Human Monoclonal Antiphospholipid Antibodies Disrupt the Annexin A5 Anticoagulant Crystal Shield on Phospholipid Bilayers

Rand, Jacob H.; Wu, Xiaomao; Quinn, Anthony S.; Chen, Pojen P.; McCrae, Keith R.; Bovill, Edwin G.; Taatjes, Douglas J.

doi:10.1016/s0002-9440(10)63479-7

Cited by 143 publications

(132 citation statements)

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“…4 These include inhibition of protein C activation and activity, 5,6 inhibition of annexin V assembly on exposed phospholipid surfaces, 7 and prevention of appropriate interactions of antithrombin with glycosaminoglycans, 8 among others. 4,9 Studies from our laboratory and others suggest that ␤ 2 GPI-dependent activation of vascular cells by APLA/anti-␤ 2 GPI antibodies plays a central role in disease pathogenesis 10,11 and may initiate the cascade of events that leads to thrombus development.…”

Section: Introductionmentioning

confidence: 99%

Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors

Allen

Hamik

Jain

et al. 2011

Blood

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IntroductionThe antiphospholipid syndrome (APS) is characterized by arterial or venous thrombosis and/or recurrent fetal loss in the presence of antiphospholipid antibodies (APLAs). [1][2][3] It is now widely accepted that the majority of pathologic antibodies in patients with this disorder are actually directed against phospholipid-binding proteins, the most common of which is ␤ 2 -glycoprotein I (␤ 2 GPI).The pathogenesis of APS-associated thrombosis is multifactorial, and a number of mechanisms have been proposed. 4 These include inhibition of protein C activation and activity, 5,6 inhibition of annexin V assembly on exposed phospholipid surfaces, 7 and prevention of appropriate interactions of antithrombin with glycosaminoglycans, 8 among others. 4,9 Studies from our laboratory and others suggest that ␤ 2 GPI-dependent activation of vascular cells by APLA/anti-␤ 2 GPI antibodies plays a central role in disease pathogenesis 10,11 and may initiate the cascade of events that leads to thrombus development. For example, ␤ 2 GPI binds to endothelial cell annexin A2, and subsequent cross-linking of annexin A2-bound ␤ 2 GPI initiates endothelial cell activation through a pathway that may involve Toll-like receptor 4 (TLR-4) [11][12][13] and leads to activation of NF-B. 14 A similar pathway may be functional in monocytes, activation of which also contributes to the development of thrombosis in patients with APLA. 15 In addition, APLA may promote platelet activation in the presence of subthreshold concentrations of agonists, 16 although whether this is a receptor-mediated process, and if so, its relationship to platelet ␤ 2 GPI binding sites, such as GP1b 17 and apoER2, 18 requires further study.In endothelial cells, activation of NF-B stimulates an inflammatory and procoagulant response 19 and plays a critical role in the ability of APLA to promote thrombosis. 20 Thus, modulation of NF-B activity may provide an opportunity to reverse the pathologic vascular response in APS. The Krüppel-like factors (KLFs), 21 particularly KLF2 and KLF4, inhibit inflammatory cytokinemediated responses in endothelial cells, 22,23 at least in part through inhibition of NF-B activity. 23 However, expression of KLF2 itself may be inhibited by inflammatory cytokines and/or vascular injury, [23][24][25] although the expression of KLF4 appears to be increased under these conditions. 26 In considering the importance of NF-B in endothelial cell activation mediated by APLA/anti-␤ 2 GPI antibodies 14 and the potentially opposing effects of KLF2 and KLF4, we hypothesized that changes in expression of these transcription factors might influence the endothelial cell response to APLA/anti-␤ 2 GPI antibodies. Here, we report that, unlike responses to inflammatory cytokines, the expression of both KLF2 and KLF4 is decreased in response to APLA/anti-␤ 2 GPI antibodies. Moreover, restoring the expression of these KLFs blocks endothelial cell activation in response to APLA/anti-␤ 2 GPI antibodies. These activities result from inhibition of NF-B transcrip...

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Section: Introductionmentioning

confidence: 99%

Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors

Allen

Hamik

Jain

et al. 2011

Blood

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“…In one study (Rand, 2002), it was shown that the addition of aPLA reduces annexin V on the cell surface, where it binds to the apical surfaces of the trophoblastic cells and functions as an anticoagulant. It was recently shown by the same group that the presence of anti-phospholipid monoclonal antibodies (mAbs) and ␤ 2 -GP1, which is a phospholipid-binding protein, disrupt the annexin A5 crystallization pattern in the bilayer-as was seen by atomic force microscopy (Rand et al, 2003). This provides morphological evidence for the assumed connection between aPLA and annexin V. Moreover, when examining the annexin A5 anticoagulant activity, they found that the aPLA mAbs reversed the anticoagulant effect of annexin A5 and increased the generation of thrombin from the prothrombinase reaction.…”

Section: Possible Mechanisms By Which Apla Cause Pregnancy Lossmentioning

confidence: 96%

Maternal autoimmune diseases and immunologically induced embryonic and fetoplacental damage

Ornoy

Chen

Silver

et al. 2004

Birth Defects Research

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BACKGROUND:Autoimmune diseases are a group of illnesses in which autoantibodies are produced against various organs, presenting with a variety of clinical symptoms. In this review, we discuss the different aspects of autoimmune diseases in pregnancy. We also describe experimental models that help to understand the etiology and pathogenesis of the effects of this maternal disease on the developing embryo, fetus and placenta. METHODS:The possible direct effects of sera or IgG obtained from women with systemic lupus erythematosus/antiphospholipid syndrome (SLE/APS) and recurrent pregnancy loss (RPL) were examined on cultured 10.5-and 11.5-day-old rat embryos and on cultured human placental explants, as compared to sera from healthy women or synthetic medium that were used as controls. In addition, we examined the effects of the sera obtained from these women after successful treatment that allowed the birth of normal infants. RESULTS: We observed increased embryonic death and anomalies in embryos cultured on sera and IgG from SLE/APS women. Similarly, when human placental explants were cultured on these sera, trophoblastic cell growth was reduced and apoptotic rate was increased. Successful treatment also reduced the damage caused by the sera from these women in the cultured embryos and placentas. CONCLUSIONS: Our results, and the cited studies, point to the important role of the placental damage in the etiology of RPL associated with SLE/APS. Animal models, both in vivo and in vitro, as well as cultured early human placental explants can be used successfully to understand some of the pathogenic aspects of SLE/APS and RPL.

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“…Furthermore, other studies demonstrate that antiphospholipid antibodies are able to interfere with the potent anticoagulant activity of annexin [7]. The syncytiotrophoblast naturally exteriorises phosphatidylserine, a trigger of contact-dependent coagulation.…”

Section: Pathophysiologic Mechanisms Of Placental Damage In Apsmentioning

confidence: 99%

Predictors of Pregnancy Outcome in Antiphospholipid Syndrome: A Review

Tabacco¹,

Salvi²

2016

J Allergy Ther

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Human Monoclonal Antiphospholipid Antibodies Disrupt the Annexin A5 Anticoagulant Crystal Shield on Phospholipid Bilayers

Cited by 143 publications

References 41 publications

Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors

Endothelial cell activation by antiphospholipid antibodies is modulated by Krüppel-like transcription factors

Maternal autoimmune diseases and immunologically induced embryonic and fetoplacental damage

Predictors of Pregnancy Outcome in Antiphospholipid Syndrome: A Review

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