Complement Activation and Thrombin Generation by MBL Bound to β2-Glycoprotein I
- 5 August 2020
- journal article
- research article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 205 (5), 1385-1392
- https://doi.org/10.4049/jimmunol.2000570
Abstract
β2-Glycoprotein I (β2-GPI) is an abundant plasma glycoprotein with unknown physiological function and is currently recognized as the main target of antiphospholipid Abs responsible for complement activation and vascular thrombosis in patients with antiphospholipid syndrome (APS). In this study, we provide evidence that mannose-binding lectin (MBL) binds to β2-GPI in Ca++ and a dose-dependent manner and that this interaction activates complement and promotes complement-dependent thrombin generation. Surprisingly, a significant binding was observed between MBL and isolated domains II and IV of β2-GPI, whereas the carbohydrate chains, domain I and domain V, were not involved in the interaction, documenting a noncanonical binding mode between MBL and β2-GPI. Importantly, this interaction may occur on endothelial cells because binding of MBL to β2-GPI was detected on the surface of HUVECs, and colocalization of MBL with β2-GPI was observed on the endothelium of a biopsy specimen of a femoral artery from an APS patient. Because β2-GPI–mediated MBL-dependent thrombin generation was increased after priming the endothelium with TNF-α, our data suggests that this mechanism could play an important yet unrecognized role under physiological conditions and may be upregulated in pathological situations. Moreover, the complement activation and the procoagulant effects of the β2-GPI/MBL complex may contribute to amplify similar activities of anti–β2-GPI Abs in APS and possibly act independently of Abs, raising the issue of developing appropriate therapies to avoid recurrences and disability in patients at risk for these clinical conditions.Keywords
This publication has 39 references indexed in Scilit:
- Effects of MASP-1 of the Complement System on Activation of Coagulation Factors and Plasma Clot FormationPLOS ONE, 2012
- Which pathways trigger the role of complement in ischaemia/reperfusion injury?Frontiers in Immunology, 2012
- Mannose-Binding Lectin Binds to Amyloid Protein and Modulates InflammationJournal of Biomedicine and Biotechnology, 2012
- Pathogenesis of antiphospholipid syndrome: understanding the antibodiesNature Reviews Rheumatology, 2011
- SLE with C1q deficiency treated with fresh frozen plasma: a 10-year experienceRheumatology, 2009
- Annexin A2 mediates anti-β2GPI/β2GPI-induced tissue factor expression on monocytesInternational Journal of Molecular Medicine, 2009
- Anti-β2-glycoprotein I ELISA assay: The influence of different antigen preparationsThrombosis and Haemostasis, 2009
- Mechanisms of Disease: antiphospholipid antibodies—from clinical association to pathologic mechanismNature Clinical Practice Rheumatology, 2008
- Simultaneous Activation of Complement and Coagulation by MBL-Associated Serine Protease 2PLOS ONE, 2007
- Molecular cloning and mammalian expression of human β2‐glycoprotein I cDNAFEBS Letters, 1991