Autoantibodies specific to a peptide of β2-glycoprotein I cross-react with TLR4, inducing a proinflammatory phenotype in endothelial cells and monocytes

Colasanti, Tania; Alessandri, Cristiano; Capozzi, Antonella; Sorice, Maurizio; Delunardo, Federica; Longo, Agostina; Pierdominici, Marina; Conti, Fabrizio; Truglia, S.; Siracusano, Alessandra; Valesini, Guido; Ortona, Elena; Margutti, Paola

doi:10.1182/blood-2011-09-378851

Cited by 52 publications

(47 citation statements)

References 49 publications

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“…Furthermore, in vitro experiments established the ability of aPL antibodies to bind and activate endothelial cells in culture. [28][29][30][31][32][33][34][35][36][37][38] Our finding that the antib2GP1 autoantibody/b2GP1 complex does not bind to the endothelium but that the endothelium does become activated is consistent with prior experiments. This raises 2 questions: (1) Why does the antib2GP1 autoantibody/b2GP1 complex activate endothelial cells in Figure 7.…”

supporting

confidence: 89%

“…Endothelial cell binding of anti-b2GP1 antibodies and anti-b2GP1 antibodyinduced endothelial cell activation in in vitro experiments have been extensively described. [28][29][30][31][32][33][34][35][36][37][38] Two prior in vivo studies have confirmed antibody-induced endothelial cell activation in wild-type mice. 22,33 We determined whether enhanced endothelial cell activation was dependent upon the presence of platelets.…”

Section: 18mentioning

confidence: 95%

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Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS

Proulle

Furie

Merrill-Skoloff

et al. 2014

Blood

106

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• The anti-b2GP1 autoantibody/ b2GP1 complex binds to the platelet thrombus, amplifying platelet activation.• Platelets are required for enhanced activation of the endothelium and fibrin generation by the anti-b2GP1 autoantibody/b2GP1 complex.Antiphospholipid syndrome (APS) is defined by thrombosis, fetal loss, and the presence of antiphospholipid antibodies, including anti-b2-glycoprotein-1 autoantibodies (antib2GP1) that have a direct role in the pathogenesis of thrombosis in vivo. The cellular targets of the anti-b2GP1 autoantibody/b2GP1 complex in vivo were studied using a laserinduced thrombosis model of APS in a live mouse and human anti-b2GP1 autoantibodies affinity-purified from APS patients. Cell binding of fluorescently labeled b2GP1 and antib2GP1 autoantibodies revealed their colocalization on the platelet thrombus but not the endothelium. Anti-b2GP1 autoantibodies enhanced platelet activation, monitored by calcium mobilization, and endothelial activation, monitored by intercellular adhesion molecule-1 expression. When eptifibatide was infused to block platelet thrombus formation, enhanced fibrin generation and endothelial cell activation were eliminated. Thus, the anti-b2GP1 autoantibody/b2GP1 complex binds to the thrombus, enhancing platelet activation, and platelet secretion leads to enhanced endothelium activation and fibrin generation. These results lead to a paradigm shift away from the concept that binding of the anti-b2GP1 autoantibody/b2GP1 complex activates both endothelial cells and platelets toward one in which activation of platelets in response to anti-b2GP1 autoantibody/b2GP1 complex binding leads to subsequent enhanced endothelium activation and fibrin generation. (Blood. 2014;124(4):611-622) IntroductionAntiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis and/or pregnancy morbidity and is associated with circulating antiphospholipid (aPL) autoantibodies.1-3 These antibodies, including anti-b2-glycoprotein-1 (anti-b2GP1) autoantibodies, recognize plasma proteins that bind to anionic phospholipids, among which b2GP1 is the major target. 4 Antibodies directed against b2GPI 5,6 are associated with thrombotic events in APS. Antib2GP1 autoantibodies from patients with APS and thrombosis enhance arterial thrombus formation after injury in a mouse model of APS, 7 with dramatic increases in platelet thrombus size and fibrin generation.The mechanisms leading to thrombosis in APS are unresolved. In vitro and in vivo studies using animal models demonstrated that aPL antibodies interact with endothelial cells and monocytes to increase tissue factor expression and complement activation and proinflammatory cytokines. 8,9 In vitro, platelet activation occurs after the binding of complexes of anti-b2GP1 antibodies and dimerized b2GP1 to GPIba and ApoER2. [10][11][12] Furthermore, APS patients exhibit markers of platelet activation. 13 The conventional understanding is that the antib2GP1/b2GP1 complex binds to receptors on both the endothelial cell and the platelet, lea...

