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

Miyakis, Spiros; Robertson, Sarah A.; Krilis, Steven A.

doi:10.1016/j.clim.2004.02.014

Cited by 25 publications

(17 citation statements)

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“…The function of b2GPI is unclear, however, it displays effects on multiple components of the coagulation and fibrinolytic system [14]. In particular, b2GPI interacts with both plasmin and angiostatin of the plasminogen/plasmin system [10,15] with apparently opposing actions.…”

Section: Introductionmentioning

confidence: 99%

In vivo modulation of angiogenesis by beta 2 glycoprotein I

Passam¹,

Qi²,

Tanaka³

et al. 2010

Journal of Autoimmunity

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Section: Introductionmentioning

confidence: 99%

In vivo modulation of angiogenesis by beta 2 glycoprotein I

Passam¹,

Qi²,

Tanaka³

et al. 2010

Journal of Autoimmunity

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“…The physiologic function of this protein is still unclear, but the apparently healthy life of humans and mice deficient in ␤2GPI suggests that its role is not all that critical. [6][7][8][9] Most of the information now available on ␤2GPI has been collected following the observation that this protein is the main target of antiphospholipid (aPL) antibodies. 10,11 Patients with circulating antibodies to ␤2GPI are at increased risk of venous and arterial thrombosis as well as of pregnancy complications including miscarriage, preeclampsia and retarded fetal growth.…”

Section: Introductionmentioning

confidence: 99%

In vivo distribution of β2 glycoprotein I under various pathophysiologic conditions

Agostinis

Biffi

Garrovo

et al. 2011

Blood

112

109

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In vitro studies have documented ␤2 glycoprotein I (␤2GPI) binding to endothelial cells (ECs) and trophoblast using antiphospholipid antibodies. The in vivo binding of ␤2GPI to these cells and the conditions that favor their interaction have not been investigated. We analyzed the in vivo distribution of cyanine 5.5-labeled ␤2GPI in mice and evaluated the effect of pregnancy and circulating antibodies on its tissue localization. The signal was detected in the liver by whole body scan and ex vivo analysis. The ␤2GPI failed to bind to the vascular endothelium and reacted only with the ECs of uterine vessels. In pregnant mice the protein was localized on ECs and trophoblast at the embryo implantation sites. Immunized mice showed a similar ␤2GPI biodistribution to naive mice but the immunized pregnant animals exhibited a significant increase in fetal loss associated with C3 and C9 deposition at the implantation sites. Treatment of mice with LPS after ␤2GPI-Cy5.5 injection promoted protein localization on gut and brain ECs associated with IgG, C1q, and C9 deposition in immunized mice. These findings indicate that ␤2GPI binding to EC requires priming with pro-inflammatory factors which is not needed for uterine and placental localization probably dependent on hormonal changes. (Blood. 2011;118(15): 4231-4238) IntroductionAntiphospholipid syndrome (APS) is characterized by vascular thrombosis and adverse pregnancy outcome associated with circulating antiphospholipid antibodies (aPL) which are believed to play an important pathogenic role in the development of the clinical manifestations of the syndrome. 1,2 Human ␤2-glycoprotein I (␤2GPI) has been recognized as the major antigenic target for antiphospholipid antibodies and in vivo models have shown that antibodies directed against this molecule are able to mediate thrombus formation. 3,4 Beta2GPI is a heavily glycosylated glycoprotein that circulates in blood at a concentration of 150-300 g/mL 5 and is synthesized mainly in the liver, although expression of ␤2GPI mRNA has also been detected in endothelial cells (ECs), central nervous system, astrocytes, and placenta. The physiologic function of this protein is still unclear, but the apparently healthy life of humans and mice deficient in ␤2GPI suggests that its role is not all that critical. [6][7][8][9] Most of the information now available on ␤2GPI has been collected following the observation that this protein is the main target of antiphospholipid (aPL) antibodies. 10,11 Patients with circulating antibodies to ␤2GPI are at increased risk of venous and arterial thrombosis as well as of pregnancy complications including miscarriage, preeclampsia and retarded fetal growth. 1,12 For this reason antibodies with this specificity have been included among the criteria for the diagnosis of aPL syndrome (APS). 13,14 The induction of fetal loss and promotion of thrombosis in animal models as a result of immunization with ␤2GPI or passive transfer of antibodies further support the pathogenic role of these antibodies. [15][16][17...

