Anti-endothelial antibodies interfere in apoptotic cell clearance and promote thrombosis in patients with antiphospholipid syndrome.
Antiphospholipid syndrome is an important cause of recurrent thrombotic events. The pathogenesis of the thrombosis remains unclear, but it has been suggested that anti-phospholipid Abs, which are laboratory markers for the disease and include species capable of binding to vascular endothelial cells, play an important role. We hypothesized that these anti-endothelial Abs promote thrombosis through interference with clearance of dying cells. We show that healthy endothelial cell monolayers effectively remove apoptotic endothelial cells, but this clearance is markedly inhibited by serum or IgG from patients with antiphospholipid syndrome and anti-endothelial Abs. In addition, patient sera or IgG opsonize apoptotic endothelial cells and cause enhanced Fc-mediated uptake by professional phagocytes. Importantly, the delayed clearance of apoptotic cells by healthy endothelial cells and the enhanced Fc-mediated macrophage uptake each result in procoagulant consequences, as judged by increased thrombin generation. The effects on apoptotic cell clearance were reproduced by a mAb derived from a patient with antiphospholipid syndrome, which binds to endothelial cells and is thrombogenic in experimental models. Taken together, our data support a novel, dual mechanism by which anti-endothelial Abs are prothrombotic in antiphospholipid syndrome by inhibiting removal of procoagulant apoptotic cells and by diverting their clearance to provoke inflammatory and prothrombotic changes in professional phagocytes.
Graham
Audrey
A
School of Medicine, Division of Applied Medicine, University of Aberdeen, United Kingdom.
Ford
Isobel
I
Morrison
Rona
R
Barker
Robert N
RN
Greaves
Mike
M
Erwig
Lars-Peter
LP
D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000009:adverse effects* / Q000378:metabolism; D016736:Antiphospholipid Syndrome / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D001666:Binding Sites, Antibody; D001779:Blood Coagulation Factors / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006825:Hybridomas; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009895:Opsonin Proteins / Q000378:metabolism; D010587:Phagocytosis; D013927:Thrombosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D017152:Antibodies, Antiphospholipid; D001779:Blood Coagulation Factors; D009895:Opsonin Proteins; C045072:macrophage procoagulant activity