The complement system is an essential component of the immune system consisting of more than 30 plasma and membrane-bound proteins, synthesized mainly by the liver. These proteins circulate in the blood as inactive precursors (zymogens) and become activated during infection. Once activated, the complement system functions as a proteolytic cascade, in which activation of one component sequentially activates the next, resulting in amplification of the immune response.
Process of Complement Activation
Complement activation occurs through three distinct pathways, depending on the nature of the triggering stimulus:
- Classical Pathway:
Activated by antigen–antibody complexes, particularly involving IgM or IgG antibodies. This pathway links the adaptive immune system to complement activation. - Lectin Pathway:
Initiated when mannose-binding lectin (MBL) binds to specific carbohydrate residues present on microbial surfaces. This pathway is antibody-independent but mechanistically similar to the classical pathway. - Alternative Pathway:
Activated spontaneously through a process known as tick-over, or directly on microbial surfaces. It plays a key role in innate immunity.
All three pathways converge at the central component C3, which is cleaved into C3a and C3b. C3b participates in opsonization and further cascade activation, while C3a acts as an inflammatory mediator. Subsequent activation of terminal components leads to the formation of the Membrane Attack Complex (MAC) composed of C5b–C9, which causes lysis of target cells.
Significance of Complement Activation in Immunity
- First Line of Defense:
The alternative and lectin pathways provide rapid, antibody-independent protection against pathogens during early infection. - Enhanced Phagocytosis (Opsonization):
C3b coats microorganisms and binds to complement receptors on phagocytes, increasing efficiency of phagocytosis and microbial clearance. - Direct Killing of Pathogens:
Formation of the MAC leads to pore formation in microbial membranes, causing cytolysis, particularly effective against Gram-negative bacteria. - Promotion of Inflammation:
Complement fragments C3a and C5a (anaphylatoxins) induce mast cell degranulation, vasodilation, increased vascular permeability, and chemotaxis of immune cells. - Link Between Innate and Adaptive Immunity:
Antibody-dependent activation and C3d-mediated B-cell activation enhance adaptive immune responses. - Immune Regulation:
Complement aids in clearance of immune complexes and apoptotic cells, maintaining immune homeostasis and preventing tissue damage.
Conclusion
- Thus, the complement system is essential for host defense, inflammation, immune regulation, and coordination of immune responses.