The fundamentals of the complement cascade, including its activation by antibodies, was first described in the middle of the last century. Complement-dependent cytotoxicity/CDC is initiated when C1q, the initiating component of the classical complement pathway, is fixed to the Fc portion of target-bound antibodies.
Once C1q binds to the antibody Fc, C1r cleaves itself and becomes activated, which then cleaves other C1r and C1s molecules. Once C1s is cleaved, it becomes a protease that binds and cleaves C4 and C2. When C4 is cleaved into C4b, a thioester bond is exposed, which is mostly hydrolyzed by water. However, a minority of C4b becomes covalently bound to the target surface. When C2 is cleaved, the C2b fragment forms a complex with the C4b bound to the pathogen. The C4b2b complex becomes the C3 convertase of the classical pathway, which cleaves C3 into C3b and C3a fragments. C3b is then deposited on the target surface.
The deposition of C3b is amplified by the alternative pathway, which involves factor B and factor D. The input signal for this pathway involves factor B binding to a C3b fragment already bound to the target surface. The C3b and factor B complex becomes susceptible and is cleaved by factor D into C3bBb, the C3 convertase of the alternative pathway. Because C3Bb acts like C4b2b in creating more C3b, which in turn creates more C3Bb, the alternative pathway becomes a positive feedback system and amplifies the reaction started by C4b2b. This leads to C3b saturation of the pathogen surface.
As the complement cascade progresses, C3b can also bind to the C3 convertase itself, forming C4b2b3b or C3b2Bb. These new complexes are called C5 convertases, which cleaves C5 into C5b and C5a. C5b initiates the formation of the membrane attack complex. C6 and C7 bind to C5b, which exposes a hydrophobic site in C7 and inserts into the pathogen lipid bilayer. C8 then binds to C7 and also inserts into the bilayer, initiating the membrane attack complex (MAC) pore formation by the C9 components.
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