Overview of Complement Activation Pathway
Complement system activation plays an important role in both innate and acquired immunity. The complement system can be activated through three major pathways: the classical pathway (CP), the alternative pathway (AP) and the lectin pathway (LP) (Fig.1). Each pathway is activated by different components that converge in the formation of active enzyme complexes (C3 and C5 convertases), followed by the activation of the C5, C6, C7, C8, and C9 proteins, resulting in the sequential assembly of C5b-7, C5b-8, and C5b-9 complexes on the target cell. Activation of complement and the subsequent formation of C5b-9 channels (membrane attack complex, MAC) on cell membranes lead to a proteolytic cascade, which culminates in multiple biological processes including opsonization and phagocytosis of intruders, inflammation, cell lysis, and removal of immune complexes and apoptotic cells. Furthermore, it also functions as a link between the innate and adaptive immune responses.
Fig. 1 A schematic view of activation of the complement system.1
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Complement Activated in Classical Pathway
The CP is primarily initiated when the antibody-antigen complex interacts with C1-complex, which contains C1q, two molecules of C1r, and two molecules of C1s. The C1-complex cleaves C2 and C4, which then form C3 convertase (C4b2a). The formation of C3 convertase leads to the activation of C3 and formation of C3a (anaphylatoxin) and C3b (opsonin), where C3 is the convergence point of the complement cascade. C3 is then cleaved by the C3 convertase and forms C5 convertase (C4bC2aC3b) that cleaves C5 into C5a and C5b, initiating the terminal pathway and assembly of the MAC.
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Complement Activated in Alternative Pathway
The AP begins with the spontaneous hydrolysis of C3 into C3(H2O) and requires factor B and factor D. In the plasma, C3(H2O) molecules containing an unstable thioester bond undergoes slow spontaneous hydrolysis to yield C3a and C3b. C3b binds to factor B, leading to factor B exposes the site which serves as the substrate for enzymatically active factor D. Then factor D cleaves B into Ba and Bb forming C3 convertase (C3bBb). C3 convertase then forms C5 convertase which ultimately forms a MAC as in the CP.
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Complement Activated in Lectin Pathway
The LP is initiated by the binding of MBL and ficolins to carbohydrate groups or other molecules on the surface of bacterial cells. The MBL-associated serine proteases, MASP-1 and MASP-2, are activated and cleave C4 and C2, which then form the C3 convertase as in the CP. C3 convertase then forms C5 convertase which ultimately forms a MAC as in the CP.
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Serine Proteases of Complement System
Complement activation involves a very strong degree of amplification. Serine proteases play an important role in human physiology and pathology, activating each other to promote initiation and amplification of the complement cascade. They have a common domain that contains the catalytic triad of histidine, aspartic acid and serine residues. The serine proteases of the complement system include C1r and C1s of the CP, MASPs 5-1-3 of the LP, C2 of the classical/lectin pathway, and Factor B, Factor D, and Factor I of the AP.
Table 1 Serine proteases of the complement system. (Andrade, 2017)
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References
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Mathern, Douglas R., and Peter S. Heeger. "Molecules great and small: the complement system." Clinical journal of the American Society of Nephrology: CJASN 10.9 (2015): 1636.
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