Human antiphospholipid antibodies induce TNFα in monocytes via Toll-like receptor 8

Döring, Yvonne; Hurst, Julia; Lorenz, Mareike; Prinz, Nadine; Clemens, Natascha; Drechsler, Maik; Bauer, Stefan; Chapman, Joab; Shoenfeld, Yehuda; Blank, Miri; Lackner, Karl J.; Landenberg, Philipp von

doi:10.1016/j.imbio.2009.03.002

Cited by 67 publications

(70 citation statements)

References 49 publications

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“…Moreover, ex vivo studies suggest a role for TLR2 [32][33][34], CD14 [34], GPIbα [35] and TLR8 [36] in aPLA-activated monocytes and EC. Below the role of each receptor/co receptor is described in more detail.…”

Section: Candidate Receptors For Aplamentioning

confidence: 99%

“…By using the proximity ligation assay, a technique that generates information concerning the strength of the protein-protein interactions, aPLA were found to interact more strongly with TLR2 on monocytes and cytokine activated EC than with TLR4 [34]. The pathogenesis of APS is further complicated by the more recent findings that show that TNF production induced by aPLA-activated monocytes could be dependent on activation of TLR7 and TLR8 [36,56,57]. Further study is thus required to reach definitive conclusions.…”

Section: The Role Of Members Of the Tlr Familymentioning

confidence: 99%

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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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Section: Candidate Receptors For Aplamentioning

confidence: 99%

Section: The Role Of Members Of the Tlr Familymentioning

confidence: 99%

Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

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“…83 Transmission of activation signals across cell membranes usually involves ligand-receptor interactions and it is therefore not surprising that the identification of the receptor(s) that mediate the prothrombotic effects of antiphospholipid antibodies is subject of ongoing investigations. Several receptors have been reported thus far to interact with the ␤ 2 GPI-antibody complex, among others TLR2, 84 TLR4, 85,86 TLR8, 87 annexin A2, 88 glycoprotein Ib␣, 89,90 and the low-density lipoprotein (LDL)-receptor family member LDL receptor-related protein (LRP)-8, also known as ApoER2. 91 Activation of cell lines or cells isolated from blood with antiphospholipid antibodies indicates involvement of each of these receptors in the induction of a prothrombotic cellular phenotype in a ␤ 2 GPI-dependent manner.…”

Section: The Pathophysiology Of the Autoantibodiesmentioning

confidence: 99%

The significance of autoantibodies against β2-glycoprotein I

Groot

Urbanus

2012

Blood

132

115

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AbstractThe antiphospholipid syndrome (APS) is defined by the persistent presence of antiphospholipid antibodies in patients with a history of thrombosis and/or pregnancy morbidity, including fetal loss. APS is an autoimmune disease with a confusing name because the pathologic auto-antibodies are shown to be directed against the plasma protein β2-glycoprotein I and not against phospholipids. In fact, auto-antibodies that recognize phospholipids themselves are not associated with thrombosis but with infectious diseases. One of the intriguing questions is why autoantibodies against β2-glycoprotein I are so commonly found in both patients and the healthy. Several potential mechanisms have been suggested to explain the increased thrombotic risk in patients with these autoantibodies. In this overview, we will summarize our knowledge on the etiology of the autoantibodies, and we will discuss the evidence that identify autoantibodies against β2-glycoprotein I as the culprit of APS.

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“…10,13,14,19 In brief, HL5B and HL7G were cloned from a patient with primary APS. They have numerous somatic mutations indicating antigen driven maturation.…”

Section: Human Samplesmentioning

confidence: 99%

“…[7][8][9] We have shown by using human monoclonal aPL and IgG fractions from patients that aPLs induce TLR8 expression and signaling in monocytes, leading to the secretion of inflammatory cytokines. 10 However, conclusive evidence that aPLs bind to any of the TLRs has not been presented. Another model proposes that aPLs specific for ␤2GPI induce the formation of antibodylinked dimers of ␤2GPI that can activate the apolipoprotein E-receptor 2 in platelets.…”

Section: Introductionmentioning

confidence: 99%