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

Area of Science:

• Immunology
• Hematology
• Molecular Biology

Background:

• Beta2-glycoprotein I (β2-GPI) is a plasma glycoprotein implicated in antiphospholipid syndrome (APS).
• Its physiological function remains largely unknown, but it's a primary target for antiphospholipid antibodies (aPLs) that trigger complement activation and thrombosis.

Purpose of the Study:

• To investigate the interaction between mannose-binding lectin (MBL) and β2-GPI.
• To determine if this interaction activates the complement system and influences thrombin generation.
• To explore the potential role of this interaction in endothelial cells and its relevance to APS.

Main Methods:

• Binding assays to assess MBL-β2-GPI interaction in the presence of calcium.
• Analysis of complement activation and thrombin generation following MBL-β2-GPI complex formation.
• Investigation of binding sites on β2-GPI domains and detection of the complex on human umbilical vein endothelial cells (HUVECs) and patient artery biopsy specimens.

Main Results:

• MBL binds to β2-GPI in a calcium-dependent, dose-dependent manner, activating complement and promoting thrombin generation.
• Binding occurs with isolated domains II and IV of β2-GPI, indicating a noncanonical interaction mode.
• MBL-β2-GPI complex formation was detected on HUVECs and in APS patient arterial endothelium, with increased thrombin generation after TNF-α priming.

Conclusions:

• The MBL-β2-GPI interaction activates complement and promotes thrombin generation, potentially contributing to thrombosis.
• This interaction occurs on endothelial cells and may be relevant in both physiological and pathological conditions, including APS.
• The findings suggest a novel mechanism in APS pathogenesis that could be independent of aPLs, highlighting potential therapeutic targets.