Complement is activated through three initiating pathways–the classical, lectin, and alternative–that lead to the formation of two C3 convertases, one of the classical/lectin pathways (C4b2a) and one of the alternative pathway (C3bBb). Both C3 convertases generate copious C3b and converge to generate large amounts of C3bBb. As more C3bBb forms, the terminal pathway is activated by the generation of C3bBbC3b, a C5 convertase that cleaves C5 into C5a and C5b to trigger the terminal pathway. When the classical and lectin pathways are activated, C4b2aC3b, the C5 convertase of the classical/lectin pathways, is also formed. With complement activity, two potent anaphylatoxins, C3a and C5a (shown in green) are generated. C3 glomerulopathy (C3G) is driven by dysregulation of the alternative pathway in the glycocalyx, which overlies the glomerular endothelial pores and is shown at the bottom of the figure. In 60% of patients, alternative pathway dysregulation can also be detected in the fluid phase (in the circulation). Infrequently, dysregulation occurs at the level of the classical/lectin pathways. As a result of complement dysregulation, C3b is deposited on the glycocalyx and serves as a foundation for C3 convertase formation; C5 convertase and terminal pathway proteins are also deposited. Drivers of this dysregulation include genetic changes, which are not shown, and/or autoantibodies to a number of different proteins and protein complexes, which are shown (a, C3Nefs; b, C4Nefs; c, C5Nefs; d, Factor H autoantibodies (FHAAs); e, FBAAs; f, C3bAAs). The stars represent several therapeutic targets currently being tested (the purple star is the site of action of eculizumab, which is available on an off-label basis in some circumstances). The complexity of the complement system and the heterogeneity of C3G raise the possibility that no single treatment will be universally appropriate for every patient.
