Combined FXIII-C3 autoantibodies elicit bleeding and complement dysfunction in autoimmune FXIII deficiency

Area of Science:

• Immunology
• Hematology
• Pathogenesis

Background:

• Autoimmune factor XIII (FXIII) deficiency is a rare hemorrhagic disorder with unclear pathogenesis.
• Increasingly, FXIII consumption is linked to infections.
• Severe bleeding and high mortality rates characterize this condition.

Purpose of the Study:

• To elucidate the pathogenesis of autoimmune FXIII deficiency.
• To investigate the correlation between infection, autoantibody generation, and complement dysfunction.
• To identify potential therapeutic targets.

Main Methods:

• Clinical investigation of patients with autoimmune FXIII deficiency.
• In vivo experiments using mouse models.
• Analysis of combined FXIII-C3 autoantibodies and their effects on FXIII activity and complement pathways.
• Assessment of platelet activation and CD40 ligand (CD40L) release.

Main Results:

• Patients and mice with autoimmune FXIII deficiency exhibit complement dysfunction.
• A positive correlation exists between pathogenic infection and autoantibody generation.
• Combined FXIII-C3 autoantibodies were identified, neutralizing FXIII and inhibiting complement.
• Compromised immunity increases susceptibility to Candida albicans infections.
• Fungal infections trigger platelet activation and CD40L release, promoting autoantibody production, forming a self-amplifying loop.

Conclusions:

• Autoimmune FXIII deficiency involves a complex interplay between FXIII neutralization, complement inhibition, and infection-induced immune dysregulation.
• A self-amplifying loop involving autoantibodies, complement dysfunction, and opportunistic infections drives progressive FXIII consumption.
• Findings offer insights into disease pathogenesis and suggest potential therapeutic strategies for autoimmune FXIII deficiency.