Complement

Activation of the Complement System

  • The complement system is activated on surfaces, such as that of bacteria.

Mechanism of Activation

  • Activation is initiated by antibodies binding to bacterial cell surface antigens.

  • The C1 complement complex consists of:

    • 1 molecule of C1q

    • 2 molecules of C1r

    • 2 molecules of C1s

  • C1 complex binds to aggregated antibody molecules on the bacterium's surface.

Binding and Proteolysis

  • Binding of C1 complex activates the proteases C1r and C1s via cross proteolysis.

  • Active C1s cleaves the complement protein C4, releasing:

    • C4a (small peptide, anaphylatoxin)

    • C4b (large fragment with a labile thioester bond)

Attachment of C4b

  • C4b covalently attaches to the bacterial surface via ester or amide linkages.

Formation of C3 Convertase

  • The C2 pro enzyme binds to C4b and is cleaved by activated C1s, releasing peptide C2b.

  • This generates the classical pathway C3 convertase: C4bC2a.

  • C4bC2a binds to C3, cleaving it to release:

    • C3a (anaphylatoxin peptide)

    • C3b (fragments with labile thioester)

C3 Convertase Function

  • C3b binds to the bacterial surface next to C4bC2a, enhancing the C3 convertase to C4bC2aC3b.

  • This complex, known as C3C5 convertase, can cleave multiple C3 molecules, releasing C3a.

  • C3b fragments covalently attach to the bacterial surface, promoting phagocytosis.

Role of C5 in Complement Activation

  • C3C5 convertase cleaves and activates C5.

  • Fragment C5a serves as a potent anaphylatoxin and important chemoattractant.

  • The larger fragment C5b initiates membrane attack complex formation.

Formation of the Membrane Attack Complex

  • C5b interacts with C6 and C7, allowing insertion into the bacterial cell membrane.

  • C8 also binds and inserts into the membrane.

  • C5b678 complex catalyzes the assembly of C9 molecules, forming a cylindrical pore.

  • This pore disrupts ionic and osmotic balance, leading to bacterial cell death.

Key Components of the Complement System

  • Cells: The complement system involves various immune cells that participate in its activation and functions to combat pathogens.

  • Definitions:

    • C1 complex: Consists of C1q, C1r, and C1s, initiating activation upon binding to antibodies on bacterial surfaces.

    • C3 convertase: A key enzyme complex formed during the complement activation that cleaves C3 into C3a and C3b.

    • Membrane Attack Complex (MAC): A structure formed by C5b, C6, C7, C8, and C9 that disrupts bacterial cell membranes.

  • Proteins:

    • C3b: Promotes phagocytosis and enhances the C3 convertase activity.

    • C5a: Acts as an anaphylatoxin and chemoattractant, while C5b begins the MAC formation.