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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the role of autoantibodies to beta2-GPI and prothrombin (PT) in the inhibition of annexin V binding to cardiolipin (CL) and the association with clinical manifestations of the anti-phospholipid syndrome (APS). Plasma samples from 59 patients with anti-phospholipid (aPL) antibodies were studied. Affinity purification of total IgG and IgG anti-ss2-GPI antibodies was performed using staphylococcal protein A and phospholipid liposomes. Annexin V binding to CL was significantly inhibited by 31/59 (53%) aPL+ plasma samples. There was a significant association between annexin V inhibition and elevated levels of IgG anti-cardiolipin (aCL) (r = -0.62; P < 0.001), IgG anti-ss2-GPI (r = -0.67; P < 0. 001) and a weaker association with lupus anti-coagulant (r = -0.27; P = 0.05). There was no association with other isotypes of aCL and anti-ss2-GPI or with anti-PT of any isotype. In patients with clinical manifestations of the APS there were higher levels of IgG aCL (median (range) Z score): 10.0 (0-17.6) versus 5.0 (0-16.1); P = 0.03), IgG anti-ss2-GPI (4.5 (0-11.3) versus 0.9 (0-9.7); P = 0.02) and greater inhibition of annexin V binding to CL (-3.4 (-11.4-0.6) versus -1.1 (-10.8-1.2); P = 0.22). Odds ratios for the laboratory assays and the presence of clinical manifestations of the APS varied between 0.38 and 4.16, with the highest values for IgG aCL (4.16), IgG anti-ss2-GPI (3.28) and annexin V inhibition (2.85). Additional experiments with affinity-purified IgG antibodies indicated that inhibition of annexin V binding was dependent upon the concentration of ss2-GPI and anti-ss2-GPI antibodies. These results indicate that inhibition of annexin V binding to procoagulant phospholipid surfaces is dependent upon anti-ss2-GPI antibodies and suggest a role for annexin V in the pathogenesis of the APS.
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PMID:Anti-beta2-glycoprotein I (GPI) autoantibodies, annexin V binding and the anti-phospholipid syndrome. 1084 35

Anti-beta(2)-glycoprotein I antibodies are thought to cause lupus anticoagulant activity by forming bivalent complexes with beta(2)-glycoprotein I (beta(2)GPI). To test this hypothesis, chimeric fusion proteins were constructed of the dimerization domain (apple 4) of factor XI and beta(2)GPI. Both a covalent (apple 4-beta(2)GPI) and a noncovalent (apple 4-C321S-beta(2)GPI) chimer were constructed. As controls, apple 2-beta(2)GPI and apple 4-C321S-beta(2)GPI-W316S, in which beta(2)GPI-W316S is not able to bind to phospholipids, were made. In a phospholipid binding assay, apple 4-beta(2)GPI and apple 4-C321S-beta(2)GPI were able to bind to phospholipids with an affinity 35 times higher than that of plasma-derived beta(2)GPI and apple 2-beta(2)GPI. Apple 4-C321S-beta(2)GPI-W316S did not bind at all. Only apple 4-beta(2)GPI and apple 4-C321S-beta(2)GPI were able to bind to adhered platelets as shown by immunofluorescence. Using the prothrombin time, which was the most responsive coagulation assay, the clotting time was approximately doubled when 200 microg/ml apple 4-beta(2)GPI or apple 4-C321S-beta(2)GPI was added. Addition of 200 microg/ml plasma-derived beta(2)GPI, apple 2-beta(2)GPI, or apple 4-C321S-beta(2)GPI-W316S did not affect clotting time. Clotting time could be corrected with the addition of extra phospholipids, which is indicative for lupus anticoagulant activity. An additional increase in clotting times for apple 4-beta(2)GPI or apple 4-C321S-beta(2)GPI was achieved by the addition of monoclonal antibodies against beta(2)GPI. In conclusion, dimerization of beta(2)GPI explains the in vitro observed effects of beta(2)GPI-anti-beta(2)GPI antibody complexes.
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PMID:Dimers of beta 2-glycoprotein I mimic the in vitro effects of beta 2-glycoprotein I-anti-beta 2-glycoprotein I antibody complexes. 1105 20

