Complement activation: a novel pathogenic mechanism in the antiphospholipid syndrome

Area of Science:

• Immunology
• Hematology
• Pathophysiology

Background:

• Antiphospholipid antibodies (aPLs) are associated with thrombosis, endothelial cell activation, and fetal loss.
• The precise mechanisms underlying aPL-induced pathology, particularly thrombosis, remain incompletely understood.
• Emerging evidence links uncontrolled complement activation to adverse outcomes in aPL antibody-associated conditions.

Purpose of the Study:

• To investigate the role of complement activation in mediating thrombosis and endothelial cell activation induced by antiphospholipid antibodies.
• To test the hypothesis that aPL antibodies activate the complement cascade, leading to the generation of pro-thrombotic split products.

Main Methods:

• Utilized an in vivo thrombosis model where aPL antibodies were administered to assess thrombus size.
• Employed a mouse model of endothelial cell activation to evaluate leukocyte (WBC) adhesion.
• Examined the effects of complement component deficiency (C3 and C5) and C5 activation inhibition (using anti-C5 mAb) on aPL-induced thrombosis and endothelial activation.

Main Results:

• Mice deficient in complement components C3 and C5 demonstrated resistance to aPL-induced enhancement of thrombosis.
• These complement-deficient mice also showed reduced endothelial cell activation in response to aPL antibodies.
• Inhibition of C5 activation via anti-C5 monoclonal antibody administration effectively prevented aPL-induced thrombophilia.

Conclusions:

• Complement activation is a critical mediator of both thrombosis and endothelial cell activation induced by antiphospholipid antibodies.
• Targeting complement component C5 represents a potential therapeutic strategy for managing aPL antibody-mediated diseases.
• These findings elucidate a key pathway in the pathogenesis of antiphospholipid syndrome.