User:Kinkreet/Immunology/Complement System

The complement system is part of the innate immune system, and involves a selection of plasma proteins that react with each other to fight infection, opsonizing pathogens and recruiting inflammatory cells. There are 3 different pathways for activation: classical, alternative and lectin; although after activation, the function induced are the same. The classical pathway was first described in 1890s, and its proteins are heat-labile and worked with antibodies to kill bacteria; the alternative pathway was described in 1940s and functions in an antibody-independent manner, by recognizing bacterial surfaces; the lectin pathway was described in 1996, and involves lectin-dependent recognition of bacterial surfaces. Many of the complement proteins are proteases which normally exists as pro-enzymes (zymogens) and are activated through proteolytic cleavage into a small and large fragment. Often, the proteolytic cleavage of a complement protease will allow the large fragment (protease) to catalyse the proteolytic cleavage of other complement factors; this results in a cascade in which the original signal is amplified. The small fragment acts as a chemokine to attract and activate inflammatory cells.

Classical Pathway
There are four native components of the classical pathway - C1, 2, 3 and 4 - of which C1 is best characterized.

C1 is a multimer with the make-up of C1q:(C1r:C1s)2. C1q has 6 globular heads that can each bind to antigens or the Fc region of antibodies; and a collagen tail. It can bind directly to antigens on the surface of some pathogens, or to antigen-bound antibodies localized on the membrane (IgG3 binds the best to C1q, IgG and IgM can also bind) and to C-reactive protein (acute phase protein) bound to bacteria phosphocholine. C1r and C1s exist as zymogens. When C1q binds, it induces the cleavage of C1r; active C1r cleaves C1s, which generates active serine protease.


 * Acute phase response leads to the concentration of C-reactive proteins (CRP) to increase hundreds-fold.
 * Hepatocytes (main cells of the liver) generates CRP, more during responses to cytokines
 * Cinokement serves two main roles
 * Part of the innate immune response against infection
 * Opsonisation - enhance phagocytosis (C3b)
 * Chemotaxis - attract phagocytic cells (C3a, C5a)
 * Rupture membranes of foreign cells using membrane attack complexes (C5b-9)
 * Clumping of antigen-bearing agents
 * Removal of membrane and nuclear material from necrotic cells
 * CRP is a member of the pentraxin family, characterised by its cyclic pentameric structure, and Ca2+-dependent ligand binding.
 * CRPs are heat-labile, non-specific binds against all microbes and damaged cells

C3b can bind to polysaccharides or components of the cell surfaces of pathogens or damaged cells. Fcγ receptors can then recognize C3b and initiate the classical pathway by inducing phagocytosis by phagocytes.