Blocking Properdin Prevents Complement-Mediated Hemolytic Uremic Syndrome and Systemic Thrombophilia

Area of Science:

• Immunology
• Complement System Biology
• Nephrology

Background:

• Properdin (P) positively regulates the alternative complement pathway.
• P inhibition ameliorates some complement-mediated injuries but exacerbates others, like in C3 glomerulopathy.
• The role of P in atypical hemolytic uremic syndrome (aHUS) remains unclear.

Purpose of the Study:

• To investigate the role of properdin (P) in the pathogenesis of atypical hemolytic uremic syndrome (aHUS).
• To evaluate the therapeutic potential of P inhibition in a murine model of aHUS.

Main Methods:

• Utilized genetic deletion and monoclonal antibody (mAb)-mediated inhibition of P in mice with a factor H (FH) mutation causing aHUS.
• Assessed survival rates, hematological parameters, thrombotic events, and renal histology.

Main Results:

• P deficiency completely rescued FH-mutant mice from premature death, thrombocytopenia, hemolytic anemia, and renal disease.
• Anti-P mAb treatment improved platelet counts and hemoglobin levels, preventing stroke and significantly reducing renal and liver thrombi.
• P inhibition demonstrated a protective effect, contrasting with its detrimental role in other complement-mediated diseases.

Conclusions:

• Properdin plays a critical role in the pathogenesis of aHUS.
• Inhibition of properdin may represent a promising therapeutic strategy for treating aHUS.
• Findings challenge the general assumption of P inhibition being universally beneficial in complement-mediated diseases.