3 years ago

Antiphospholipid Antibody Induced Cellular Responses Depend on Epitope Specificity – Implications for Treatment of APS

Carolin Orning, Antje Canisius, Friederike Häuser, Nadine Müller-Calleja, Karl J. Lackner, Anne Hollerbach
Background Antiphospholipid antibodies (aPL) contribute to the pathogenesis of the antiphospholipid syndrome (APS) by induction of an inflammatory and procoagulant state in different cell types and several signaling pathways have been described. Objectives We hypothesized that signaling depends on epitope specificity of aPL. Methods Cellular effects of three human monoclonal aPL with distinctly different epitope specificities were analyzed in vitro. Expression of tumor necrosis factor α mRNA by mouse and human monocytes was the major read out. Analysis included cells from genetically modified mice as well as the use of specific inhibitors in human monocytes. Data were validated with IgG isolated from 20 APS patients. Results Cofactor independent anticardiolipin aPL activated monocytes by induction of endosomal NADPH-oxidase (NOX). Activation could be blocked by hydroxychloroquine (HCQ). Anti-β2 glycoprotein I (β2GPI) aPL activated monocytes by interaction with LDL-receptor related protein 8 (LRP8). This could be blocked by rapamycin. Analysis of 20 APS patient IgG showed that all IgG fractions activated the same two pathways as the monoclonal aPL depending upon their epitope patterns determined by ELISA. Monocyte activation by APS IgG could be blocked completely by HCQ and/or rapamycin suggesting that in most if not all APS patients there is no other relevant signaling pathway. Conclusions aPL activate two major proinflammatory signal transduction pathways depending on their epitope specificity. HCQ and rapamycin either alone or in combination completely suppress signaling by APS IgG. These observations may provide a rationale for specific treatment of APS patients according to their aPL profile. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/jth.13865

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