β2-Glycoprotein I: a novel component of innate immunity

Ağar, C.; Groot, Philip G. de; Mörgelin, Matthias; Monk, Stephanie D.D.C.; Os, G. M. A. Van; Levels, Johannes H.M.; Laat, Bas de; Urbanus, Rolf T.; Herwald, Heiko; Poll, Tom van der; Meijers, Joost C. M.

doi:10.1182/blood-2010-12-325951

Cited by 103 publications

(131 citation statements)

References 38 publications

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“…34 Thus, one role of PF4 might also be to protect from endotoxic shock, as has been shown for ␤ 2 -glycoprotein I. 35 Lipid A also binds antimicrobial peptides, such as the bactericidal/permeability-increasing protein (BPI) 36,37 and the cyclic lipopeptide polymyxin B, which interacts with the phosphate groups of lipid A. [38][39][40][41][42] In line with our other findings, BPI and polymyxin B inhibited PF4 binding to isolated lipid A ( Figure 3B), further confirming that PF4 interacts with lipid A.…”

Section: Discussionmentioning

confidence: 99%

Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes

Krauel

Weber

Brandt

et al. 2012

Blood

100

105

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The positively charged chemokine platelet factor 4 (PF4) forms immunogenic complexes with heparin and other polyanions. Resulting antibodies can induce the adverse drug effect heparin-induced thrombocytopenia. PF4 also binds to bacteria, thereby exposing the same neoantigen(s) as with heparin. In this study, we identified the negatively charged lipopolysaccharide (LPS) as the PF4 binding structure on Gram-negative bacteria. IntroductionBesides their pivotal role in hemostasis, platelets are involved in host defense against pathogens and in modulation of immune reactions. This function of platelets occurs either indirectly through their interaction with endothelial cells and leukocytes 1,2 or directly by secretion of antimicrobial substances from platelet storage granules and lysosomes. 3,4 Recently, we have shown that the chemokine platelet factor 4 (PF4), which is stored within platelet ␣-granules, plays a role in bacterial host defense by inducing a humoral immune response to PF4-coated bacteria. 5 During bacterial infections, platelets are activated 6,7 and release positively charged PF4, which can bind in a charge-dependent manner to the bacterial surface, thereby inducing neoepitopes. The formation of antigenic PF4 clusters is probably the result of neutralization of the positive charge of PF4 by polyanions, 8 which allows narrowing of the distance between single PF4 tetramers down to 3 to 5 nm. This creates linear, ridge-like complexes and exposes new antigenic epitopes on PF4. 9 Antibodies to PF4/polyanion complexes bind to PF4 on the bacterial surface, leading to opsonization and increased phagocytosis of PF4-coated bacteria. 5 As PF4 is capable of binding to a large variety of bacteria, the antibody response to PF4/polyanion complexes constitutes a very broad reactive defense mechanism and could represent an evolutionary interface between innate and specific immunity. Antibodies induced by PF4 clusters would be an example of antibodies with a limited target antigen repertoire that nevertheless could result in binding to a large variety of bacteria when these bacteria are coated with PF4. 5 In medicine, research on the immune reaction to PF4/polyanion complexes to date has primarily focused on its role in causing an adverse reaction to the anticoagulant heparin as PF4 forms immunogenic complexes with heparin on platelet surfaces. Anti-PF4/polyanion antibodies bind to these PF4/heparin complexcoated platelets and induce Fc-receptor-dependent platelet activation, 10,11 leading to intravascular consumption of platelets, associated potentiation of in vivo thrombin generation, and the prothrombotic syndrome, heparin-induced thrombocytopenia (HIT).We and others have recently demonstrated the prevalence of anti-PF4/heparin antibodies of the IgM class in up to 20% and of the IgG class in up to 6% of the general population and in a slightly lower number of normal blood donors. 5,12 These antibodies are highly significantly associated with periodontitis, one of the most prevalent human infections, often associate...

