The association between circulating antibodies against domain I of beta2‐glycoprotein I and thrombosis: an international multicenter study

Laat, Bas de; Pengo, Vittorio; Pabinger, Ingrid; Musiał, Jacek; Voskuyl, Alexandre E.; Bultink, Irene E. M.; Ruffatti, Amelia; Rozman, B; Kveder, T; Moerloose, P de; Boehlen, Françoise; Rand, Jacob H.; Z, Ulcová-Gallová; Mertens, Koen; Groot, Philip G. de

doi:10.1111/j.1538-7836.2009.03588.x

Cited by 264 publications

(248 citation statements)

References 20 publications

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“…1(A)], 14 whereas it interacts with pathogenic aAbs by the N-terminal domain (DmI). 4,15 Of note, high plasma levels of anti-b2GpI…”

Section: Introductionmentioning

confidence: 99%

“…5 b2GpI is now recognized as the major autoantigen involved in APS, 3,6 and the presence of anti-b2GpI Abs strongly correlates with the occurrence of thrombotic events in APS patients. 4,7 The mature sequence of human b2GpI consists of 326 amino acids with four N-linked carbohydrate chains, 8,9 localized in the third and fourth domain (see below) and accounting for about 19% of the protein mass (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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Chemical synthesis and characterization of wild‐type and biotinylated N‐terminal domain 1–64 of β2‐glycoprotein I

et al. 2010

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The antiphospholipid syndrome (APS) is a severe autoimmune disease associated with recurrent thrombosis and fetal loss and characterized by the presence of circulating autoantibodies (aAbs) mainly recognizing the N-terminal domain (DmI) of b2-glycoprotein I (b2GpI). To possibly block anti-b2GpI Abs activity, we synthesized the entire DmI comprising residues 1-64 of b2GpI by chemical methods. Oxidative disulfide renaturation of DmI was achieved in the presence of reduced and oxidized glutathione. The folded DmI (N-DmI) was purified by RP-HPLC, and its chemical identity and correct disulfide pairing (Cys4-Cys47 and Cys32-Cys60) were established by enzymatic peptide mass fingerprint analysis. The results of the conformational characterization, conducted by far-and near-UV CD and fluorescence spectroscopy, provided strong evidence for the native-like structure of DmI, which is also quite resistant to both Gdn-HCl and thermal denaturation. However, the thermodynamic stability of N-DmI at 37°C was remarkably low, in agreement with the unfolding energetics of small proteins. Of note, aAbs failed to bind to plates coated with N-DmI in direct binding experiments. From ELISA competition experiments with plate-immobilized b2GpI, a mean IC 50 value of 8.8 lM could be estimated for N-DmI, similar to that of the full-length protein, IC 50 (b2GpI) 5 6.4 lM, whereas the cysteine-reduced and carboxamidomethylated DmI, RC-DmI, failed to bind to anti-b2GpI Abs. The versatility of chemical synthesis was also exploited to produce an N-terminally biotin-(PEG) 2 -derivative of N-DmI (Biotin-N-DmI) to be possibly used as a new tool in APS diagnosis. Strikingly, Biotin-N-DmI loaded onto a streptavidin-coated plate selectively recognized aAbs from APS patients.

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“…1(A)], 14 whereas it interacts with pathogenic aAbs by the N-terminal domain (DmI). 4,15 Of note, high plasma levels of anti-b2GpI…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemical synthesis and characterization of wild‐type and biotinylated N‐terminal domain 1–64 of β2‐glycoprotein I

et al. 2010

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“…Moreover, autoantibodies against b2GPI consist of heterogeneous populations including subclasses directed against various epitopes of the molecule . Only the subpopulation that recognizes specific epitopes on domain I of b2GPI showed a good correlation with thrombosis and pregnancy morbidity (de Laat et al, 2006(de Laat et al, , 2009. Interestingly, Colasanti et al (2012) proposed a novel pathogenic mechanism in which autoantibodies specific to a peptide of the b2GPI domain I, which shares 88% identity with an epitope of human TLR4 and is present in serum from APS and SLE patients, are able to directly engage human TLR4 in b2GPI-independent manner, inducing a pro-inflammatory phenotype in ECs and monocytes.…”

