Complement Activation and Thrombin Generation by MBL Bound to b2-Glycoprotein i

P. Durigutto, P. MacOr, N. Pozzi, C. Agostinis, F. Bossi, P.L. Meroni, C. Grossi, M.O. Borghi, W. Planer, P. Garred, F. Tedesco

Research output: Contribution to journalArticlepeer-review

Abstract

b2-Glycoprotein I (b2-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 b2-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 b2-GPI, whereas the carbohydrate chains, domain I and domain V, were not involved in the interaction, documenting a noncanonical binding mode between MBL and b2-GPI. Importantly, this interaction may occur on endothelial cells because binding of MBL to b2-GPI was detected on the surface of HUVECs, and colocalization of MBL with b2-GPI was observed on the endothelium of a biopsy specimen of a femoral artery from an APS patient. Because b2-GPI-mediated MBL-dependent thrombin generation was increased after priming the endothelium with TNF-a, 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 b2-GPI/MBL complex may contribute to amplify similar activities of anti-b2-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.

Original languageEnglish
Pages (from-to)1385-1392
Number of pages8
JournalJournal of Immunology
Volume205
Issue number5
DOIs
Publication statusPublished - 2020

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