Complement System Functions

Complement System

• The complement system plays a crucial role in eliminating microbes during innate and adaptive immune responses.
• The system has three main functions: opsonization, cell lysis, and inflammation.

Opsonization

• Coating microbes with C3b, which is recognized by complement receptor 1 (CR1/CD35), leading to phagocytosis.
• Most important function of complement in defense against microbes.

Cell Lysis

• Effective against microbes with thin cell walls or no glycocalyx.
• Involves late-stage complement activation, allowing water and ions to enter the microbe, leading to osmotic lysis.

Inflammation

• Triggered by C3 and C5 proteolysis, releasing C3a and C5a, which stimulate the release of inflammatory mediators from leukocytes.
• Leads to the movement of leukocytes to the site of infection.

Complement System Regulation

• Inhibition of complement activation can be expressed in mammalian cells via regulatory proteins (plasma or membrane proteins).

Complement System Pathways

• Three major pathways: alternative, classical, and lectin.
• Alternative pathway is initiated by microbes in the absence of antibodies.
• Classical pathway is initiated by a certain isotype of antibodies attached to antigens.
• Lectin pathway is initiated by microbes in the absence of antibodies.

Alternative Pathway

• Triggered by spontaneous hydrolysis of C3 in plasma at a low level.
• Leads to the formation of C3b, which is deposited on the surface of the microbe.
• Forms stable covalent bonds with microbial proteins and polysaccharides.
• C3 convertase breaks down more C3, leading to the recruitment of more C3b and C3bBb molecules to the microbe.

Classical Pathway

• Triggered when IgM or IgG binds to antigen on a microbial cell surface.
• C1 complement protein binds to the Fc region of the antibody, leading to the binding and cleavage of C2 and C4 protein.
• C4b2a complex forms the classical pathway C3 convertase.

Lectin Pathway

• Initiated by the attachment of the mannose-binding lectin (MBL) to microbes.
• Serine proteases, related to C1, lead to the binding and cleavage of C2 and C4 protein.
• C4b2a complex forms the classical pathway C3 convertase.

Early Steps of Complement Activation

• The net result is that microbes acquire a coat of covalently attached C3b.
• Alternative and lectin pathways are part of innate immunity, while the classical pathway is part of humoral immunity.

Late Steps of Complement Activation

• Initiated by the binding of C5 to C5 convertase and subsequent proteolysis of C5, generating C5b.
• The remaining components (C6, C7, C8, and C9) bind sequentially to a complex nucleated by C5b.