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

Autoimmune factor XIII (FXIII) deficiency is a rare hemorrhagic disease characterized by severe bleeding and a high mortality rate. However, the pathogenesis of this disease remains unclear. FXIII consumption caused by infections is becoming increasingly common. Our clinical investigation, combined with in vivo experiments, revealed that patients and mice with autoimmune FXIII deficiency displayed complement dysfunction and that pathogenic infection and autoantibody generation were positively correlated. Further analysis revealed the presence of combined FXIII-C3 autoantibodies in patients with autoimmune FXIII deficiency. These combined autoantibodies neutralize FXIII, cause bleeding, and form a complex with C3, inhibiting complement activation and complement-mediated adaptive immune responses. Therefore, compromised immune responses increase host susceptibility to pathogenic Candida albicans infections. Consequently, uncontrolled exogenous fungal infections further activate platelets and cause platelet-related CD40 ligand (CD40L) release. By interacting with the CD40 on the B cell surface, the released CD40L further promotes autoreactive B cell activation to produce more autoantibodies, thereby forming a self-amplification loop for the progressive consumption of FXIII. We believe this study provides a perspective on disease pathogenesis and therapeutic guidance for better treatment of autoimmune FXIII deficiency.