Section: Open Questionsmentioning

confidence: 99%

“…In circular b2GPI, the epitopes for the autoantibodies interacts with domain V of the same molecule. After binding to anionic surfaces, b2GPI changes conformation, thus exposing the hidden epitopes recognizable by the autoantibodies in the APS, especially the cryptic epitope (Gly40-Arg43) on the domain I of b2GPI, which is recognized by anti-b2GPI antibodies (de Laat et al, 2006(de Laat et al, , 2009.…”

Section: B2-glycoprotein I (B2gpi) and Its Receptors On The Cell Surfacementioning

confidence: 99%

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

et al. 2013

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SummaryThe antiphospholipid syndrome (APS) is an autoimmune disease characterized by the clinical features of recurrent thrombosis in the venous or arterial circulation and fetal losses. Antiphospholipid antibodies (aPL), particularly against the phospholipid binding protein beta-2 glycoprotein I (b2GPI), play an important role in APS pathological mechanisms. aPL can activate intracellular signal transduction in a b2GPI-dependent manner to induce inflammatory responses, and promote hypercoagulable state and recurrent spontaneous abortion when b2GPI is associated with the cell surface receptor. In vivo and in vitro studies show that Annexin A2 (ANXA2) is the high affinity receptor that connects b2GPI to the target cells. However, ANXA2 is not a transmembrane protein and lacks an intracellular signal transduction pathway. Growing evidences suggest that the transmembrane protein toll-like receptor 4 (TLR4) might act as an 'adaptor' for intracellular signal transduction. This review focuses on the role of TLR4 and its signalling pathway in APS pathological mechanisms which will help us better understand the pathological processes of this syndrome.

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“…Another multicenter study from the same group reported that 55% of patients with various autoimmune diseases, all positive for anti-b 2 GPI, had anti-domain I antibodies. 89 These patients had an odds ratio of 3.5 for thrombosis compared to those without anti-domain 1 antibodies. Additionally, they found that anti-domain I antibodies were associated with pregnancy morbidity.…”

Section: The Epitopes Of Apl and Treatment Outcomementioning

confidence: 99%

Management of Women with Recurrent Pregnancy Losses and Antiphospholipid Antibody Syndrome

Kwak‐Kim

Agcaoili

Aleta

et al. 2013

American J Rep Immunol

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Antiphospholipid antibodies (aPL) have been associated with recurrent pregnancy losses (RPL) and other obstetrical complications. The diagnostic criteria for the classical antiphospholipid antibody syndrome (APS) have been utilized for the detection of obstetrical APS in women with RPL. However, laboratory findings and immunopathology of obstetrical APS are significantly different from those of classical APS. In addition, many women with RPL who have positive aPL do not have symptoms consistent with the current APS criteria. The induction of a proinflammatory immune response from trophoblasts and complement activation by aPL rather than thromboembolic changes has been reported as a major immunopathological feature of obstetrical APS. Heparin treatment has been reported to be effective in prevention of early pregnancy loss with APS but not for the late pregnancy loss or complications. The complex effects of heparin may explain the limited efficacy of heparin treatment in RPL. New diagnostic criteria for obstetrical APS are needed urgently, and new therapeutic approaches should be explored further.

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The association between circulating antibodies against domain I of beta2‐glycoprotein I and thrombosis: an international multicenter study

Cited by 264 publications

References 20 publications

Chemical synthesis and characterization of wild‐type and biotinylated N‐terminal domain 1–64 of β2‐glycoprotein I

Chemical synthesis and characterization of wild‐type and biotinylated N‐terminal domain 1–64 of β2‐glycoprotein I

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

Management of Women with Recurrent Pregnancy Losses and Antiphospholipid Antibody Syndrome

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