Introduction to Pathways of Complement activation:

The complement system is a group of proteins that play a critical role in the immune response by targeting and destroying invading pathogens. It is a cascade system that can be activated by three pathways, namely the classical, alternative, and lectin pathways. In this study, we will examine the pathways of complement activation in detail.

I. The Classical Pathway:

The classical pathway is activated by the binding of antibodies to an antigen on the surface of a pathogen. This pathway can also be activated by other immune complexes such as C-reactive protein or certain polysaccharides.

1. Initiation: The first step of the classical pathway is the recognition of the antigen-antibody complex by C1q, a protein in the complement system.
2. Activation: C1q then binds to and activates the C1r and C1s proteins, which in turn cleave C4 and C2, leading to the formation of the C3 convertase enzyme (C4b2a).
3. Amplification: The C3 convertase enzyme then cleaves C3 into C3a and C3b. C3b can bind to the surface of the pathogen and serve as an opsonin, promoting phagocytosis.
4. Terminal pathway: Cleavage of C5 by the C3 convertase results in the formation of the C5 convertase enzyme (C4b2a3b). This enzyme cleaves C5 into C5a and C5b. C5a is a potent chemoattractant for neutrophils and other immune cells, while C5b initiates the formation of the membrane attack complex (MAC) which can lyse the pathogen.

II. The Alternative Pathway:

The alternative pathway can be activated in the absence of antibodies, by the direct binding of complement proteins to the surface of a pathogen.

1. Initiation: The alternative pathway is initiated by the spontaneous hydrolysis of C3, resulting in the formation of C3(H2O).
2. Activation: C3(H2O) can then bind to complement factor B, which is cleaved by complement factor D to form the C3 convertase enzyme (C3(H2O)Bb).
3. Amplification: The C3 convertase enzyme cleaves C3 into C3a and C3b. C3b can bind to the surface of the pathogen and serve as an opsonin.
4. Terminal pathway: Cleavage of C5 by the C3 convertase results in the formation of the C5 convertase enzyme (C3bBbC3b). This enzyme cleaves C5 into C5a and C5b. C5a is a potent chemoattractant for neutrophils and other immune cells, while C5b initiates the formation of the MAC.

III. The Lectin Pathway:

The lectin pathway is similar to the classical pathway in that it requires the recognition of a pathogen-associated molecular pattern (PAMP) by a recognition protein.

1. Initiation: The first step of the lectin pathway is the recognition of a PAMP by a mannose-binding lectin (MBL), ficolin, or collectin.
2. Activation: MBL, ficolin, or collectin then binds to and activates MBL-associated serine proteases (MASPs), which in turn cleave C4 and C2, leading to the formation of the C3 convertase enzyme (C4b2a).
3. Amplification: The C3 convertase enzyme then cleaves C3 into C3a and C3b. C3b can bind to the surface of the pathogen and
4. serve as an opsonin, promoting phagocytosis.

IV. Terminal pathway:

Cleavage of C5 by the C3 convertase results in the formation of the C5 convertase enzyme (C4b2a3b). This enzyme cleaves C5 into C5a and C5b. C5a is a potent chemoattractant for neutrophils and other immune cells, while C5b initiates the formation of the MAC.

V. Regulation of Complement Activation:

• The complement system is tightly regulated to prevent overactivation, which can lead to tissue damage and autoimmune disorders. There are several mechanisms of regulation.
• Decay-accelerating factor (DAF): DAF is a cell membrane protein that inhibits the formation and function of C3 and C5 convertases by promoting the dissociation of complement proteins from the cell surface.
• Factor H: Factor H is a plasma protein that binds to C3b and accelerates its decay, preventing the formation of C3 convertase.
• C1 inhibitor: C1 inhibitor is a plasma protein that inhibits the activation of the classical pathway by binding to and inactivating C1r and C1s.
• Membrane cofactor protein (MCP): MCP is a cell membrane protein that promotes the decay of C3b and C4b by acting as a cofactor for factor I. Factor I a plasma protein that cleaves complement proteins.

Conclusion:

In summary, the complement system is a complex cascade of proteins that plays a critical role in the immune response against invading pathogens. The classical, alternative, and lectin pathways each have unique mechanisms of activation. But all lead to the formation of the MAC, which can lyse pathogens. The complement system is tightly regulated to prevent overactivation, and there are several mechanisms of regulation to maintain immune homeostasis.