title: Cofactor-independent human antiphospholipid antibodies induce venous thrombosis in mice.
abstract: Essentials Cofactor-independent antiphospholipid antibodies (CI-aPL) are generally considered non-pathogenic. We analyzed the effects of human monoclonal CI-aPL in a mouse model of venous thrombosis. As shown in vitro, CI-aPL induce a procoagulant state in vivo by activation of endosomal NADPH-oxidase. Contrary to common belief, CI-aPL induce venous thrombosis in vivo.
  
  
  
  Background There is general consensus that the antiphospholipid syndrome (APS) is caused by antiphospholipid antibodies (aPL) with antibodies against β2-glycoprotein-I being the most relevant. aPL that bind phospholipids in the absence of protein cofactors are generally considered pathogenetically irrelevant. We showed that cofactor-independent human monoclonal aPL isolated from APS patients induce proinflammatory and procoagulant cellular responses by activating endosomal NADPH-oxidase 2 (NOX2). Similar aPL were detected in all IgG fractions from APS patients analyzed. Objectives We aimed to clarify if cofactor-independent aPL can be thrombogenic in vivo and, if so, whether these effects are mediated via activation of NOX2. Methods Two cofactor-independent human monoclonal aPL, HL5B and RR7F, were tested in a mouse model of venous thrombosis. Genetically modified mice and in vitro assays were used to delineate the mechanisms underlying thrombus induction. Results HL5B and RR7F dramatically accelerate thrombus formation in this mouse model. Thrombus formation depends on tissue factor activation. It cannot be induced in NOX2-deficient mice. Bone marrow chimeras of C57BL/6J mice reconstituted with NOX2-deficient bone marrow showed that leukocyte activation plays a major role in thrombus formation. Neither TLR4 signaling nor platelet activation by our aPL is required for venous thrombus formation. Conclusions Cofactor-independent aPL can induce thrombosis in vivo. This effect is mainly mediated by leukocyte activation, which depends on the previously described signal transduction via endosomal NOX2. Because most APS patients have been shown to harbor aPL with similar activity, our data are of general relevance for the APS.
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany.|Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Manukyan
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Müller-Calleja
authors.affiliation: Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Jäckel
authors.affiliation: Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Luchmann
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Mönnikes
authors.affiliation: Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Kiouptsi
authors.affiliation: Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Reinhardt
authors.affiliation: Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Jurk
authors.affiliation: Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Walter
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany.
authors.forename: K J
authors.initials: KJ
authors.lastname: Lackner
mesh_terms: D000328:Adult; D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D004195:Disease Models, Animal; D011992:Endosomes / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2 / Q000235:genetics / Q000276:immunology*; D013916:Thrombelastography; D013927:Thrombosis / Q000276:immunology; D014682:Vena Cava, Inferior / Q000473:pathology; D020246:Venous Thrombosis / Q000188:drug therapy / Q000276:immunology*; D053482:beta 2-Glycoprotein I / Q000276:immunology*
chemical_list: D017152:Antibodies, Antiphospholipid; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D053482:beta 2-Glycoprotein I; C056558:CYBB protein, human; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2
keywords: NADPH-oxidase; antiphospholipid antibodies; antiphospholipid syndrome; tissue factor; venous thrombosis