Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A multicenter study was set up to evaluate the prevalence, clinical and biological significance of antiphosphatidylethanolamine antibodies (aPE) in thrombotic patients with or without the main known clinical and biological risk factors for thrombosis. APE and antibodies, defined as the laboratory criteria of antiphospholipid syndrome (APS) -lupus anticoagulant, anticardiolipin and anti-beta(2)-GPI antibodies were measured in 270 patients with thrombosis (234 venous and 37 arterial) and 236 matched controls. APE were found in 15% of thrombotic patients compared to 3% of controls (p < 0.001) with no predominant isotype, no association with the main known clinical or biological risk factors for thrombosis neither with a type of thrombosis, arterial or venous. In a multivariate logistic regression analysis of antibodies, aPE showed the highest association with thrombosis (odds ratio [OR]: 4.2, p < 0.001). Moreover, using a multivariate analysis in a case-control subgroup study on 158 patients, IgGaPE were found to be significantly associated with venous thrombosis (OR:6;p = 0.005). Interestingly, 25 of the 40 aPE-positive patients (63%) were negative for the APS laboratory criteria. Most of them (21/25) had venous thrombosis, recurrent in ten of them. Four patients also suffered from early or late miscarriages. Our results underline the strength of the association between the presence of aPE and thrombosis and suggest their measurement in thrombotic patients, especially when lupus anticoagulant, anticardiolipin or anti-beta(2)-GPI antibodies are absent.
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PMID:Antiphosphatidylethanolamine antibodies are associated with an increased odds ratio for thrombosis. A multicenter study with the participation of the European Forum on antiphospholipid antibodies. 1754 97

The immunolocalization of oxidized low-density lipoproteins (ox-LDL), beta2-glycoprotein I (beta(2)GPI), CD4(+)/CD8(+) immunoreactive lymphocytes, and immunoglobulins in atherosclerotic lesions strongly suggested an active participation of the immune system in atherogenesis. Oxidative stress leading to ox-LDL production is thought to play a central role in both the initiation and progression of atherosclerosis. ox-LDL is highly proinflammatory and chemotactic for macrophage/monocyte and immune cells. Enzyme-linked immunosorbent assays (ELISAs) to measure circulating ox-LDL have been developed and are being currently used to assess oxidative stress as risk factor or marker of atherosclerotic disease. ox-LDL interacts with beta(2)GPI and circulating ox-LDL/beta(2)GPI complexes have been demonstrated in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). It has been postulated that beta(2)GPI binds ox-LDL to neutralize its proinflammatory and proatherosclerotic effects. Because beta(2)GPI is ubiquitous in plasma, its interaction with ox-LDL may mask oxidized epitopes recognized by capture antibodies potentially interfering with immunoassays results. The measurement of ox-LDL/beta(2)GPI complexes may circumvent this interference representing a more physiological and accurate way of measuring ox-LDL.
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PMID:Determination of oxidized low-density lipoproteins (ox-LDL) versus ox-LDL/beta2GPI complexes for the assessment of autoimmune-mediated atherosclerosis. 1778 19

Anti-prothrombin (anti-PT) antibodies are recently identified antibodies directed toward a phospholipid-binding protein (prothrombin), which deserve attention for the reported clinical and pathogenic relevance in antiphospholipid syndrome and systemic lupus erythematosus (SLE). We have recently carried out a longitudinal study on the predictive value of anti-PT antibodies in SLE showing that they have a higher diagnostic accuracy for thrombosis than anti-beta(2)-GPI and anticardiolipin antibodies, and, along with LAC activity, are the best predictors of thromboembolic events in SLE patients.
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PMID:Biological and clinical relevance of anti-prothrombin antibodies. 1778 39