beta(2)-Glycoprotein I (beta(2)GPI) consists of five tandem repeated domains (I, II, III, IV, and V). The nicked form of beta(2)GPI (N-beta(2)GPI ) which was cleaved by plasmin in vitro at Lys 317-Thr 318 in domain V, showed reduced affinity for the negatively charged phospholipids, especially cardiolipin (CL). Recently, the N-beta(2)GPI was detected in the plasma of patients with disseminated intravascular coagulation syndrome (DIC) by an immunological method. In the present study, we prepared monoclonal antibodies for the nicked form, and demonstrated that the concentrations of this form of beta(2)GPI, which were analyzed by a sandwich ELISA using two specially prepared monoclonal antibodies, were significantly increased in the plasma of patients with leukemia (n = 51, mean +/- SD: 162.0 +/- 118.3 ng/ml) and with lupus anticoagulant (LA) (n =40, mean +/- SD: 3,041.5 +/- 16,579.7 ng/ml), compared to the normals (n = 33, mean +/- SD: 1.04 +/- 1.54 ng/ml). We found a significant correlation between the concentrations of N-beta(2)GPI and those of typical molecular markers for a fibrinolytic state such as plasmin-alpha(2) plasmin inhibitor complex (PIC) and D-dimer in patients with leukemia, but not in patients with LA. These results suggested that the generation of N-beta(2)GPI was caused by plasmin in the patients with leukemia, and by unknown proteases in the patients with LA. In the patients with LA, the levels of N-beta(2)GPI tended to be higher in those without thrombosis than in those with thrombosis.
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PMID:Highly increased plasma concentrations of the nicked form of beta(2) glycoprotein I in patients with leukemia and with lupus anticoagulant: measurement with a monoclonal antibody specific for a nicked form of domain V. 1109 45

Previous studies have demonstrated that ethnicity plays a role in the prevalence, isotype distribution, and clinical significance of anticardiolipin (aCL) and anti-beta2 glycoprotein I (abeta2-GPI) antibodies in systemic lupus erythematosus (SLE) patients. Few studies have been done in Latin American populations. Serum samples from 129 Chilean SLE patients were tested for IgG, IgM and IgA aCL and abeta2-GPI by ELISA. Clinical data were reviewed with the focus on clinical manifestations of antiphospholipid syndrome (APS). Positivity for at least one isotype of aCL was found in 30% of patients, while only 10% were positive for at least one isotype of abeta2-GPI. IgG was the most prevalent isotype for aCL (16%), and the isotype distribution was similar (4%) for abeta2-GPI. In general, the presence of aCL was significantly associated with the presence of abeta2-GPI, but a number of samples were positive for only one antibody, some of them associated with clinical manifestations of APS. ACL antibodies at medium-high titers were significantly correlated with thrombosis (P = 0.0007) and fetal loss (P = 0.009); however, the sensitivity of abeta2-GPI for detecting thrombosis and fetal loss was lower than aCL (19 and 17% vs 56 and 50%, respectively), and the specificity slightly higher (91 and 90% vs 84 and 82%). In Chilean SLE patients, aCL and abeta2-GPI antibodies are important in the evaluation of patients with APS. However, the utility of abeta2-GPI antibodies was limited by the low prevalence of these antibodies in comparison with other ethnic groups. Further studies are needed to define the basis of the observed differences among ethnic groups.
Lupus 2001
PMID:Prevalence and isotype distribution of antiphospholipid antibodies in Chilean patients with systemic lupus erythematosus (SLE). 1123 29

