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

The 'lupus anticoagulant' phenomenon is the best documented functional effect of antiphospholipid (aPL) antibodies, occurring either by inhibition of the prothrombinase and/or Factor X activation reactions. Understanding the mechanism by which aPL antibodies inhibit phospholipid dependent coagulation reactions may yield important clues about their 'thrombogenic effects' in vivo. We conducted a series of studies to determine the specificity, diversity, and mechanism by which aPL antibodies inhibit phospholipid dependent reactions. Results showed that purified immunoglobulins with lupus anticoagulant and anti-cardiolipin activities were absorbed by negatively charged phospholipids and both activities were recovered from the phospholipid-antibody precipitate. Purified aPL antibodies inhibited the prothrombinase reaction in a plasma free system in which beta 2-glycoprotein 1 (beta 2-GP1) was absent. Affinity purified aPL antibodies had 25-50 times the inhibitory activity of immunoglobulin preparations. The phospholipid binding proteins, beta 2-GPI and placental anticoagulant protein I (PAP I), independently inhibited the prothrombinase reaction, and when these proteins were combined with aPL, inhibition of the prothrombinase reaction was additive. Antibodies of syphilis had no inhibitory effect, partially accounted for by lack of specificity for phosphotidylserine (PS). Although aPL antibodies inhibited the protein C activation reaction, there was no correlation of these activities with inhibition of the prothrombinase reaction. Together, these results show that aPL exert their effects by interaction with negatively charged phospholipids, in particular phosphotidylserine, but lack of correlation between inhibition of the prothrombinase and protein C activation reactions, suggests that the nature of the coagulation protein is also important.
Lupus 1996 Oct
PMID:Functional effects of anticardiolipin antibodies. 890 63

Cardiolipin binding of IgG-class anticardiolipin antibody (aCL) depends on the existence of beta 2-glycoprotein I (beta 2-GPI). We developed an EIA system that enables detection of antibodies against beta 2-GPI, without the presence of cardiolipin. This system involves use of irradiated polystyrene plates, in which oxygen atoms are introduced onto the surfaces of the plates. beta 2-GPI bound to the surface of these plates is assumed to undergo a conformational change that exposes normally cryptic epitopes. Anti-beta 2-GPI antibody measured using this EIA system showed good correlation with aCL measured by conventional EIA methods and may prove useful in evaluating the risk of thrombosis and monitoring the clinical course in patients with SLE. Utilizing this EIA system and beta 2-GPI-deleted mutants, we found that the fourth domain of beta 2-GPI is involved in expression of one of the cryptic epitopes recognized by aCL. We also found that oxidized LDL are sequentially targeted by beta 2-GPI and aCL.
Lupus 1996 Oct
PMID:Anti-beta 2-glycoprotein I antibody: specificity and clinical significance. 890 64

Antiphospholipid' (aPL) antibodies are of important clinical significance because of their association with thrombosis both arterial and venous, recurrent foetal loss, specific neurological sequelae like seizures and chorea, cardiac valvular abnormalities and thrombocytopenia. Traditionally these autoantibodies have been assayed using phospholipid (PL) dependent tests and are classified as lupus anticoagulants (LA) and anticardiolipin (aCL) antibodies based on the method of detection. The antibodies thus, had been thought to bind PLs but it has now become clear that the true antigens are PL-binding proteins. The major protein consistently found as the target antigen for these autoantibodies is beta 2-glycoprotein I (beta 2-GPI). Other candidate PL-binding proteins have also been investigated including prothrombin, protein C and protein S but thus far appear to play less important roles in the binding of these antibodies.
Lupus 1996 Oct
PMID:beta 2-Glycoprotein I: target antigen for autoantibodies in the 'antiphospholipid syndrome'. 890 65

