Molecular analysis of major histocompatibility complex alleles associated with the lupus anticoagulant.

Arnett, Frank C.; Olsen, Mary L.; Anderson, K O; Reveille, John D.

doi:10.1172/jci115158

Cited by 113 publications

(60 citation statements)

References 34 publications

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“…Strong HLA class II antigen correlations have been found for several autoantibodies, including LA and ACA, in patients with some autoimmune diseases. 36 Therefore, further studies are necessary to clarify multiple genetic factors that are definitely linked with MMS in different ethnic groups.…”

Section: Discussionmentioning

confidence: 99%

Prothrombotic Disorders in Children With Moyamoya Syndrome

Bonduel¹,

Hepner

Sciuccati

et al. 2001

Stroke

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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–β 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–β 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.

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Section: Discussionmentioning

confidence: 99%

Prothrombotic Disorders in Children With Moyamoya Syndrome

Bonduel¹,

Hepner

Sciuccati

et al. 2001

Stroke

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“…Analyses of T cell subsets (77), HLA class I1 associations (78), and IgG subclass distribution (79) and V gene analysis (80) suggest that T lymphocytes play an important role in autoantibody production and disease pathogenesis. It has recently been shown that T cells are critical in the transfer of A P S by bone marrow transplantation in an animal model (81).…”

Section: Immunopathogenesis Of Apsmentioning

confidence: 99%

Immunology of the antiphospholipid antibody syndrome

Roubey

1996

Arthritis & Rheumatism

286

170

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Like the femme fatale in The Beatles' Rocky Raccoon, antiphospholipid antibodies (aPL) and the syndrome with which they are associated (thrombosis, recurrent fetal deaths, thrombocytopenia) have attracted considerable attention despite a serious nomenclature problem. Along with increasing experience in the optimal management of patients with the aPL syndrome and growing evidence that autoantibodies may play a direct pathophysiologic role, research over the past several years demonstrates that a large proportion of "antiphospholipid" autoantibodies do not, in fact, recognize phospholipids. These new data indicate that the antigenic targets of antibodies detected in conventional anticardiolipin and lupus anticoagulant assays are phospholipid-binding plasma proteins, most notably, &-glycoprotein I (&GPI) and prothrombin or complexes of these proteins with phospholipids. Further, autoantibodies to other phospholipid-binding plasma proteins and certain molecules expressed on vascular endothelium may also be associated with the antiphospholipid antibody syndrome (APS) although they are not detectable in standard aPL assays.This review summarizes recent information on the specificities of autoantibodies associated with APS and discusses the insights these data offer into the potential role of autoantibodies in the syndrome's pathophysiology. Antigenic specificities of aPL: historical perspective Current concepts of aPL date to the early part of this century and the development of nontreponemal serologic tests for syphilis (STS). In the early 1940s, Mary Pangborn identified the antigenic component of the tissue extracts used in these tests as a novel anionic phospholipid, which she named cardiolipin (1). As a result of widespread population screening for syphilis, in the 1950s it was observed that individuals with chronically false-positive STS results, when followed up for many years, often developed systemic lupus erythematosus (SLE) (2). False-positive STS results were also noted to be present in early reports of SLE patients with acquired inhibitors of in vitro phospholipid-dependent coagulation tests, in particular, the activation of prothrombin (3). Laurel1 and Nilsson investigated this association and suggested that the anticoagulant effect and the positive reactions with phospholipid antigen were ascribable to the same causal factor (4). Additional support for the hypothesis that these acquired coagulation inhibitors were directed against phospholipid came from studies demonstrating that the anticoagulant effect was enhanced when the phospholipid in the test system was diluted (5).In contrast, a number of key features of the inhibitors, subsequently termed lupus anticoagulants (6), were not compatible with phospholipid specificity and suggested an important role of plasma proteins. First, certain lupus anticoagulants were species specific, for example, they prolonged coagulation reactions of human plasma but not bovine plasma (7). Second, certain lupus anticoagulants did not inhibit phospholipid-dependent reacti...

