Interaction of β2-Glycoprotein I with Lipopolysaccharide Leads to Toll-like Receptor 4 (TLR4)-dependent Activation of Macrophages

Laplante, Patrick; Amireault, Pascal; Subang, Rebecca; Dieudé, Mélanie; Levine, Jerrold S.; Rauch, Joyce

doi:10.1074/jbc.m111.230383

Cited by 33 publications

(29 citation statements)

References 38 publications

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“…The lack of evidence in support of the TLR4 role emerged in this study might be ascribable to a cell-specific orchestra of receptors, co-receptors and accessory molecules deputed to aPL binding. Since b2GPI specifically binds to LPS via its domain V, it has been proposed that such a binding might account for TLR4 engagement [14]. To rule out this hypothesis, in-vitro experiments were conducted in the presence of increasing amounts of exogenous LPS.…”

Section: Key Pointsmentioning

confidence: 99%

Update on the pathogenesis and treatment of the antiphospholipid syndrome

Chighizola

Raschi

Borghi

et al. 2015

Current Opinion in Rheumatology

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Section: Key Pointsmentioning

confidence: 99%

Update on the pathogenesis and treatment of the antiphospholipid syndrome

Chighizola

Raschi

Borghi

et al. 2015

Current Opinion in Rheumatology

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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: 67%

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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“…However, in the additional presence of LPS, the activation threshold was markedly lowered. b2GPI also could interact specifically with LPS to induce TNF-a production in macrophages in a TLR4-dependent manner (Laplante et al, 2011;Gladigau et al, 2012). These experiments provided strong evidence that inflammatory processes might represent second hits and are able to trigger aPL-associated thrombotic events.…”

Section: Tlr4 In Apl-mediated Thrombosis and Pregnancy Loss: In Vivo mentioning

confidence: 69%

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

et al. 2013

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SummaryThe antiphospholipid syndrome (APS) is an autoimmune disease characterized by the clinical features of recurrent thrombosis in the venous or arterial circulation and fetal losses. Antiphospholipid antibodies (aPL), particularly against the phospholipid binding protein beta-2 glycoprotein I (b2GPI), play an important role in APS pathological mechanisms. aPL can activate intracellular signal transduction in a b2GPI-dependent manner to induce inflammatory responses, and promote hypercoagulable state and recurrent spontaneous abortion when b2GPI is associated with the cell surface receptor. In vivo and in vitro studies show that Annexin A2 (ANXA2) is the high affinity receptor that connects b2GPI to the target cells. However, ANXA2 is not a transmembrane protein and lacks an intracellular signal transduction pathway. Growing evidences suggest that the transmembrane protein toll-like receptor 4 (TLR4) might act as an 'adaptor' for intracellular signal transduction. This review focuses on the role of TLR4 and its signalling pathway in APS pathological mechanisms which will help us better understand the pathological processes of this syndrome.

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Interaction of β2-Glycoprotein I with Lipopolysaccharide Leads to Toll-like Receptor 4 (TLR4)-dependent Activation of Macrophages

Cited by 33 publications

References 38 publications

Update on the pathogenesis and treatment of the antiphospholipid syndrome

Update on the pathogenesis and treatment of the antiphospholipid syndrome

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

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

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