It has been demonstrated that atherosclerosis (ATS) is enhanced in autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE). The reason for this accelerated process is still debatable and, although traditional risk factors are more prevalent in SLE patients than in general population, they do not seem to fully explain the enhanced risk. ATS has the characteristics of an autoimmune chronic disease, involving both the innate and the adaptive immunity. Moreover, it satisfies the four criteria defining an autoimmune disease, proposed by Witebsky and Rose. It has been shown that some autoantibodies, including anti-oxLDL, anti-beta(2)GPI, anti-HSP60/65, and more recently anti-oxLDL/beta(2)GPI, play a key role in the pathogenesis of ATS. However the role of these autoantibodies in accelerated ATS in SLE patients is still controversial. In fact, some of them seem to be proatherogenic and other protective; moreover, it has been demonstrated that induced oral tolerance has a protective role against ATS. We have recently observed that the levels of oxLDL/beta(2)GPI antigenic complexes and their antibodies were higher in patients with SLE than in healthy subjects, but we did not find a clear association between oxLDL/beta(2)GPI complexes and IgG or IgM anti-oxLDL/beta(2)GPI autoantibodies and subclinical ATS in SLE patients. Many other studies are required to explain the role of autoantibodies in the pathogenesis of ATS in SLE patients, because the characteristics of SLE seem to mask their effects for atherogenesis.
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PMID:OxLDL/beta2GPI-anti-oxLDL/beta2GPI complex and atherosclerosis in SLE patients. 1796 26

Several interpretations have been made regarding the specificity of antiphospholipid antibodies and antibodies against oxidized low-density lipoprotein (oxLDL), but these are still controversial. In the present study, we delineated specificity of these two types of antibodies and analyzed their regulatory effect on oxLDL and/or beta( 2)-glycoprotein I (beta(2)GPI) binding to macrophages. Scavenger receptor-mediated binding of oxLDL (or its beta(2)GPI complexes) to macrophages was observed and the binding was partly prevented by beta( 2)GPI. The IgG monoclonal anti-beta(2)GPI antibody (WB-CAL-1), which was derived from NZW x BXSB F1 mouse (a model of antiphospholipid syndrome), significantly increased the oxLDL/beta(2)GPI binding to macrophages. In contrast, IgM anti-oxLDL natural antibody, EO6 (derived from apoe( -/-) mouse), prevented the binding. Different antigenic specificity of these antibodies to oxLDL and its beta(2)GPI complexes was also confirmed in TLC-ligand blot and ELISA. Thus, IgG anti-beta(2) GPI autoantibodies contribute to lipid metabolism (housekeeping of oxLDL by macrophages) whereas IgM natural anti-oxLDL antibodies may protect against atherogenesis. In addition, in vitro data suggest that relatively high dose of intravenous immunoglobulin preparations (mainly contain IgG anti-oxLDL antibodies) might also prevent atherogenesis by inhibiting the oxLDL binding to macrophages.
Lupus 2007
PMID:Distinguished effects of antiphospholipid antibodies and anti-oxidized LDL antibodies on oxidized LDL uptake by macrophages. 1804 86

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

Oxidative modification of low-density lipoprotein (LDL) is one of the earliest events in atherosclerosis. Oxidized LDL (oxLDL) represents a variety of modification of both lipid and apolipoprotein B (apoB) components by lipid peroxidation. This promotes atherosclerosis through inflammatory and immunologic mechanisms that lead to the formation of macrophage foam cells. Recent findings also suggest that oxLDL forms complexes with beta(2)-glycoprotein I (beta(2)GPI) and/or C-reactive protein (CRP) within atherosclerotic lesions and that these complexes appear in the circulation. Autoantibodies (auto-Abs) against oxLDL/beta(2)GPI complexes occur in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). These autoantibodies significantly correlate with arterial thrombosis. IgG auto-Abs having similar specificity emerge spontaneously in NZWxBXSB F1 mice, which generally are considered to be an animal model of APS, and these mice produce a monoclonal IgG auto-Ab (WB-CAL-1) against oxLDL/beta(2)GPI complexes. WB-CAL-1 significantly increased the in vitro uptake of oxLDL/beta(2)GPI complexes by macrophages, which suggests that such IgG auto-Abs are pro-atherogenic. In contrast, IgM anti-oxLDL natural Abs found in the atherosclerosis-prone mice have been proposed to be protective. The presence of such Abs in humans has been documented in many publications but their exact pathophysiological significance remains unclear. In this article, we review recent progress in our understanding of the clinical significance of oxidation of LDL, formation of oxLDL complexes, and Abs in atherosclerotic and/or autoimmune disease.
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PMID:Oxidation of LDL and its clinical implication. 1862 45

