Current Insights into the “Antiphospholipid” Syndrome: Clinical, Immunological, and Molecular Aspects

Kandiah, David Arumaisingam; Šali, Andrej; Sheng, Yonghua; Victoria, Edward J.; Marquis, David M.; Coutts, Stephen M.; Krilis, Steven A.

doi:10.1016/s0065-2776(08)60393-4

Cited by 75 publications

(63 citation statements)

References 203 publications

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“…Recurrent miscarriage constitutes one of the main features of APS [1,2]; however, the pathogenic mechanisms remain unknown and indeed evidence of a causal link has proven difficult to generate. Early experiments incubating aPL with human placental trophoblast cells showed inhibition of proliferation and secretory activity was elicited by antibodies reacting with h 2 GPI, confirming the involvement of h 2 GPI in APS-related pregnancy loss, and suggesting that h 2 GPI contains the critical antigenic determinants for anticardiolipin antibodies [48].…”

Section: Gpi and Pregnancy Lossmentioning

confidence: 99%

“…It must be emphasized that considerable homology in structure exists between human and mouse h 2 GPI [1,76]. This assigns the mouse as a very useful tool for elucidating the role of h 2 GPI, both in homeostasis and in APS.…”

Section: Gpi and Pregnancy Lossmentioning

confidence: 99%

“…The antiphospholipid antibody syndrome (APS) is determined by a constellation of clinical features (mainly recurrent venous and arterial thrombosis, recurrent fetal loss, and livedo reticularis) in combination with the detection of antiphospholipid antibodies (aPL) in the sera of affected patients [1,2]. The disorder may occur alone (referred as the primary APS) or in association with systemic lupus erythematosus (SLE), other autoimmune diseases, and rarely with other diseases, certain infections, and drugs (secondary APS) [2 -5].…”

Section: Introductionmentioning

confidence: 99%

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Beta-2 glycoprotein I and its role in antiphospholipid syndrome—lessons from knockout mice

Miyakis

Robertson

Krilis

2004

Clinical Immunology

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The antiphospholipid syndrome is characterized by the presence in serum of autoantibodies against h2GPI. Although the role of h2GPI in the pathogenesis of antiphospholipid antibody syndrome (APS) is well recognized, its exact physiological functions still remain undisclosed. Several interactions of h2GPI with components of the coagulation cascade have been proposed, resulting in both procoagulant and anticoagulant effects. Additionally, h2GPI has been implicated in the mechanism of recurrent fetal loss entailed in APS. Recently, using a homologous recombination approach, reproduction of mice homozygous for deletion of the b2GPI gene has been feasible. h2GPI knockout mice offer a valuable tool for revealing the physiological role of the protein. These mice show decreased in vitro ability for thrombin generation. Furthermore, although mice lacking h2GPI are fertile, the success of early pregnancy is moderately compromised and functional h2GPI is believed necessary for optimal implantation and placental morphogenesis. AbstractThe antiphospholipid syndrome is characterized by the presence in serum of autoantibodies against h 2 GPI. Although the role of h 2 GPI in the pathogenesis of antiphospholipid antibody syndrome (APS) is well recognized, its exact physiological functions still remain undisclosed. Several interactions of h 2 GPI with components of the coagulation cascade have been proposed, resulting in both procoagulant and anticoagulant effects. Additionally, h 2 GPI has been implicated in the mechanism of recurrent fetal loss entailed in APS. Recently, using a homologous recombination approach, reproduction of mice homozygous for deletion of the b 2 GPI gene has been feasible. h 2 GPI knockout mice offer a valuable tool for revealing the physiological role of the protein. These mice show decreased in vitro ability for thrombin generation. Furthermore, although mice lacking h 2 GPI are fertile, the success of early pregnancy is moderately compromised and functional h 2 GPI is believed necessary for optimal implantation and placental morphogenesis. D

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Section: Gpi and Pregnancy Lossmentioning

confidence: 99%

Section: Gpi and Pregnancy Lossmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Beta-2 glycoprotein I and its role in antiphospholipid syndrome—lessons from knockout mice

