The complement system is a powerful tool of innate immunity to combat pathogens and maintaining host homeostasis. Pathogens activate the classical (CH50) and lectin pathway wherein the alternative pathway (AP) can serve as an “amplification loop”. The AP is also capable of autoactivation, allowing continuous monitoring for pathogens by generating small amounts of C3b. Complement factor I (CFI) plays a crucial role in the negative regulation of C3b, leading to the generation of degradation products such as C3d. Unrestricted localized overactivation of the AP due to a CFI deficiency is mainly associated with renal diseases like atypical hemolytic-uremic syndrome (aHUS) and C3 glomerulopathies (C3G).
We present two cases illustrating the laboratory hallmarks of a CFI defect.
In both patients CH50, AP50 and serum complement factor C3 was reduced. A quantitative CFI deficiency was found in one patient, whereas the serum level of CFI was normal in the second patient thus initially misdiagnosed as a C3 deficiency. However, based on reduced levels of C3d, targeted sequencing revealed a compound heterozygous mutation in the CFI gene confirming a functional CFI defect. Interestingly, both patients presented with recurrent and invasive pneumococcal infections.
Inherited quantitative and functional deficiencies of regulator CFI can induce overactivation of the alternative pathway and typically results in reduced levels of the degradation product C3d; a diagnostic hallmark for CFI deficiency. In case of general overactivation, CFI deficiency can also present with recurrent pneumococcal infections rather than renal disease due to reduced serum C3, secondary to overconsumption.