Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS.

Area of Science:

• Immunology
• Hematology
• Genetics

Background:

• Antiphosphospholipid syndrome (APS) is defined by thrombosis and/or pregnancy morbidity.
• Antiphospholipid antibodies, particularly anti-β2-glycoprotein-I (anti-β2GPI), are central to APS pathogenesis.
• Animal studies suggest a role for complement in APS-related clinical events.

Purpose of the Study:

• To investigate the association between complement activation and thrombotic events in APS.
• To determine the role of anti-β2GPI antibodies in complement activation.
• To explore the genetic basis of complement dysregulation in catastrophic APS (CAPS).

Main Methods:

• Utilized the modified Ham (mHam) assay to measure complement-dependent cell killing and C5b-9 deposition.
• Assessed sera from patients with CAPS, APS, systemic lupus erythematosus (SLE), and healthy controls.
• Analyzed germline variants in complement regulatory genes in patient cohorts.

Main Results:

• Positive mHam assay and C5b-9 deposition were found in high percentages of CAPS (85.7%) and APS (35.6%) patients, especially those with recent thrombosis.
• A positive mHam assay correlated with triple antibody positivity and recurrent thrombosis.
• Patient-derived anti-β2GPI antibodies activated complement via the classical pathway, inhibited by anti-C5 but not factor D inhibition.
• CAPS patients exhibited a high frequency (60%) of rare germline variants in complement regulatory genes.

Conclusions:

• Anti-β2GPI antibodies activate complement, contributing to thrombosis in APS.
• Uncontrolled complement activation, potentially due to germline variants in regulatory genes, acts as a "second hit" in CAPS, leading to severe thrombosis.