The aim of this study was to examine whether the clinical features of antiphospholipid antibody syndrome are associated with anti-cardiolipin and anti-beta2 glycoprotein I antibodies in Indian patients with SLE. Seventy-six patients (71 females), who fulfilled 1982 ACR criteria for SLE, were prospectively studied for the clinical features of antiphospholipid antibody syndrome (APS), and their sera were analysed for the presence of IgG/IgM/IgA anti-cardiolipin antibodies (aCL) by an in-house ELISA and, in 65 of them, for the presence of IgG anti-beta2 glycoprotein I antibodies (anti-beta2 GPI) by a commercial kit. Thirty-nine (51%) patients were positive for aCL, all of which were positive for IgG aCL, either alone (79.6%) or along with IgM and/or IgA. Twenty-seven (69.3%) out of 39 aCL-positive and seven (26.9%) out of 26 aCL-negative sera were positive for IgG antibodies to beta2 GPI. There was a significant correlation (r = 0.66, P < 0.05) between the levels of aCL and anti-beta2 GPI antibodies. Forty-one patients had features of definite or suggestive APS. Thrombocytopenia, recurrent pregnancy loss and CNS manifestations (seizures eight, infarct one) were seen in 20, 13 and nine patients, respectively. Thrombosis of the peripheral vessels was seen in only one patient. Only the presence of seizures was significantly associated with the presence of aCL and anti-beta2 GPI antibodies (P < 0.05). The characteristic association of definite APS (recurrent pregnancy loss and arterial/venous thrombosis) was lacking.
Lupus 2001
PMID:Anti-cardiolipin and anti-beta2 glycoprotein I antibodies in Indian patients with systemic lupus erythematosus: association with the presence of seizures. 1124 9

The aim of this study was to examine potential links between antiOxLDL antibodies and the clinical and biological features of secondary antiphospholipid syndrome (II APLS) associated with systemic lupus erythematosus (SLE). A cohort study was done of 98 SLE patients followed-up for 1 y, including 18 with definite II APLS and 13 patients with definite primary APLS (I APLS). IgG anticardiolipin, IgG anti beta2 GPI, lupus anticoagulant, VDRL and IgG antiOxLDL were measured in all 98 study subjects. High antiOxLDL titers were found in seven (39%) of the 18 patients with II APLS vs 10 (12.5%) of the 80 patients without APLS (P < 0.01; OR = 4.45; 95% CI = 1.4-14.1) and none of the 13 patients with I APLS (P < 0.02). The mean antiOxLDL titer was not significantly higher in the SLE patients with than without II APLS (P > 0.05). A high antiOxLDL titer was correlated with deep venous thrombosis (P < 0.01; OR = 5.77; 95% CI = 0.54-61) but not with arterial thrombosis (P > 0.05; OR = 1; 95% CI = 0.29-3.09), thrombocytopenia, central nervous system involvement, livedo reticularis, or a positive Coombs test. The antiOxLDL antibody titer was correlated with the IgG anticardiolipin antibody titer (r = 0.235; P = 0.02) and with the IgG anti-beta2 GPI antibody titer (r = 0.224; P = 0.026). AntiOxLDL elevation was found in 17% of SLE patients and was significantly associated with II APLS and venous thrombosis. We found no evidence suggesting that antiOxLDL may be associated with atherosclerosis.
Lupus 2001
PMID:Anti-oxidized low-density-lipoprotein (OxLDL) antibodies in systemic lupus erythematosus with and without antiphospholipid syndrome. 1140 65

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.
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PMID: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. 1147 15