Miyakis

Robertson

Krilis

2004

Clinical Immunology

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“…The primary function of heparin in normal individuals is to bind to mast cell proteases, and it probably does not interact with ␤2-GPI under physiological conditions. However, heparin is regularly used in the treatment of APS patients both in acute therapy and prophylaxis (21,22). The manner by which ␤2-GPI binds to heparin has not been deduced.…”

Section: ␤2-glycoprotein I (␤2-gpi)mentioning

confidence: 99%

Heparin Inhibits the Binding of β2-glycoprotein I to Phospholipids and Promotes the Plasmin-mediated Inactivation of This Blood Protein

Guerin

Sheng

Reddel

et al. 2002

Journal of Biological Chemistry

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The phospholipid-binding plasma protein ␤2-glycoprotein I (␤2-GPI) is the primary antigen recognized by the circulating autoantibodies in patients with the "anti-phospholipid syndrome" (APS). Although heparin is routinely used in the treatment and prophylaxis of APS patients, the primary heparin-binding site within ␤2-GPI has not been identified. More importantly, how heparin exerts its beneficial effects in vivo in APS patients has not been deduced at the molecular level. Using an expression/site-directed mutagenesis approach, we now show that the positively charged site that resides in the first domain of ␤2-GPI is not the primary heparin-binding site. Rather it is the second positively charged site located within the fifth domain of the protein that also binds to phospholipids. Lys 284 , Lys 286 , and Lys 287 in this domain are essential for the interaction of ␤2-GPI with heparin. These data indicate that ␤2-GPI binds to heparin in a relatively specific manner even though the affinity for the interaction is rather low. Lys 317 resides in the center of the high affinity phospholipid-binding site. Surprisingly, heparin at concentrations that can be achieved in vivo during anticoagulation therapy greatly enhances the plasmin-mediated cleavage of the Lys 317 -Thr 318 site in ␤2-GPI. Because the cleaved form cannot bind to phospholipids effectively, the combined actions of heparin and plasmin result in a diminished ability of ␤2-GPI to recognize phospholipids. This, in turn, decreases the prothrombotic activity of the endogenous circulating anti-␤2-GPI antibodies in the patients. Thus, heparin exerts its beneficial effects in APS patients by at least two distinct mechanisms.

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“…These aPL are, in fact, directed against an array of protein cofactors, such as ␤ 2 GPI, protein C, protein S, and prothrombin, which then bind to anionic phospholipids. ␤ 2 GPI is the most extensively studied (14)(15)(16)(17) of these protein cofactors and appears to be one of the most relevant clinically (18)(19)(20). In contrast, nonpathogenic aPL, which are not associated with the development of clinical features of APS, do not recognize ␤ 2 GPI and bind both neutral and negative phospholipids without any cofactor dependence (21).…”

Section: Introductionmentioning

confidence: 99%

How do antiphospholipid antibodies bind β₂‐glycoprotein I?

Giles¹,

Isenberg²,

Latchman³

et al. 2003

Arthritis & Rheumatism

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Current Insights into the “Antiphospholipid” Syndrome: Clinical, Immunological, and Molecular Aspects

Cited by 75 publications

References 203 publications

Beta-2 glycoprotein I and its role in antiphospholipid syndrome—lessons from knockout mice

Beta-2 glycoprotein I and its role in antiphospholipid syndrome—lessons from knockout mice

Heparin Inhibits the Binding of β2-glycoprotein I to Phospholipids and Promotes the Plasmin-mediated Inactivation of This Blood Protein

How do antiphospholipid antibodies bind β₂‐glycoprotein I?

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Current Insights into the “Antiphospholipid” Syndrome: Clinical, Immunological, and Molecular Aspects

Cited by 75 publications

References 203 publications

Beta-2 glycoprotein I and its role in antiphospholipid syndrome—lessons from knockout mice

Beta-2 glycoprotein I and its role in antiphospholipid syndrome—lessons from knockout mice

Heparin Inhibits the Binding of β2-glycoprotein I to Phospholipids and Promotes the Plasmin-mediated Inactivation of This Blood Protein

How do antiphospholipid antibodies bind β2‐glycoprotein I?

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How do antiphospholipid antibodies bind β₂‐glycoprotein I?