations. Lupus anticoagulant, anticardiolipin antibodies, and anti-beta(2)-glycoprotein I antibodies assays were also performed. The clinical characteristics, underlying diseases, family history of thrombosis, radiological findings, treatment, and outcome were also recorded. RESULTS: In our series, prothrombotic disorders were detected in 4 patients (40%). Inherited protein S deficiency was found in 1 patient; lupus anticoagulant and anticardiolipin antibodies were detected in the remaining 3 patients. One presented persistent lupus anticoagulant for 2.7 years until his death. In the case of the other 2 patients, 1 has maintained lupus anticoagulant for 9 months, whereas the other has kept anticardiolipin/anti-beta(2)-glycoprotein I antibodies for 10 months. CONCLUSIONS: We report the hemostatic data of the largest prospective pediatric study carried out at a single center in the western hemisphere. In 4 patients (40%), a prothrombotic disorder was detected. It is tempting to speculate that these hemostatic abnormalities may contribute to the pathogenesis of moyamoya syndrome in some of our patients. (+info)