The family of autoantibodies known as antiphospholipid antibodies (aPL) and the lupus anticoagulant (LA) are associated with a spectrum of clinical manifestations including life-threatening thrombosis. While our current knowledge of thrombosis is imperfect and the mere presence of aPL is imprecisely associated with clinical events, our knowledge in this area has greatly expanded in recent years. It is clear that high levels of IgG aPL are associated with an increased risk of thrombosis. In 1990, investigators demonstrated that some aPL are directed against the beta2-Glycoprotein I (beta2-GPI) 50 kDa subunit and reported that these showed concordance with risk of clotting in certain groups of patients. Studies have also demonstrated that aPL reacted with antigens other than beta2-GPI, namely prothrombin, annexin V, protein S, protein C and high molecular weight kininogen. We review the clinical features of the antiphospholipid syndrome (APS), including vascular occlusion, pregnancy loss, thrombocytopenia and catastrophic APS. We also review the role of antibodies in the pathogenesis of APS as well as the spectrum of autoantibodies that have been found in APS.
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PMID:Antiphospholipid antibodies in systemic lupus erythematosus and the antiphospholipid syndrome. 1172 83

We previously showed that beta(2)-glycoprotein I (beta(2)GPI)-dependent lupus anticoagulants (LAs) form bivalent antigen-antibody complexes with high affinity for phospholipids; these complexes are responsible for their in vitro anticoagulant effect. We now studied the role of these bivalent complexes in arterial thrombosis in the hamster. Three monoclonal antibodies (mAbs) raised against human beta(2)GPI were selected on the basis of their cross-reactivity with hamster beta(2)GPI. Two of these, one with LA activity, 5H2, and one with only anticardiolipin properties, 11E8, were infused at 0 to 10 mg/kg prior to photochemically induced vessel damage. 5H2 promoted thrombus formation dose dependently, raising the thrombus size from 6.0 arbitrary units (AU) in controls (n = 9) to 65.0 AU in the high-dose group (10 mg/kg, n = 6, P =.007). The LA(-) mAb 11E8 and mAb 27A8, reactive with human beta(2)GPI exclusively, did not significantly promote thrombus formation. In a second set of experiments, intact mAb 5H2 was compared to its fragments. Intact mAb 5H2 at 3.3 mg/kg and the equimolar dose of F(ab')(2) fragments (2.2 mg/kg) promoted thrombus formation equally well (55.8 AU, n = 8 and 62.5 AU, n = 7, respectively); mAb 5H2-derived Fab' fragments were inactive. Immunohistochemical analysis showed platelet-rich thrombi, with 5H2 or its F(ab')(2) fragments mainly bound to individual platelets. Our results indicate that bivalent immune complex formation plays an important role in the genesis of arterial thrombosis by certain antiphospholipid antibodies. Cellular activation via the Fc portion of these immune complexes, however, is not essential, because F(ab')(2) fragments of 5H2 still promote thrombus formation.
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PMID:Thrombogenicity of beta 2-glycoprotein I-dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster. 1239 62

We report a severe hemorrhagic disorder in two pediatric patients with lupus anticoagulant (LA) associated to acquired factor II (prothrombin) deficiency. In both patients, hemorrhagic symptoms resolved after corticosteroid therapy. Serial coagulation studies showed that Staclot LA assay was more sensitive than DVVconfirm and Staclot PNP tests to confirm the presence of LA when associated with severe factor II deficiency. Both patients had non-neutralizing anti-prothrombin antibodies and their titers inversely correlated with factor II activity (r = -1.0, P < 0.0001). Associated findings in these patients included positive immunologic tests for systemic lupus erythematosus, a positive anti-cardiolipin antibody, and anti-beta(2) GPI antibodies in one case. Our findings point out the difficulty in diagnosing LA associated with acquired factor II deficiency and suggest that, in confirmation of its phospholipid dependency, the inclusion of a source of normal human plasma in the test sequence to correct for any factor deficiency and a confirmatory step utilizing hexagonal (II) phase phospholipids may be crucial to the diagnosis of LA in some patients with LA-hypoprothrombinemia syndrome.
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PMID:Diagnosis of lupus anticoagulant in the lupus anticoagulant-hypoprothrombinemia syndrome: report of two cases and review of the literature. 1241 May 76


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