Introduction
The complement system is a set of about 30 plasma proteins, made mainly by the liver and found in the blood, with enzymatic function. There are no cells in the system. The proteins circulate as inactive precursors, mostly proteases, and are activated one after another in a cascade when they meet a pathogen. The central factor is C3. It is part of innate immunity (like the clotting system, it is a cascade of plasma proteins) and also works together with antibodies in adaptive immunity. This topic covers its characteristics, pathways and functions.
Functions of complement
The effects of the complement system are:
- opsonisation: complement proteins coat the pathogen, so phagocytes recognise and ingest it more easily;
- inflammation: complement proteins amplify the inflammatory response;
- chemotaxis;
- lysis (cytotoxicity): the membrane attack complex makes pores in the pathogen membrane and destroys it.
How complement is activated
Complement can be activated in two main ways:
- by innate (non-specific) triggers, with no antibodies or T cell receptors involved. For example, polysaccharides on bacterial and fungal cell walls activate it at once, without earlier exposure.
- in the specific immune response, which is the most potent way: an antibody (IgG or IgM) binds antigen on a cell surface, which exposes its Fc region so that the first complement protein (C1) can bind.
At the centre of the cascade, a complement protein is cut by proteolysis into a smaller peptide and a larger protein. The larger protein stays bound to the complex on the microbe surface, while the small peptide diffuses away.
All three pathways (classical, alternative, lectin) involve cleavage of C3 into C3a and C3b.
- C3b stays on the microbe surface, activates the next step and is a good opsonin.
- C3a diffuses away and acts as a chemotactic factor and an inflammatory anaphylatoxin: it activates mast cells, causing release of vasoactive mediators such as histamine.
Classical pathway
- Uses components C1, C2 and C4. It is triggered by antibody-antigen complexes (IgG or IgM) binding to C1, which has three subcomponents: C1q, C1r and C1s.
- The C1 complex leads to the formation of C4b and C2a, which combine into the C3 convertase C4b2a.
- The convertase splits C3 into C3b (opsonin, attaches to the pathogen) and C3a (activates mast cells).
- Red cells with antibody on their surface can also activate the classical and lytic pathways and become susceptible to lysis.