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confidence: 89%

Section: 18mentioning

confidence: 95%

Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS

Proulle

Furie

Merrill-Skoloff

et al. 2014

Blood

106

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“…6,7,9,10 Few studies have addressed the role of TLRs in thrombosis in vivo, 11,12 and none has addressed the role of TLRs in arterial models of thrombosis. While the precise mechanism by which aPL induce cell signaling events remains undetermined, it is clear that anti-b2GPI antibodies, particularly in the presence of b2GPI, can activate endothelial cells (ECs) [13][14][15] and monocytes.…”

Section: Introductionmentioning

confidence: 97%

Antiphospholipid antibody-mediated effects in an arterial model of thrombosis are dependent on Toll-like receptor 4

Laplante

Fuentes

Salem

et al. 2015

Lupus

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Patients with antiphospholipid syndrome (APS) produce antiphospholipid antibodies (aPL) and develop vascular thrombosis that may occur in large or small vessels in the arterial or venous beds. On the other hand, many individuals produce aPL and yet never develop thrombotic events. Toll-like receptor 4 (TLR4) appears to be necessary for aPL-mediated prothrombotic effects in venous and microvascular models of thrombosis, but its role in arterial thrombosis has not been studied. Here, we propose that aPL alone are insufficient to cause thrombotic events in an arterial model of APS, and that a concomitant trigger of innate immunity (e.g. TLR4 activation) is required. We show specifically that anti-β2-glycoprotein I (anti-β2GPI) antibodies, a subset of aPL, accelerated thrombus formation in C57BL/6 wild-type, but not TLR4-deficient, mice in a ferric chloride-induced carotid artery injury model. These aPL bound to arterial and venous endothelial cells, particularly in the presence of β2GPI, and to human TLR4 by enzyme-linked immunoassay. Arterial endothelium from aPL-treated mice had enhanced leukocyte adhesion, compared to control IgG-treated mice. In addition, aPL treatment of mice enhanced expression of tissue factor (TF) in leukocytes induced by the TLR4 ligand lipopolysaccharide (LPS). aPL also enhanced LPS-induced TF expression in human leukocytes in vitro. Our findings support a mechanism in which aPL enhance TF expression by leukocytes, as well as augment adhesion of leukocytes to the arterial endothelium. The activation of TLR4 in aPL-positive individuals may be required to trigger thrombotic events.

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“…Besides, cytokines are provided with the help of TLRs to induce the differentiation of B cells and T cells, leading to the activation of acquired immunity. Thus, it is believed that TLRs build a bridge between innate immunity and autoimmunity [29, 30]. TLRs are expressed on both lymphoid and nonlymphoid cells including monocytes, macrophages, DCs, B cells, and endothelial cells [31].…”

Section: Signaling Pathway Of Tlr4 In B Cells In Apsmentioning

confidence: 99%

The Role of TLR4 on B Cell Activation and Anti-β2GPI Antibody Production in the Antiphospholipid Syndrome

Cheng

Wang

Zhou

2016

Journal of Immunology Research

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High titer of anti-β 2-glycoprotein I antibodies (anti-β 2GPI Ab) plays a pathogenic role in antiphospholipid syndrome (APS). Numerous studies have focused on the pathological mechanism in APS; however, little attention is paid to the immune mechanism of production of anti-β 2GPI antibodies in APS. Our previous study demonstrated that Toll-like receptor 4 (TLR4) plays a vital role in the maturation of bone marrow-derived dendritic cells (BMDCs) from the mice immunized with human β 2-glycoprotein I (β 2GPI). TLR4 is required for the activation of B cells and the production of autoantibody in mice treated with β 2GPI. However, TLR4 provides a third signal for B cell activation and then promotes B cells better receiving signals from both B cell antigen receptor (BCR) and CD40, thus promoting B cell activation, surface molecules expression, anti-β 2GPI Ab production, and cytokines secretion and making B cell functioning like an antigen presenting cell (APC). At the same time, TLR4 also promotes B cells producing antibodies by upregulating the expression of B-cell activating factor (BAFF). In this paper, we aim to review the functions of TLR4 in B cell immune response and antibody production in autoimmune disease APS and try to find a new way for the prevention and treatment of APS.

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Autoantibodies specific to a peptide of β2-glycoprotein I cross-react with TLR4, inducing a proinflammatory phenotype in endothelial cells and monocytes

Cited by 52 publications

References 49 publications

Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS

Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS

Antiphospholipid antibody-mediated effects in an arterial model of thrombosis are dependent on Toll-like receptor 4

The Role of TLR4 on B Cell Activation and Anti-β2GPI Antibody Production in the Antiphospholipid Syndrome

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