Illustrations of key features of the complement system. (A) Schematic drawing of the complement cascade. The complement initiation pathways of the CP and LP are triggered through recognition of danger signals by soluble pattern recognition molecules in blood cumulating in the assembly of the bimolecular C3 convertase C4b2a. Spontaneous hydrolysis of C3 (tick-over activation) assembles the early AP convertase autonomously of any danger signal. The C3 convertases activate C3 into the anaphylatoxin C3a and the opsonin C3b, which can auto-amplify via the AP amplification loop. Strong activation of CP/LP and/or impaired inactivation of C3b and convertases lead to a high surface density of C3b (±C4b). The latter recruits C5 and induces conformational changes (called priming) that allow the convertases to proteolytically activate primed C5 into the anaphylatoxin C5a and C5b initiating the terminal pathway. C5b launches the assembly of the MAC. Complement inhibitors targeting C5 hinder C5 priming and/or block convertase mediated activation of C5. Although TP is blocked in the presence of C5 inhibitors, the complement routes upstream of C5 continue to function. The figure is reproduced from Mannes et al,¹²² with modifications. (B) C3 activation and regulation cycles under physiologic conditions. The opposite directionality of the complement activation and regulation cycle maintain a fine-tuned balance controlling the unleashing of the 3 main effector functions of the complement cascade. The C3 activation cycle summarizes all routes and complement components that assemble the complement convertases, whereas the regulatory cycle is built from the convertase-directed regulators that decay the convertase (decay accelerating function) and/or proteolytically inactivate C3b (cofactor activity). Key components of each cycle are indicated in the respective boxes next to the cycles. Components and regulators associated purely with the CP and LP are displayed separately at the top of the boxes. The opsonization with C3 fragments and release of anaphalytoxins are directly effectuated and controlled by the C3 activation and regulation cycles, respectively. The formation of the membrane attack complex (initiated by C5 activation) is a consequence of strong C3 deposition by convertases and hence is indirectly regulated by the C3 regulation cycle. However, direct regulators of C5b-9 assemble exist in forms of the GPI-anchored CD59 on host surfaces and the 2 soluble plasma proteins Clusterin and Vitronectin (also called S protein) as indicated.