Schematic representation of complement activation and interactions with other systems. The alternative pathway (AP) is constantly activated through slow spontaneous hydrolysis of C3 forming C3(H₂O) (ie, tickover). Activated C3(H₂O) pairs with factor B, generating C3(H₂O)B. Factor B is then cleaved by factor D and generates the fluid phase AP C3 convertase, or C3(H2O)Bb. The latter catalyzes the cleavage of additional C3 molecules to generate C3a and C3b. C3b binds factor B on cell surfaces, which is subsequently cleaved by factor D to generate a second (surface phase) AP C3 convertase (C3bBb), initiating the amplification loop. Binding and cleavage of an additional C3 to C3 convertase form the APC C5 convertase (C3bBbC3b) that cleaves C5 to C5a and C5b. Both C3 and C5 AP convertases are stabilized by properdin, or factor P, which also serves as a selective pattern recognition molecule for de novo C3 AP convertase assembly. Classical pathway activation mainly depends on antibody-antigen complexes recognized via complement component C1q. C1q also binds directly to certain epitopes from microorganisms or apoptotic cells and to cell-surface molecules. C1q then cleaves C1r, which activates C1s protease. Subsequently, C1s cleaves C4 and C2, leading to the formation of classical pathway C3 convertase (C4bC2a). C3 convertase cleaves C3, generating the anaphylatoxin C5a and C5 convertase (C4bC2aC3b), which cleaves C5 into C5a and C5b, which initiate the terminal pathway of complement. Lectin pathway activation is initiated by recognition of carbohydrate structures on the microbial surfaces by mannose-binding lectins (MBLs). Additional pattern recognition molecules of the lectin pathway include ficolins and collectin 11. These molecules act through MBL-associated serine proteases (MASPs), generating C3 convertase (C4bC2a), similarly to the activation of classical pathway. Proximal complement activation initiated by any of the 3 pathways (classical, alternative, or lectin) leads to C3 activation and C3 convertase formation on C3-opsonized surfaces. In the presence of increased surface density of deposited C3b, C5b initiates the terminal complement pathway, binding to C6 and generating C5b-6, which in turn binds to C7, creating C5b-7. C5b-7 is able to insert itself into lipid layers of the membrane. Once there, C5b-7 binds C8 and C9, forming a complex that unfolds in the membrane and binds several C9 molecules, thereby forming the membrane attack complex (MAC) on the surface of target cells. C3a and C5a mediate complement interactions with inflammation, coagulation, platelet activation, leukocyte recruitment, and endothelial cell activation. Professional illustration by Somersault 18:24.