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

Abstract

Objectives Complete deficiency of alternative pathway (AP) complement factors, explained by homozygous mutations, is a well‐known risk factor for invasive bacterial infections; however, this is less obvious for heterozygous mutations. We describe two siblings with a heterozygous NM_001928.3(CFD):c.125C>A p.(Ser42*) mutation in the complement factor D (fD) gene having a history of recurrent bacterial infections. We determined the effect of heterozygous fD deficiency on AP complement activity. Methods We determined the effect of fD levels on complement activation as measured by AP activity, complement C3 binding to the bacterial surface of Neisseria meningitidis (Nm), Streptococcus pneumoniae (Sp) and non‐typeable Haemophilus influenzae (NTHi), and complement‐mediated killing of Nm and NTHi. In addition, we measured the effect of vaccination of complement C3 binding to the bacterial surface and killing of Nm. Results Reconstitution of fD‐deficient serum with fD increased AP activity in a dose‐ and time‐dependent way. Reconstitution of patient serum with fD to normal levels increased complement C3 binding to Sp, Nm and NTHi, as well as complement‐mediated killing of Nm and NTHi. Vaccination increased complement C3 binding and resulted in complete killing of Nm without fD reconstitution. Conclusion We conclude that low fD serum levels (< 0.5 μg mL −1 ) lead to a reduced speed of complement activation, which results in diminished bacterial killing, consistent with recurrent bacterial infections observed in our index patients. Specific antibodies induced by vaccination are able to overcome the diminished bacterial killing capacity in patients with low fD levels.

Low‐molecular weight inhibitors of the alternative complement pathway

“… 55 This shows that bacterial infections are an important safety concern for patients taking complement inhibitors. To date, only two individuals with factor B deficiency 124 , 125 and 13 individuals with factor D deficiency have been identified, 70 , 126 , 127 , 128 , 129 , 130 , 131 who were discovered based on a history of infections with encapsulated bacteria, (for example, Neisseria meningitidis, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes ) in at least one family member. While 10 of the 13 individuals with factor D deficiency had a history of infections, this was not the case for the other three.…”

“… 69 Initially, factor D was thought to be the rate‐limiting protease of the alternative pathway, based on low plasma concentrations and studies with reconstituted factor D deficient plasma. 70 , 71 However, more recently it has become clear that in diseases with increased alternative pathway activity, such as C3G, very low levels of factor D (~1% of plasma levels) are sufficient to activate the alternative pathway, especially if the C3 convertase is stabilized. This also suggested that >90% of enzyme inhibition may be required to fully shut down the alternative complement pathway.…”