The Complement system (Components, Activation and Pathways, Regulation, Biologic effects and Consequences of Complement deficiencies)

What are complement proteins?

  • The serum and membrane-bound proteins which are synthesized mainly by liver and phagocytic cells and are major components o f complement system are called complement proteins.
  • They help in both adaptive and innate host defense systems.
  • These proteins are highly regulated and interact through a series of proteolytic cascades. The term ‘complement’ refers to the ability of these proteins to complement other components of the immune system like antibodies to carry out their effects.

Complement activation:

  • Several complement components are proenzyes which need to be activated before they carry out their biologic effects.
  • The components of the classic pathway are numbered from C1 to C9, and the reaction sequence is C1-C4-C2-C3-C5-C6-C7-C8-C9.
  • Activation of proteins from C1 to C5 occurs through proteolytic cleavage which releases smaller fragments from C2 through C5. The smaller fragments and larger fragments are represented by letter ‘a’ (e.g. C4a) and ‘b’ (e.g. C5b) respectively after the name of protein.
  • Either antigen-antibody complexes or a variety of non-immunologic molecules initiate the activation of the complement system.
  • Sequential activation of complement components occurs via three main pathways:

1. The classic pathway:

    • Only IgM and IgG (only IgG4 out of the four subclasses of IgG), activate or fix complement via the classic pathway.
    • C1, which is bound to a site in Fc region, is composed of three proteins: C1q, C1r and C1s.
    • C1q is an aggregate of polypeptides that binds to the Fc portion of IgG and IgM.
    • The antibody-antigen immune complex, bound to C1q activates C1r and then C1s. Activated C1s cleaves C4 to form C4a and C4b. similarly, C1s cleaves C2 to form C2a and C2b. C4b binds with C2b to form C4b2b (formerly C4b2a).
    • C4b2b is a C3 convertase and cleaves C3 molecules into C3a and C3b. C3a is an anaphylatoxin. C3b binds with C4b2b to form C4b2b3b which is a C5 convertase.
    • C5 convertase cleaves C5 to form C5a and C5b. C5a is an anaphylatoxin and a chemotactic factor whereas C5b binds to C6 and C7 to form a complex that inserts into the membrane bilayer of the microorganism.
    • C8 then binds to the C5bC6C7 complex, followed by the polymerization of up to sixteen C9 molecules to produce the membrane attack complex (MAC) that generates a channel or pore in the membrane and causes cytolysis by allowing free passage of water across the cell membrane.

2. The alternative pathway:

    • In this pathway, complement system is activated without antibody. Many substances like complex chemicals (endotoxin), infectious agents (parasites) etc. activate complement system in this pathway.
    • Therefore, immunity provided by this pathway is an example of innate immunity. This pathway involves serum proteins like C3, factor B, factor D and properdin system.
    • At first, C3 undergoes slow hydrolysis to form C3b and C3a. Factor B then binds C3b on the surface of microorganisms.
    • Then factor D cleaves factor B releasing smaller fragment Ba and bigger fragment Bb. C3b binds with Bb forming C3bBb which is a C3 convertase.
    • This C3 convertase is highly unstable and hence another complement protein called propedin binds and stabilizes C3 convetase.
    • C3 convertase cleaves C3 releasing C3a and C3b. C3b binds with C3bBb again to form C3bBbC3b which is the alternative pathway C5 convertase. Once C5 is formed, this C5 convertase generates C5b, leading to the production of membrane attack complex as described in the classic pathway.

3. Mannan-binding Lectin pathway:

    • This is a newly discovered additional pathway of complement activation.
    • Like alternate pathway, it doesn’t require antibody. However, its mechanism of action is more similar to classic pathway.
    • Its main constituent is a plasma protein termed MBL (Mannan-binding Lectin).
    • MBL binds to sugar residues like Mannose found in microbial surface polysachharides such as LPS in Salmonlla Typhi, Listeria, Neisseria, Candida albicans
    • When MBL binds to Mannose on microbial cell surface, MBL associates serine proteases (MASP1 and MASP2) are activated.
    • Function of activated MASP1 and MASP2 is same as that of C1s in classic pathway. They cleave C4 and C2 and generate C5 convertase. The rest of this pathway is the same as in the classic pathway of complement activation.
                                                                             3 pathways of Complement Activation


Regulation of the complement system:

  • Complement system is regulated at different stages by several serum proteins :
    1. C1 inhibitor binds to and inactivates the seine protease activity of C1r and C1s.
    2. Factor I cleaves C3b and C4b, thereby reducing the amount of C5 convertase available.
    3. The effect of factor I, i.e. to cleave C3b is enhanced by Factor H.
    4. Factor P (properdin) protects C3b and stabilizes the C3 convertase of the alternative pathway.
    5. Regulation is also provided by proteins that have the ability to accelerate the decay of the complement proteins, for e.g. decay-accelerating factor, am membrane protein found on most blood cell surfaces that can act to accelerate dissociation of the C3 convertases of both pathways.

Major biologic effects of Complement system:

  • Opsonization: Cells, antigen-antibody complexes, and other particles are phagocytosed much more efficiently in the presence of C3b because of the presence of C3b receptors on the surface of many phagocytes.
  • Chemotaxis: C5a stimulates the movement of neutrophils and monocytes towards the sites of antigen deposition.
  • Anaphylatoxins: C3a, C4a, C5a can produce increased vascular permeability and smooth muscle contraction. Mast cells are stimulated by C3a and C5a to release histamine.
  • Cytolysis: The membrane attack complex (C5b6789) formed on the cell surface leads to killing or lysis of many types of cells like erythrocytes, bacteria and tumor cells.

Clinical consequences of Complement deficiencies:

  • Many genetic deficiencies of complement proteins have been described, and these generally lead to enhanced susceptibility to infectious disease, for e.g. Deficiency of complement protein C2, frequently leads to serious pyogenic infections caused by bacteria..
  • Deficiency in components of the membrane attack complex greatly enhances the susceptibility to neisserial infections.
  • Properdin deficiency is associated with greater susceptibility to meningococcal disease.
  • Lack of complement regulating protein (C1 inhibitor protein) leads to hereditary angioedema (swelling in the deep layers of skin).

The Complement system (Components, Activation and Pathways, Regulation, Biologic effects and Consequences of Complement deficiencies)