Structural and functional characterization of a human IgG monoclonal antiphospholipid antibody

Prinz, Nadine; Häuser, Friederike; Lorenz, Mareike; Lackner, Karl J.; Landenberg, Philipp von

doi:10.1016/j.imbio.2010.05.001

Cited by 20 publications

(28 citation statements)

References 36 publications

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“…To further investigate the effects on platelets, we performed light transmission aggregometry with human platelets as described in the Methods section. While HL5B had no effect in this system, another monoclonal aPL from the same patient, HL7G, which binds to β2GPI , and IgG isolated from an APS patient with high‐titer anti‐β2GPI IgG induced full platelet aggregation after subthreshold preactivation by ADP (Table ).…”

Section: Resultsmentioning

confidence: 90%

Cofactor‐independent human antiphospholipid antibodies induce venous thrombosis in mice

Manukyan

Müller‐Calleja

Jäckel³

et al. 2016

Journal of Thrombosis and Haemostasis

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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. Summary BackgroundThere 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. ObjectivesWe aimed to clarify if cofactor‐independent aPL can be thrombogenic in vivo and, if so, whether these effects are mediated via activation of NOX2. MethodsTwo 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. ResultsHL5B 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. ConclusionsCofactor‐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.

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Section: Resultsmentioning

confidence: 90%

Cofactor‐independent human antiphospholipid antibodies induce venous thrombosis in mice

Manukyan

Müller‐Calleja

Jäckel³

et al. 2016

Journal of Thrombosis and Haemostasis

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“…The highly related monoclonal aPL HL7G, which differs only in few amino acids, acquired the capability to bind ␤2GPI but retained its cardiolipin binding. 13,14 A third monoclonal aPL, RR7F, binds also exclusively to anionic phospholipids without the need for a protein cofactor. It is very similar to a known germline sequence and has the same effects in our system, indicating that antigen maturation may not be a precondition for activation of TLR7/8.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells

Prinz

Clemens

Strand

et al. 2011

Blood

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130

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“…Furthermore, the human monoclonal IgG antibodies HL5B and HL7G, generated from a patient with primary APS and recurrent cerebral microemboli, were included [17,18]. Both antibodies are of the IgG2 subtype with lambda light chains; however, they differ in their aPL reactivity.…”

Section: Methodsmentioning

confidence: 99%

Single-step autoantibody profiling in antiphospholipid syndrome using a multi-line dot assay

et al. 2011

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IntroductionDiagnosis of antiphospholipid syndrome (APS) still remains a laboratory challenge due to the great diversity of antiphospholipid antibodies (aPL) and their significance regarding APS-diagnostic criteria.MethodsA multi-line dot assay (MLDA) employing phosphatidylserine (PS), phosphatidylinositol (PI), cardiolipin (CL), and beta2-glycoprotein I (β2 GPI) was used to detect aPL, immunoglobulin G (IgG) and immunoglobulin M (IgM) in 85 APS patients, 65 disease controls, and 79 blood donors. For comparison, anti-CL and anti-β2 GPI IgG and IgM were detected by enzyme-linked immunosorbent assay (ELISA).ResultsThe level of agreement of both methods was good for anti-CL IgG, moderate for anti-CL IgM, very good for anti-β2 GPI IgG, and moderate for anti-β2 GPI IgM (kappa = 0.641, 0.507, 0.803 and 0.506, respectively). The frequency of observed discrepancies for anti-CL IgG (1.75%), anti-CL IgM (3.93%), anti-β2 GPI IgG (1.75%), and anti-β2 GPI IgM (0.87%) was low (McNemar test, P < 0.05, not-significant, respectively). Sensitivity, specificity, positive (+LR) and negative (-LR) likelihood ratios for at least one positive aPL antibody assessed by ELISA were 58.8%, 95.8%, 14.1, and 0.4, respectively, and for at least three positive aPl IgM and/or one positive aPL IgG by MLDA were 67.1%, 96.5%, 19.3, and 0.3, respectively. The frequency of IgM to PI, PS and CL, and combination of three or more aPL IgM detected by MLDA was significantly higher in APS patients with cerebral transient ischemia (P < 0.05, respectively).ConclusionsThe novel MLDA is a readily available, single-step, sensitive diagnostic tool for the multiplex detection of aPL antibodies in APS and a potential alternative for single aPL antibody testing by ELISA.

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Structural and functional characterization of a human IgG monoclonal antiphospholipid antibody

Cited by 20 publications

References 36 publications

Cofactor‐independent human antiphospholipid antibodies induce venous thrombosis in mice

Cofactor‐independent human antiphospholipid antibodies induce venous thrombosis in mice

Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells

Single-step autoantibody profiling in antiphospholipid syndrome using a multi-line dot assay

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