“Super factor B” and its gains-of-function. (A) Host cells, including endothelial cells, have multiple mechanisms to protect against complement-mediated destruction. As C3b is generated in the circulation, it deposits on all exposed cell membrane surfaces. (Left) Factor H (FH) outcompetes factor B (B) for binding to C3b on the host cell, acting as a cofactor for factor I (FI)–mediated generation of inactive C3b (iC3b), thereby suppressing further complement activation. (Right) If factor B does manage to bind to any host cell surface C3b, the B is cleaved and activated (dotted line) by factor D (D) to yield the alternative pathway C3 convertase (C3bBb). This complement-activating C3 convertase, however, is not long-lived, as FH rapidly and effectively destabilizes the C3bBb complex, promoting its dissolution, enhancing further generation of iC3b, and overall protecting the host cell from damage. (B) “Super factor B” (B*) has unique properties that overcome the protective functions of FH. (Left) B* binds more avidly to C3b and thus prevents FH from interacting with C3b. B* is then cleaved by factor D, and the so-formed C3 convertase (C3bBb*), particularly resistant to the normal destabilizing properties of FH, is able to generate more C3 convertase and C5 convertase (C3bBb*C3b). This causes the release of anaphylatoxins C3a and C5a, respectively, and the formation of the membrane attack complex (MAC), which damages or lyses the host cell. (Right) If FH does manage to bind to C3b and facilitate the generation of iC3b, the “super factor B” has the unique capacity to bind to the iC3b, recruiting it as a component of a novel C3 convertase (iC3bBb*). This in turn yields C5 convertase, leading to formation of the MAC that integrates into the host cell membrane. The resultant endothelial cell damage is believed to increase the risk of developing the thrombotic microangiopathy, atypical hemolytic uremic syndrome. Professional illustration by A. Y. Chen.