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“…Hartung et al [29] reported that HLA-DR4 and DR7 were increased in aCL positive patients in European SLE populations and aCL were significantly associated with DRw53. In a study of 20 patients with SLE and LA, an association with HLA-DQw7 (HLA DQB1*0301) linked to HLA-DR4 and/or -DR5 haplotypes was found in 70 % of patients and was significantly increased compared with 139 matched control individuals (p = 0.002) [30]. According to this study, several HLA-DQB1 alleles shared a common aminoacid sequence (positions 71-77) in the third hypervariable region of the outermost domain.…”

Section: Genes Associated With Antiphospholipid Syndromementioning

confidence: 99%

Genetics of Antiphospholipid Syndrome

Hancer¹

2011

Human Genet Embryol

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Antiphospholipid syndrome (APS) is defined as recurrent arterial and/or venous thrombosis and obstetric complications in the presence of antiphospholipid antibodies (aPL). The possibility of a genetic predisposition to develop antiphospholipid syndrome (APS) and to produce anticardiolipin antibodies and lupus anticoagulant has been examined by family studies and population studies. Similar to many other polygenic autoimmune diseases, human leukocyte antigen associations have been reported. The genetics of β2-glycoprotein I, one of the most representative target antigens of aPL, has been extensively studied. Additional genetic risk factors for the development of thrombosis in patients with aPL have also been discussed. Although the mechanisms and pathophysiology of thrombosis in APS are highly heterogeneous and multifactorial, different genes seem to be involved.The term "antiphospholipid syndrome" has been proposed to describe the association of arterial and venous thrombosis, recurrent fetal loss, and immune thrombocytopenia with a spectrum of autoantibodies directed against cellular phospholipid components. Because of the antigen spesifity of antiphospholipid antibodies (aPL) and the pathophysiology of thrombosis in antiphospholipid syndrome (APS) are heterogeneous and multifactorial, a single scenario can not explain the mechanisms of thrombophilia or pregnancy morbidity in pateints. Investigation of the clinical epidemiology of APS is in its early stages. During the past 20 years, studies of aPL and APS have been made in many countries [1][2][3][4][5][6][7][8][9][10][11]. aPL appear to occur in all populations studied, with some variations noted in their frequency and in the clinical complications [1,9,10,12,13]. Environmental and genetic factors contribute to ethnic variation and susceptibility to APS and thus interethnic differences in disease patterns may be due to environmental or genetic factors, or both [1,14]. A genetic basis for aPL antibodies was suggested for the first time when a familial clustering of chronic false-positive syphilis test individuals were detected [15]. The first description about aPL showed two pairs of siblings with lupus anticoagulant (LA) [16]. Subsequently, primary APS was described [17] and Cevallos et al. [18] reported the development of primary APS in one woman whose identical twin sister was an asymptomatic carrier of aPL. Relatives of patients with sistemic lupus erythematosus (SLE) or primary APS had a higher incidence of anticardiolipin antibodies (aCL) [19,20] suggesting that a genetic factor may relevant with aPL. Mackie et al. [21] reported three families having more than one member with LA and called familial lupus anticoagulants. The identification of several pedigrees with an increased frequency of aPL antibodies and the associated clinical manifestations further support the familial form of APS. In one of these studies, a large kindred in which nine individuals had aPL antibodies was described. Associated clinical manifestations included stroke, deep ve...

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Molecular analysis of major histocompatibility complex alleles associated with the lupus anticoagulant.

Cited by 113 publications

References 34 publications

Prothrombotic Disorders in Children With Moyamoya Syndrome

Prothrombotic Disorders in Children With Moyamoya Syndrome

Immunology of the antiphospholipid antibody syndrome

Genetics of Antiphospholipid Syndrome

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