Compliment

• the complement system is a key aspect of innate immunity which is initiated after a pathogen has broken through initial defences. it also has a role in the adaptive immune response
• more than 30 proteins are involved with the compliment system within the blood and other body fluids with the majority made in the liver before circulating the body in an inactive form
• complement proteins need to be activated first to save energy and resources
• complement proteins are are activated by the presence of pathogens or antibody:antigen complexes - a combination of proteins result in different complement pathways
• there are three pathways in the complement system:

  1. classical - triggered by antigen:antibody complexes
  2. lectin - triggered by lectin type proteins binding to repeated type structures on pathogen surfaces
  3. alternative - triggered by pathogen surfaces
• Complement pathways are initiated by pattern recognition receptors - proteins which detect the presence of a pathogen
• the activation of an initial zymogen – the inactive precursor of an enzyme causes a cascade of proteolysis and then further sequential activation which activates protease which cleaves and activates next within the cascade.
• in the classical pathway C1 complex can be broken down into C1s C1r and C1q
• C1q has 6 identical subunits with globular heads
• C1r and C1s form C1r2:Cis2 comples
• C1 q binds to the antigen-antibody complex or pathogen
• C1q binds to the Fc region of IgM and IgG - 2 globular heads bind to the constant structure
• the major pathways of complement activation:

  1. C1q binds antigen-bound antibody, activating C1r and C1s
  2. C1s cleaves C4 and C2
  3. C4b binds C2 - C1 cleaves C2 creating C3 convertase C4b2a
  4. C3 convertase hydrolysed C3 molecule combining and making C5 convertase (C4b2a3b)
  5. C3b of C5 convertase binds C5 allowing it to be cleaved
• C1q binds antigen-bound antibodies and induces a conformational change in one C1r molecule activating it - this C1r then activates the second C1r and the two C1s molecules
• C1s cleaves C4 producing C4a and C4b the latter then binds to the membrane close to C1. C4b binds C2 and exposes it to the action of C1s which cleaves C2 into C2a and C2b creating the C3 convertase C4b2a
• C3 convertase hydrolyses many C3 molecules and some combine with C3 convertase to form C5 convertase (C4b2a3b)
• the C3b component of C5 convertase binds C5 allowing it to be cleaved by C4b2a
• the lectin pathway is initiated by mannose binding lectin (MBL) which recognises repeating patterns on a microorganisms surface
• MBL forms a complex with MBL-associated serine proteases MASP1 and MASP2
• MBL binds to pathogen surface causing a conformational change in MASP 2 which cleaves and activates the second MASP 2
• activated MASP-2 associated with MBL or ficolan cleaves C4 to C4a and C4b whihc binds to the microbial surface
• C4b then binds C2 which is cleaved by MASP-2 to C2a and C2b forming the C4b2a complex
• C4b2a is an active C3 convertase cleaving C3 to C3a and C3b which binds to the microbial surface or to the convertase itself
• one molecule of C4b2a can cleave up to 1000 molecules of C3 to C3b many C3b molecules bind to the microbial surface
• the alternative pathway can be activated via classical/lectin pathway and by tick-over
• in the alternative pathway C3 convertases are short-lived but can be stabilised bu properdin (factor P) which binds to C3b
• tick-over is where C3 undergoes spontaneous hydrolysis to C3(H2O) which binds to factor B allowing it to be cleaved by factor D into Ba and Bb
• the C3(H2O)Bb complex is a C3 convertase cleaving more C3 into C3a and C3b (C3b is rapodly inactivated unless it binds to the cell surface)
• Factor B binds noncovalently to C3b on a cell surface and is cleaved to Bb by factor D
• C3 is present in large ammounts in plasma and so spontaneous hydrolysis causes a steady low production of C3H2O - this fluid-phase C3 convertase is short lived
• all pathways converge at C3 convertase
• C3 is cleaved to C3a and C3b the latter being deposited on the pathogen surface
• C3 is abundant in plasma with its main effect being opsonisation
• C3b binds C3 convertase to create C5 convertase

  • C4b2a3b in classical and lectin pathway
  • C3b2Bb in alternative pathway
• C5 convertase cleaves C5 to C5a and C5b - C5 binds to a site on C3b and enables cleavage by C2a or Bb which are active enzymes
• C5a is a strong inflammatory mediator
• C5b initiates the formation of the membrane attack components (MAC)
• C4a and C3a are both inflammatory mediators
• all pathways follow the same way from C5 convertase onwards
• the membrane attack complex is the result of the deposition of C5b, C6, C7, C8, and C9 in target cell membranes - this pore structure disrupts osmotic integrity resulting in cell death or cell lysis