The Antiphospholipid Syndrome is defined by the association between peculiar clinical manifestations, namely arterial and/or venous thrombosis, recurrent abortions and thrombocytopenia, and the antiphospholipid antibodies. These antibodies are directed to plasma proteins bound to anionic phospholipids or other anionic surfaces: so far, beta 2-glycoprotein I is the best known and characterized antiphospholipid 'cofactor' (this issue is specifically treated in other parts of this journal). In recent years, such a role has been reported also for prothrombin, activated Protein C, Protein S, Annexin V, Thrombomodulin, high- and low-molecular weight kininogens. Anti-prothrombin antibodies are detected in approximately 50% of the antiphospholipid-positive patients; conversely, limited data are available regarding the prevalence the other antibodies. 'Cofactors' are necessary for the expression of both the immunological and the functional properties of their respective antiphospholipid antibodies. In particular, the recognition of the calcium-mediated prothrombin/lipid complex by anti-prothrombin antibodies hampers prothrombin activation, thus causing the prolongation of the phospholipid-dependent coagulation reactions. The interaction between antiphospholipid antibodies and natural inhibitors of coagulation such as activated Protein C, its non-enzymatic accessory protein Protein S or Thrombomodulin might increase the risk to develop thromboembolic events. Similarly, the presence of antibodies to surface-bound Annexin V has been hypothesized to play a role in recurrent abortions and fetal deaths. However, to clearly establish whether and which antiphospholipid antibodies represent risk factors for the thromboembolic events of the antiphospholipid syndrome, further studies of their behaviour and properties as well as the identification and characterization of (possibly) other antibodies are required.
Lupus 1996 Oct
PMID:Non beta 2-glycoprotein I cofactors for antiphospholipid antibodies. 890 67

Most autoantibodies associated with the antiphospholipid (aPL) syndrome and detected in standard anticardiolipin and/or lupus anticoagulant assays are directed against beta 2-glycoprotein I (beta 2-GPI) or prothrombin. Recent data indicate that these antibodies can also be detected in immunoassays utilizing purified protein antigens, in the absence of phospholipids. Initial clinical studies suggest that positivity in anti-beta 2-GPI immunoassays is more closely associated with the clinical manifestations of the aPL syndrome than is positivity in conventional anticardiolipin ELISAs. Anti-beta 2-GPI immunoassays may detect certain anti-beta 2-GPI antibodies that are not detectable in conventional anticardiolipin assays, but do not detect authentic (beta 2-GPI-independent) anticardiolipin antibodies. It appears that the former, but not the latter, antibodies are associated with the clinical manifestations of the aPL syndrome. The potential advantages and disadvantages of these new immunoassays in the clinical evaluation of the aPL syndrome are discussed.
Lupus 1996 Oct
PMID:Antigenic specificities of antiphospholipid autoantibodies: implications for clinical laboratory testing and diagnosis of the antiphospholipid syndrome. 890 74

The family of antiphospholipid antibodies includes antibodies binding to cardiolipin in serological test for syphilis, antibodies prolonging the clotting time in lupus anticoagulant test, antibodies reacting with plasma phospholipid-binding proteins, such as beta 2-glycoprotein I and prothrombin, and antibodies binding to oxidized low-density lipoprotein (LDL). Antiphospholipid antibodies are traditionally associated with arterial and venous thrombosis in patients with primary or secondary antiphospholipid syndrome. The recent studies, especially those on patients with myocardial infarction, extend the concept of antiphospholipid antibodies, and suggest that they play a role also in atherosclerosis. Based on the clinical studies and immunological findings, it seems that the differences in the specificity of antiphospholipid antibodies may reflect to their pathogenetic mechanisms and, finally, to their clinical consequences. The present review suggests that antibodies to oxidized LDL may not interfere directly with blood coagulation, but seem to have importance in the inflammation of the vessel wall in atherosclerosis and in vasculitis. Instead, antibodies to beta 2-glycoprotein I and to prothrombin show a closer association with thrombosis. It is possible that in the atherosclerotic plaque, the plasma proteins, such as beta 2-glycoprotein I or prothrombin, are bound to the endothelial surface and antibodies to cryptic epitopes revealed in these proteins are induced. These antibodies may contribute to the formation of atherosclerotic thrombosis by changing the balance of haemostasis toward hypercoagulative state.
Lupus 1996 Oct
PMID:Antiphospholipid antibodies and atherosclerosis. 890 78

beta 2-glycoprotein I (beta 2-GP-I) the plasma cofactor for anti-phospholipid antibodies adheres on the endothelial surfaces and can be recognized by anti-beta 2-GP-I antibodies naturally occurring in patients with the anti-phospholipid syndrome. As for the cofactor binding to cardiolipin- or gamma irradiated-plates, the endothelial binding is mediated by the so-called phospholipid binding site, a cationic structure able to react with anionic molecules. Endothelial monolayers appear to represent a substrate able to bind beta 2-GP-I and to present it in a suitable manner in order to allow the binding of anti-beta 2-GP-I beta 2 antibodies. The complex between beta 2-GP-I and the respective antibodies induce an endothelial cell activation as demonstrated by the up-regulation of adhesion molecule expression, the secretion of proinflammatory cytokines and the modulation of arachidonic acid metabolism. Taken together these findings strongly sustain a pivotal role for beta 2-GP-I in allowing antibody deposition on the endothelium and in affecting endothelial cell functions potentially responsible for a procoagulant state.
Lupus 1996 Oct
PMID:Modulation of endothelial cell function by antiphospholipid antibodies. 890 79

Lupus anti-DNA may have higher homology with germline than those from normal subjects. However, in NZB/NZW mice, bacterial DNA is more antigenic than mammal DNA, which could indicate an antigen-driven origin. High-affinity antibodies to double-stranded DNA cross-react with small nuclear ribonucleoprotein and ribosomal P proteins. These cross-reactive anti-DNA may penetrate live cells. Antibodies to ribosomal P proteins are associated with neuropsychiatric, renal, and hepatic lupus involvement. IgG antibodies to (H2A-H2B)-DNA complexes antedate procainamide-induced lupus. Autoantibodies to some La/Ro peptides in a mother indicates that her children may develop neonatal lupus and determine who will have congenital heart block. Perinuclear antineutrophil cytoplasmic antibodies are present in 25% of systemic lupus erythematosus patients without correlation with anti-DNA or disease activity. Different antiphospholipid antibodies require different protein cofactors for reactivity. Those to anionic phospholipids require beta 2-glycoprotein I, whereas anti-phosphatidylethanolamine antibodies require kininogen or its binding protein. Antibodies to phospholipid-free beta 2-glycoprotein I are associated more strongly with clinical antiphospholipid syndrome than are antiphospholipid antibodies.
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PMID:Autoantibodies in systemic lupus erythematosus. 894 42

Phospholipid dependent antibodies are usually measured with assays for antiphospholipid/anticardiolipin antibodies (aPLA) or for lupus anticoagulant (LA) activity. Most of them are targeted to complexes of beta 2-glycoprotein I (beta 2-GPI) and anionic phospholipids (PLP) or to prothrombin for some LA. New understandings allow a better standardisation and optimisation of assays' reactivity. Antigenic targets of phospholipid dependent antibodies were studied on plasmas from 38 patients with the antiphospholipid syndrome (APS) and presenting aPLA and/or LA. Using human beta 2-GPI-PLP complexes as solid phase antigen offers the highest sensitivity for measuring aPLA. Many aPLA, but not all, also react with beta 2-GPI coated on solid phase, however there is no evidence until now that this latter reactivity shows a closest association with the clinical context. Most of the patients with LA present an immunological reactivity to beta 2-GPI alone or to prothrombin, when these proteins are coated on solid phase. In two cases there was a reactivity to only beta 2-GPI-PLP complexes. For the various immunoassays, using NUNC type I plates offers a good binding capacity for coating antigens. They are then present at enough density on solid phase for insuring an efficient binding of autoantibodies. This is an important factor for assay sensitivity and reproducibility. Interestingly, in 1 case with LA, autoantibodies were reactive with coated beta 2-GPI alone but not with its PLP-complexes. In another case reactivity to beta 2-GPI was much higher than that to beta 2-GPI-PLP.
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PMID:Different target specificities of phospholipid-dependent antibodies. 895 54

There has been a recent, dramatic surge in interest in antiphospholipid antibodies and associated clinical disorders, especially focal ischemic cerebrovascular disease. Antiphospholipid antibodies are a heterogeneous group of antibodies with varying specificities. Coagulation assays will detect lupus anticoagulants while enzyme-linked immunosorbent assays detect anticardiolipin antibodies. There are numerous potential links between antiphospholipid antibodies and coagulation disorders, including interaction of antiphospholipid antibodies and a cofactor, beta 2-glycoprotein I, which itself is involved in coagulation mechanisms. While the specific mechanism of antiphospholipid antibody-related coagulopathy is unknown, it is clear that antiphospholipid antibodies are associated with an immune-mediated prothrombotic state. Patients with the highest titers of IgG antiphospholipid antibodies have a relatively high risk of recurrent thrombotic events, especially stroke, deep venous thrombosis, and spontaneous abortion. Because of limited controlled, prospective data, current therapy remains empiric and directed at coagulation mechanisms, immune mechanisms, or both.
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PMID:Cerebrovascular disease with antiphospholipid antibodies: immune mechanisms, significance, and therapeutic options. 896 22


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