Complement activation in sickle cell disease: Dependence on cell density, hemolysis and modulation by hydroxyurea...

Area of Science:

• Immunology
• Hematology
• Innate Immunity

Background:

• The complement system, part of innate immunity, can damage tissues when overactivated.
• Previous studies suggest complement overactivation in sickle cell disease (SCD) patients, but mechanisms remain unclear.

Purpose of the Study:

• To investigate the mechanisms of complement system overactivation in sickle cell disease (SCD).
• To assess the impact of complement overactivation on different cell types and the effect of hydroxyurea therapy.

Main Methods:

• Measured plasma sC5b-9 (terminal complement activation marker) in untreated SCD patients.
• Assessed in vitro complement activation by SCD erythrocytes and regulatory protein expression (CD35, CD55, CD59, CD46).
• Evaluated complement deposition on endothelial cells and the effect of hemopexin; analyzed hydroxyurea treatment effects.

Main Results:

• Elevated sC5b-9 in 61% of untreated SCD patients indicates terminal complement activation.
• SCD erythrocytes promote greater complement activation, correlated with dense red blood cells (DRBCs) with reduced regulatory proteins.
• Reduced CD46 on granulocytes inversely correlated with sC5b-9; hydroxyurea therapy decreased complement activation and increased CD46.

Conclusions:

• Complement overactivation is a common pathogenic event in SCD, associated with DRBC formation, hemolysis, and affecting red cells, leukocytes, and endothelial cells.
• Inefficient complement regulation on DRBCs and reduced CD46 expression contribute to overactivation.
• Hydroxyurea therapy partially alleviates complement overactivation in SCD patients.