Pleiotropic role of CFH in complement regulation. Simplified illustration of complement activation/regulation on PNH erythrocytes. Spontaneous, continuous hydrolysis of C3 results in low-grade activation of the alternative pathway through the generation of the fluid phase C3 convertase C3H₂0:Bb; this activates further C3, with surface-bound C3b leading to surface-bound C3 convertase. This initial step is usually disabled on human cells by CD55, but on PNH erythrocytes, the lack of CD55 results in surface complement activation. PNH erythrocytes have continuous and uncontrolled generation of C3 convertase, which in turn generates surface C5 convertase, which can cleave C5, enabling the terminal pathway of the complement, which is not blocked by CD59 (missing on PNH erythrocytes). As a consequence, PNH erythrocytes undergo continuous complement-mediated lysis owing to the formation of its effector membrane attack complex (MAC). CFH is a fluid-phase complement regulator that prevents the formation and promotes the decay of the C3 convertases. CFH also contributes (as cofactor of CFI) to degrading activated C3 (C3b) into inactivated C3 (iC3b). Inherited variants of the CFH gene may account for differences in CFH activity, owing to both variants affecting the CFH complement-regulatory domain or its membrane-binding domain. Furthermore, at least 5 FH-related proteins (FHR-1 to FHR-5) may affect CFH activity by competing with its surface binding; and polymorphisms of FHR genes are quite frequent, with possible functional consequences. In PNH, owing to the lack of the membrane complement regulators, subtle differences in CFH activity may eventually lead to clinical consequences. When the terminal complement is inhibited (eg, by anti-C5 agents such as eculizumab) and MAC-mediated intravascular hemolysis is prevented, these differences may account for different degree of proximal complement activation, leading to different extent of C3-mediated extravascular hemolysis.⁴ Professional illustration by Luk Cox, Somersault18:24 (based in part on Ricklin and Cines¹¹).