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The Complement System / Cascade


The complement system or complement cascade as it is also known is a complex system of multiple proteins involved in inflammation and immunological response. The components of the complement system can be found throughout the body in fluids, providing the body with a systemic means of protection. Antibodies depend on complement for many of their biological activities.

Why is complement important?

  • It opsonises pathogens to promote phagocytosis by phagocytes which display receptors for complement
  • Certain components of complement act as good chemoattractants recruiting and activating phagocytes at the site of infection
  • Complement structures can cause cytolysis or damage to certain bacteria by puncturing their membrane

The important protein components of complement are number C1 to C9 (they are numbered in their order of discovery however and not their order of action as you will see later). Upon activation certain components may split into sub components, usually the small components are named with an ‘a’ e.g. C5a (these are the components which are able to diffuse through tissue readily) and the larger components with a ‘b’ e.g. C5b (these are the components which do not easily diffuse).

The complement system is known as a cascade because of the triggering and amplification of further components of the system. In the cascade once a component has been activated by a proteinase, the molecule itself which was activated becomes a proteinase for the next component of the cascade. The whole complement cascade can be triggered in its entirety in a matter of microseconds. During the activation process the smaller ‘a’ subcomponent peptides which are formed, mediate many of the other effects caused by the complement cascade, for example acting as chemoattractants.

There are three types of complement cascade, the classical and alternative pathways and the Mannan-binding lectin pathway. Both provide a path to the cleavage of C3 which is a central event in complement activation.

The Classical Pathway

The classical pathway of the complement cascade can be summarised as below:

  1. Antibodies from IgG or IgM bind to the cell wall of the antigen
  2. The complement component C1 has three sub-components, q, r and s. The antibodies bound to the antigen have receptors for the C1q subcomponent which bind causing the activation of C1r and C1s to form the complex C1qrs
  3. The C1qrs complex cleaves the next components C2 and C4. The C1qrs complex binds with the C4b and C2b subcomponents, releasing C4a and C2a. C1qrs is able to activate many molecules of C4 and C2 like this
  4. The C4b and C2b subcomponents are deposited on a nearby cell wall protein close to the antibody
  5. C3 binds to this C4bC2b  complex, activating it and resulting in the release of C3a and the binding of C3b to the C4bC2b complex
  6. The bound C3b activates the next complement component C5, which again splits up into the subcomponents C5a and C5b upon activation. C5a is released and C5b binds independently of the C2bC3bC4b complex to the antigen. C3b is able to activate a number of C5 molecules like this.
  7. C5b forms a base for the further binding of the components C6, 7, 8 and 9
  8. The final step is the formation of the membrane attack complex (MAC); this is a ring which is formed by the components C5b, C6, 7, 8 and 9 on the surface of the cell of the pathogen. It is able to penetrate the cell membrane allowing ionic leakage.
  9. The result is lysis of the foreign cell

Below is a summary table, on the left you can see the components of the current complex and on the right you can see the actions taken to get to the next stage of the process.

The Alternative Pathway

In a similar manner to the classical pathway, the alternative pathway works by forming the MAC (membrane attack complex). However in the alternative pathway the complement cascade does not require that an antibody binds to the antigen. Instead C3 is activated directly by foreign substances.

This works because certain surface components of bacteria and parasites are able to directly activate C3 resulting in the generation of C3b resulting in the eventual formation of a membrane attack complex:

  • C3 is activated directly by certain bacteria/parasites
  • C3b is generated which must be activated
  • C3b is stabilised by factors B and D
  • The now activated C3b acts as an enzyme (C3b convertase) for further recruitment of C3
  • The additional C3 results in an abundance of C3b being formed
  • The cycle is then inhibited by Factor H
  • The cascade now continues like the classical pathway, with membrane bound C3b activating C5
  • C5b forms the MAC with C6, 7, 8 and 9

Mannan-binding Lectin Pathway

Mannan binding lectin is a protein produced in the liver; it is able to initiate the complement cascade by binding to the surface of pathogens

In a similar fashion to the C1qrs complex, the membrane bound mannan-binding lectin cleaves C2 and C4 into their subcomponents.

The pathway can now continue like the classical pathway with the activation of C3, resulting in the activation of C5. The activation of C5 leads to the formation of the C5b, C6, 7, 8, 9 membrane attack complex and the cell is lysed

Biological Effects

The complement cascade is responsible for more than just the lysis of the foreign cell; the different subcomponents released at each stage are responsible for a number of other biological functions.


Opsonisation is the process of making a foreign cell more ‘appealing’ to a phagocytic cell. This is useful as it helps to remove the foreign cell by phagocytosis. The complement component responsible for the opsonisation of cells is C3b. It increases the efficiency of phagocytes as they have specific receptors for the C3b component (C3bR). When the C3b binds to its receptor on the phagocyte, the process of phagocytosis begins and the foreign cell is engulfed.

Anaphylatoxin Formation

The peptide subcomponents C3a and C5a are anaphylatoxins meaning they have a number of inflammation properties. They are able to increase vascular permeability at the site of infection and they are also chemotactic. This means they are able to attract phagocytes into the site of infected tissue.

Both C3a and C5a are able to activate neutrophils and cause mast cell degranulation which leads to the release of vasoactive amines (responsible for the induction of smooth muscle contraction and further increase in vascular permeability). These cause the characteristic features of inflammation (heat, redness, swelling, pain and loss of function).

Tissue Damage

Although all the above mechanisms are designed to protect the body against infection and disease, if complement is activated at the wrong time or for the wrong reasons then it can cause damage to the host. All the above factors are able to be used against the body’s own cells for example a MAC forming on the host cells is not good, resulting in tissue damage.