Complement factor D haplodeficiency is associated with a reduced complement activation speed and diminished bacterial...

Area of Science:

• Immunology
• Genetics
• Complement System

Background:

• Complete deficiency of alternative pathway (AP) complement factors increases risk for invasive bacterial infections.
• Heterozygous mutations in complement factors, like complement factor D (fD), are less understood regarding infection risk.
• Recurrent bacterial infections can be linked to genetic variations affecting immune response.

Purpose of the Study:

• To investigate the impact of heterozygous complement factor D (fD) deficiency on AP complement activity.
• To analyze the relationship between low fD serum levels and bacterial infection susceptibility.
• To evaluate the efficacy of vaccination in individuals with heterozygous fD deficiency.

Main Methods:

• Measured AP activity and complement C3 binding to bacterial surfaces (Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae).
• Assessed complement-mediated bacterial killing in patients with heterozygous fD deficiency.
• Evaluated the effect of vaccination on complement C3 binding and bacterial killing.

Main Results:

• Reconstitution of fD-deficient serum with fD dose-dependently restored AP activity.
• Low fD serum levels (<0.5 μg/mL) correlated with reduced complement C3 binding and bacterial killing.
• Vaccination enhanced complement C3 binding and bacterial killing capacity, even without fD reconstitution.

Conclusions:

• Low fD serum levels slow complement activation, impairing bacterial killing and leading to recurrent infections.
• Specific antibodies induced by vaccination can compensate for diminished bacterial killing in individuals with low fD levels.
• Heterozygous fD deficiency represents a risk factor for bacterial infections, but this can be mitigated by vaccination.