The antiphospholipid syndrome (APS) is an acquired thrombophilia, characterized by the occurrence of venous and arterial events. This article examines the laboratory and key clinical aspects of APS. Particular focus is given to anti-beta 2-glycoprotein I (beta(2)GPI) antibodies in view of their recent inclusion in the APS classification criteria. The clinical utility of using the beta(2)GPI enzyme-linked immunosorbent assay, in conjunction with the established lupus anticoagulant assays and cardiolipin enzyme-linked immunosorbent assay, for diagnosing and risk stratifying patients suspected of having APS is discussed. The relative importance of the various assays in diagnosing obstetric APS (early and late gestation miscarriages) is explored. The implications of recent epidemiologic findings for possibly understanding the underlying pathophysiologic mechanisms of obstetric APS are highlighted. Insights into which patients with obstetric APS may be at most risk of thrombotic complications are presented.
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PMID:How we diagnose the antiphospholipid syndrome. 1875 86

In the antiphospholipid syndrome (APS), pathogenic antiphospholipid antibodies (aPL) that cause thrombosis or pregnancy morbidity are characterized by binding to anionic phospholipids (PL) and beta2-glycoprotein I (beta(2)GPI). Sequence analysis of human monoclonal aPL has shown that high affinity for these antigens is associated with the presence of three particular amino acids: arginine (Arg), asparagine and lysine in the complementarity determining regions (CDRs) of their heavy and light chains. In vitro expression systems have been used to create variants of the antibodies in which these amino acids have been altered. In general, removal of Arg residues reduces affinity for anionic PL and beta(2)GPI. Arg at different positions in the sequence, however, have different effects on binding affinity and effects on binding are not always mirrored by effects on pathogenicity. This review will focus upon the sequence motifs that have been found to distinguish pathogenic from non-pathogenic aPL, and whether these or other properties may help to identify distinct pathogenic subsets of aPL. In particular, we will focus on our recent work in which we are trying to develop a better understanding of the molecular mechanisms involved in activation of target cells by pathogenic aPL. These studies, together with molecular models of antigen/antibody complexes, help us to understand exactly how pathogenic antibodies interact with antigens. Ultimately, this understanding may aid the design of more powerful diagnostic/prognostic assays and targeted therapeutic agents to block the pathogenic effects of these antibodies.
Lupus 2008 Oct
PMID:Examining the non-linear relationship between monoclonal antiphospholipid antibody sequence, structure and function. 1882 54

It is generally accepted that the major autoantigen for antiphospholipid antibodies (aPL) is beta(2)glycoprotein I (beta(2)GPI). Interestingly, some aPL bind to beta(2)GPI and the homologous enzymatic domains of several proteases involved in hemostasis and fibrinolysis, and correspondingly hinder anticoagulant regulation and resolution of clots. These findings are consistent with several early findings of aPL and provide a new perspective about some aPL in terms of their binding specificities and related functional properties in promoting thrombosis. In addition, homologous enzymatic domains of the involved proteases share conformation epitope(s) with beta(2)GPI, thus providing a possible structural basis for some non-mutually exclusive mechanisms of aPL-mediated thrombosis.
Lupus 2008 Oct
PMID:Some antiphospholipid antibodies bind to hemostasis and fibrinolysis proteases and promote thrombosis. 1882 56


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