The complement system is an important component of the innate immunity that functions primarily as a first-line host defense against pathogenic infections. Complement mediates responses to inflammatory triggers through a co-ordinated sequential enzyme cascade leading to clearance of foreign cells. Besides, complement also possesses anti-inflammatory functions by binding to immune complexes and apoptotic cells, thereby assisting in their removal from the circulation and damaged tissues.
The Activation of the Complement System
The complement system can be activated through three major pathways: classical, alternative, and lectin pathway. The classical pathway is initiated by IgM or IgG antigen/antibody complexes binding to the C1 complex. This, in turn, activates the serine proteases that lead to the cleaving of C4 and C2, leading to the formation of C4b2a (C3 convertase). The lectin pathway is activated by the binding of mannose-binding lectin (MBL) or ficolins to an array of mannose groups on the surface of bacterial cells. This activates the MBL-associated serine proteases, MASP1, MASP2, and MASP3, which can then cleave C4 and C2 to generate C3 convertase, as in the classical pathway. The alternative pathway is initiated by hydrolyzed C3 and factor B and the subsequent formation of the alternative pathway C3 convertase, C3bBb. The generation of the C3 convertase allows the formation of the C5 convertase enzyme, which initiates the formation of the C5b-9 terminal complement complex (membrane attack complex (MAC)).
Fig. 1 Complement activation pathways and assembly of the terminal pathway.1
The Regulation of Complement System
The activation of the complement system is in such a rapidly amplified way through a triggered-enzyme cascade, which makes it necessary to be tightly regulated to protect the host from the destructive effects resulting from improper activation. This is achieved predominantly with the help of complement control proteins (or complement regulators). For example, C1 esterase inhibitor (C1-INH) inhibits the activation of early pathway activation of all three pathways, while C4b-binding protein (C4BP) controls activation at the C4 level of the classical pathway and lectin pathway. develop factor I and develop factor H regulate the C3 and C5-convertase. Furthermore, the membrane-bound inhibitors include complement receptor 1 (CR1), membrane cofactor protein (MCP) that acts as co-factors for factor I and decay-accelerating factor (DAF) which accelerates the decay of C3-convertases. The membrane-bound regulator Clusterin and CD59 drug prevent the generation of the C5b-9. The S protein/vitronectin binds to C5b-7 and leads to the formation of a cytolytically inactive SC5b-9 complex.
The Effector Functions of the Complement System
Complement activation, regardless of the pathway, converges on the generation of three broad effector pathways that serve to enable the complement to fulfill its physiological imperatives in host defense: (1) a number of activated complement proteins (e.g., C3b, C4b) can bind covalently to pathogens, opsonizing them for engulfment by phagocytes bearing corresponding receptors; (2) generation of anaphylatoxins (C3a and C5a) for the recruitment of inflammatory cells and release of mediators that amplify the inflammatory response; (3) the MAC inserts into membrane creating functional pores in bacterial membranes leading to its lysis.
Especially, Creative Biolabs offers innovative complement drug discovery services targeting various complement components (including proteases, receptors, and regulators) for different indications. Besides, we offer complement testing services, including complement function test, complement autoantibody test, and complement genetic test. If additional help is needed, please directly contact us and consult our technical supports for more detail
Reference
-
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.
Related Product
For Research Use Only.
Related Sections:
