What causes the antiphospholipid syndrome?

Merrill, Joan T.

doi:10.1007/s11926-001-0033-2

Cited by 6 publications

(5 citation statements)

References 93 publications

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“…The second hypothesis is based on the recognition of a cryptic epitope by aPL antibodies. This epitope is only exposed after binding of β2-GPI to a negatively charged surface (Wang et al, 2000;Merrill, 2001). Supporting this latter hypothesis is the fact that the structure of β2-GPI in solution differs from that of crystallized β2-GPI.…”

Section: Direct Activity Of Anti-b2-gpi Antibodies In Reproductive Failurementioning

confidence: 94%

Pathogenic role of anti-β2-glycoprotein I antibodies on human placenta: functional effects related to implantation and roles of heparin

Simone¹,

Meroni²,

D’Asta³

et al. 2006

Human Reproduction Update

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Most of the clinical manifestations of the antiphospholipid syndrome (APS) can be related to thrombotic events; however, placental thrombosis cannot explain all of the pregnancy complications that occur in women with this syndrome. In this regard, it has been hypothesized that antiphospholipid (aPL) antibodies can directly attack trophoblasts, but it is still unclear what pathogenetic mechanisms play a role and which aPL antibodies subpopulations are involved. Although it has been assumed that aPL antibodies are directed against anionic phospholipids (PLs), current advances in the field suggest that antibodies to PL-binding plasma protein such as beta2-glycoprotein-I (beta2-GPI) are the clinically relevant aPL antibodies. It appears that following the attachment of beta2-GPI to PLs, both molecules undergo conformational changes that result in the exposure of cryptic epitopes within the structure of beta2-GPI allowing the subsequent binding of antibodies. aPL antibodies detected by anti-beta2-GPI assays are associated with fetal loss. However, there is still debate on how the antibodies might induce the obstetrical manifestations. The significantly improved outcome of pregnancies treated with heparin has stimulated interest in the drug's mechanisms of action. Several mechanisms could explain its beneficial effects, because in addition to a direct effect of heparin on the coagulation cascade, it might protect pregnancies by reducing the binding of aPL antibodies, reducing inflammation, facilitating implantation and/or inhibiting complement activation. Further investigations are needed to better understand how aPL antibodies induce obstetric complications and to better clarify the functional role of heparin in the human placenta leading to more successful therapeutic options.

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Section: Direct Activity Of Anti-b2-gpi Antibodies In Reproductive Failurementioning

confidence: 94%

Pathogenic role of anti-β2-glycoprotein I antibodies on human placenta: functional effects related to implantation and roles of heparin

Simone¹,

Meroni²,

D’Asta³

et al. 2006

Human Reproduction Update

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show abstract

“…This hypothesis is based on the recognition of a cryptic epitope by aPL. This epitope is only exposed after the binding of β2GPI to a negatively charged surface 44,45 . Supporting this latter hypothesis is the fact that the structure of β2GPI in solution differs from that of crystallized β2GPI 29,35,46,47 …”

Section: Introductionmentioning

confidence: 96%

Antiphospholipid Antibodies: Effects on Trophoblast and Endothelial Cells

D’Ippolito

Simone

Nicuolo

et al. 2007

American J Rep Immunol

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“…This epitope is only exposed after binding of ␤ 2 -GPI to a negatively charged surface. [16][17][18] Supporting this latter hypothesis is the fact that the structure of ␤ 2 -GPI in solution differs from that of crystallized ␤ 2 -GPI. 9,10,19 Moreover, no ␤ 2 -GPI-antibody complexes can be detected in the circulation of patients with the antiphospholipid syndrome (B.d.L., unpublished observations, May 2004).…”

Section: Introductionmentioning

confidence: 99%

Pathogenic anti-β2-glycoprotein I antibodies recognize domain I of β2-glycoprotein I only after a conformational change

Laat

Derksen

Lummel

et al. 2006

Blood

204

218

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Recently, we published the existence of 2 populations of anti-␤ 2 -glycoprotein I (␤ 2 -GPI) IgG antibodies. Type A antibodies recognize epitope G40-R43 in domain I of ␤ 2 -GPI and are strongly associated with thrombosis. Type B antibodies recognize other parts of ␤ 2 -GPI and are not associated with thrombosis. In this study we demonstrate that type A antibodies only recognize plasma-purified ␤ 2 -GPI when coated onto a negatively charged surface and not when coated onto a neutrally charged surface. The affinity of type B antibodies toward plasma-purified ␤ 2 -GPI was independent of the charge of the surface to which ␤ 2 -GPI was coated. Type A antibodies did not recognize plasmapurified ␤ 2 -GPI in solution, whereas they did recognize recombinant ␤ 2 -GPI both in solution and coated onto a neutrally charged plate. When the carbohydrate chains were removed from plasma-purified ␤ 2 -GPI, we found that type A antibodies did recognize the protein in solution. This supports the hypothesis that the difference in recognition of plasma-purified and recombinant ␤ 2 -GPI is caused by the difference in glycosylation and that epitope G40-R43 of plasma-purified ␤ 2 -GPI is covered by a carbohydrate chain. Type A anti-␤ 2 -GPI antibodies can only recognize this epitope when this carbohydrate chain is displaced as a result of a conformational change. This finding has major implications both for the detection of pathogenic anti-␤ 2 -GPI antibodies and the comprehension of the pathophysiology of the antiphospholipid syndrome.

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What causes the antiphospholipid syndrome?

Cited by 6 publications

References 93 publications

Pathogenic role of anti-β2-glycoprotein I antibodies on human placenta: functional effects related to implantation and roles of heparin

Pathogenic role of anti-β2-glycoprotein I antibodies on human placenta: functional effects related to implantation and roles of heparin

Antiphospholipid Antibodies: Effects on Trophoblast and Endothelial Cells

Pathogenic anti-β2-glycoprotein I antibodies recognize domain I of β2-glycoprotein I only after a conformational change

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