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“…[8][9][10][11] The physiological function of b2GPI is not well defined 12 and its deficiency in humans or mice does not result in apparent abnormalities. [13][14][15][16] b2GPI acquires prothrombotic properties only after association with antibodies. 10,12 Treatment with anti-b2GPI antibodies or recombinant dimers of b2GPI mimicking b2GPI/antibody complexes results in increased thrombus size in animal models of thrombosis and cellular activation in vitro.…”

mentioning

confidence: 99%

Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome

Kolyada

Porter

Beglova

2014

Blood

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• A1-A1 inhibits thrombotic properties of anti-b2GPI antibodies in mice.• A1-A1 does not affect thrombus size in the absence of anti-b2GPI antibodies.Antiphospholipid syndrome (APS) is an autoimmune disorder with increased risk for thrombosis and pregnancy losses. b2-glycoprotein I (b2GPI) is the major antigen for clinically relevant antibodies in APS. We engineered a molecule, A1-A1, which interferes with 2 prothrombotic mechanisms in APS: the binding of b2GPI to negatively charged cellular surfaces and ApoE receptor 2. We studied how A1-A1 affects arterial thrombosis in vivo in lupus-prone (NZW 3 BXSB)F 1 male mice. For the first time, we demonstrated that A1-A1 efficiently reduces thrombus size in vivo in the presence of chronic autoimmune antib2GPI antibodies. We have shown that A1-A1 interferes with thrombotic properties of b2GPI/antibody complexes and does not affect normal thrombus formation in the absence of anti-b2GPI antibodies. A1-A1 inhibits prothrombotic properties of b2GPI/antibody complexes in wild-type mice after acute infusion with anti-b2GPI antibodies, as well as in mice expressing persistent autoimmune anti-b2GPI antibodies. A1-A1 reduced thrombus size in a mouse model of APS in the presence of lupus features, suggesting that A1-A1 might effectively interfere with thrombosis not only in primary APS but also in APS secondary to lupus. Our results suggest that A1-A1 could be a prototype for an antithrombotic drug in APS. (Blood. 2014;123(7):1090-1097) IntroductionAntiphospholipid syndrome (APS) is an autoimmune disorder with increased risk for thrombosis and pregnancy loss. [1][2][3] It is diagnosed based on the combination of clinical features and laboratory tests for circulating autoantibodies. Thrombotic events in APS nearly equally occur in veins and arteries, and about 30% of patients with thrombosis are men. [4][5][6][7] Thrombosis in APS correlates with the presence of antibodies to b2-glycoprotein I (b2GPI). [8][9][10][11] The physiological function of b2GPI is not well defined 12 and its deficiency in humans or mice does not result in apparent abnormalities. [13][14][15][16] b2GPI acquires prothrombotic properties only after association with antibodies. 10,12 Treatment with anti-b2GPI antibodies or recombinant dimers of b2GPI mimicking b2GPI/antibody complexes results in increased thrombus size in animal models of thrombosis and cellular activation in vitro. 2,3,[17][18][19][20] It was demonstrated both in vitro and in vivo that exposure of endothelial cells, monocytes, and platelets to b2GPI/anti-b2GPI antibody complexes shifts the cellular phenotype to prothrombotic and proinflammatory (reviewed in Giannakopoulos and Krilis,2 Tripodi et al, 3 and Harper et al 20 ). Anionic phospholipids, Toll-like receptors 2 and 4 (TLR2 and TLR4), annexin A2, and ApoER2 are cell-surface molecules involved in binding and activation of endothelial cells and monocytes by b2GPI/antibody complexes. [21][22][23][24][25][26] The binding of b2GPI to anionic phospholipids and the assembly of b2GPI/antibody c...

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

Cited by 25 publications

References 85 publications

In vivo modulation of angiogenesis by beta 2 glycoprotein I

In vivo modulation of angiogenesis by beta 2 glycoprotein I

In vivo distribution of β2 glycoprotein I under various pathophysiologic conditions

Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome

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