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Section: Discussionmentioning

confidence: 99%

Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes

Krauel

Weber

Brandt

et al. 2012

Blood

100

105

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“…Indeed, human homozygotes for β2GP1 deficiency do not present any clinical complications [27]. The function of β2GP1 proteins in APS was recently re-evaluated by Agar et al [28]. β2GP1 appears to modulate the innate immune system through its ability to downregulate LPS-induced TF and IL-6 expression by monocytes.…”

Section: Cell Activation By Aplamentioning

confidence: 99%

Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

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The antiphospholipid syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). The plasma protein β2-glycoprotein 1 (β2GP1) has been identified as a major target of aPLA associated with APS. Cell activation by aPLA appears to be a major pathogenic cause in the pathogenesis of APS. Receptors, co-receptors and accessory molecules are known to assist the pathogenic effects of aPLA. Members of the TLR family and the platelet receptor apolipoprotein E receptor 2' (apoER2'), a receptor belonging to the low-density lipoprotein receptor (LDL-R) family, as well as GPIbα, were identified as putative candidates for aPLA recognition. CD14, a co-receptor for TLR2 and TLR4, and annexin A2, a ubiquitous Ca2+ -binding protein that is essential for actin-dependent vesicle transport, could serve as important accessory molecules in mediating the pathogenic effects of aPLA. Finally, complement activation has been reported in association with the pathogenicity of APS. The relative contribution of these different mechanisms in the pathogenesis of APS is controversial. Here, we review the various in vivo and in vitro models that have been used to investigate the pathogenic mechanisms of aPLA in APS

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“…It took quite a while to unravel the physiologic role of β 2 GPI: only recently, two independent groups demonstrated that the C-terminal of the protein interacts specifically with lipopolysaccharide (LPS). Such observation suggests β 2 GPI may act as a carrier or as a scavenger for LPS [8,9]. The interaction between β 2 GPI and LPS is further supported by the inverse correlation between plasma levels of β 2 GPI and inflammatory markers such as tumour necrosis factor (TNF) α, interleukin (IL)-6 and IL-8.…”

Section: Anti-phospholipid Antibodies In Systemic Lupus Erythematosusmentioning

confidence: 87%

“…The interaction between β 2 GPI and LPS is further supported by the inverse correlation between plasma levels of β 2 GPI and inflammatory markers such as tumour necrosis factor (TNF) α, interleukin (IL)-6 and IL-8. Moreover, in vivo LPS injection induced a 25% reduction of baseline β 2 GPI serum levels [8].…”

Section: Anti-phospholipid Antibodies In Systemic Lupus Erythematosusmentioning

confidence: 95%

Reactivity against the Five Domains of β2 Glycoprotein I: A Focus on Systemic Lupus Erythematosus

Chighizola¹,

Borghi²,

Grossi³

et al. 2014

J Clin Cell Immunol

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Beta-2 glycoprotein I (β 2 GPI) is the main antigenic target for antiphospholipid antibodies (aPL), the serological markers of antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by vascular thrombosis and/or pregnancy morbidity. aPL are detected in 20 to 50% of patients with systemic lupus erythematosus (SLE), representing a poor prognostic factor. Indeed, thrombotic events heralds high morbidity and mortality, being regarded as the strongest predictors of death in the first five years after SLE onset. It would be thus very important to identify a reliable laboratory tool such as anti-domain antibodies to better risk-stratify lupus patients according to the aPL profile, in order to tailor treatment strategies. Domain I (DI) of β 2 GPI has lately been identified as the main epitope targeted by antibodies reacting against β 2 GPI isolated from APS patients, well correlating with thrombotic as well as obstetric manifestations. Interestingly, anti-DI antibodies have been shown to well correlate with lupus anticoagulant and to predict the clinical manifestations of the syndrome, thrombotic events as well as pregnancy complications. Further, anti-DI antibodies allow to identify patients at highest clinical risk, presenting a good specificity for APS. On the other hand, anti-β 2 GPI antibodies from aPL asymptomatic carriers or subjects with infectious diseases preferentially display reactivity towards DIV or DV of the molecule.Few studies have to date evaluated the domain profile of anti-β 2 GPI antibodies in subjects with SLE, even though it would be very relevant from a clinical point of view to understand whether among patients with SLE the domain specificities of anti-β 2 GPI antibodies display a clinical meaning comparable to the one they exert in APS. It is therefore rather appropriate to review the available evidence about anti-domain specificities with a particular focus on SLE.

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β2-Glycoprotein I: a novel component of innate immunity

Cited by 103 publications

References 38 publications

Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes

Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes

Receptors involved in cell activation by antiphospholipid antibodies

Reactivity against the Five Domains of β2 Glycoprotein I: A Focus on Systemic Lupus Erythematosus

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