TY - JOUR

T1 - Complement Activation and Thrombin Generation by MBL Bound to β2-Glycoprotein I

AU - Durigutto, Paolo

AU - Macor, Paolo

AU - Pozzi, Nicola

AU - Agostinis, Chiara

AU - Bossi, Fleur

AU - Meroni, Pier Luigi

AU - Grossi, Claudia

AU - Borghi, Maria O

AU - Planer, William

AU - Garred, Peter

AU - Tedesco, Francesco

N1 - Copyright © 2020 by The American Association of Immunologists, Inc.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Antiphospholipid Syndrome/immunology

KW - Calcium/metabolism

KW - Cell Line

KW - Complement Activation/immunology

KW - Endothelial Cells/immunology

KW - Endothelium/immunology

KW - Human Umbilical Vein Endothelial Cells

KW - Humans

KW - Mannose-Binding Lectin/immunology

KW - Protein Binding/immunology

KW - Thrombin/immunology

KW - Thrombosis/immunology

KW - Tumor Necrosis Factor-alpha/immunology

KW - beta 2-Glycoprotein I/immunology

U2 - 10.4049/jimmunol.2000570

DO - 10.4049/jimmunol.2000570

M3 - Journal article

C2 - 32759297

VL - 205

SP - 1385

EP - 1392

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 5

ER -