Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice.

Area of Science:

• Immunology
• Nephrology
• Genetics

Background:

• Atypical hemolytic uremic syndrome (aHUS) is linked to complement system dysregulation.
• Gain-of-function mutations in complement-activating proteins are implicated in aHUS pathogenesis.

Purpose of the Study:

• To establish a mouse model for studying aHUS driven by complement C3 gain-of-function mutations.
• To investigate the therapeutic potential of targeting the complement cascade, specifically C5, in aHUS.

Main Methods:

• Generated homozygous C3 p.D1115N knock-in (C3KI) mice exhibiting aHUS-like symptoms.
• Analyzed clinical, hematological, and renal pathology in C3KI mice.
• Evaluated the therapeutic effect of C5 blockade or genetic deletion on aHUS development in C3KI mice.

Main Results:

• Homozygous C3KI mice spontaneously developed chronic thrombotic microangiopathy, hematuria, thrombocytopenia, elevated creatinine, and hemolysis.
• Active disease in C3KI mice showed reduced plasma C3 and deposition of C3 fragments and C9 in the kidney.
• Therapeutic C5 blockade or deletion prevented thrombotic microangiopathy and aHUS in C3KI mice without causing other renal complications.

Conclusions:

• Gain-of-function mutations in complement C3 are sufficient to drive aHUS in vivo.
• Targeting C5 is a viable therapeutic strategy for aHUS.
• This preclinical model is valuable for testing novel complement inhibitors for various complement-mediated diseases.