The Complement System
The complement system is an ancient part of the innate immune system comprising a group of small, heat labile, protein components found in high concentrations in serum. Once initiated, a cascade of protein activation results in a series of pathogen-clearance and pro-inflammatory mechanisms. The components of the complement system are generated by a number of different cells, including liver hepatocytes, fibroblasts and monocytes. The complement system is important in general housekeeping (such as clearing apoptotic cells) and in initiating immune responses to invading pathogens. Because of its evolutionary ancient origins, the complement system is a fundamental mechanism of self/non-self recognition in vertebrate immune systems. This article will cover the following: Complement Protein Synthesis Pathways of Complement Activation Functions of Complement Complement Regulation Complement Dysregulation and Pathologies Further Reading
1. Complement Protein Synthesis
The majority of complement protein is synthesised by liver hepatocytes, but many leukocytes are capable of complement protein synthesis in response to inflammation. Complement proteins are secreted in high concentrations into the circulation via the hepatic portal vein; they constitute roughly 5% of the total circulatory proteins. Transcription is regulated in a number of ways through cytokine signalling. An inflammatory environment with high levels of IL-1, IL-6, IL-8 IFN-y and TGF-β will increase local complement protein production which diminishes in the resting state. Hepatocytes will also respond to the inflammatory demand of complement proteins in the acute phase response, which acts by producing large volumes of anti-microbial proteins in response to pathogen invasion.
2. Pathways of Complement Activation
This section of the article will cover:
- The Classical Pathway
- The Lectin Pathway
- The Alternative Pathway
- The C1 complex binds to the Fc regions of antibodies IgG1,2,3 and pathogen-bound IgM to activate the serine protease Cs2 associated with C1q.
- Natural antibodies, which are secreted without prior antigen exposure, are important in this process by providing a primary response to invading pathogens.
- The active site of the protease cleaves C2 and C4 into C2a and C2b and C4a and C4b, respectively.
- This results in the formation of C2a4b; the C3 convertase of the classical pathway.
- C3 is cleaved into C3a and C3b by the C3 convertase.
- C3a is released into the circulation as an anaphylatoxin, whereas C3b, associated with the C3 convertase, forms the C5 convertase of the classical pathway (C2a4b3b).
- C5 convertase cleaves C5 into C5a and C5b.
- C5a is released into the circulation as an anaphylatoxin.
- C5b then associates with C6, C7, C8 and poly-C9 inserting itself through the membrane.
- This membrane attack complex (MAC) can cause lysis of the pathogenic cell to which it is associated.
- The complement cascade is amplified at each activation stage to generate a large response to even weak stimuli.
- Mannose binding lectin (MBL) and ficolins initiate the lectin pathway of complement activation.
- When bound to their ligands these proteins undergo activation of their associated serine proteases, mannose associated serine protease 1 (MASP1) and MASP2.
- MBL and ficolins act like pattern recognition receptors (PPRs) with the ability to bind to various pathogen-associated molecular patterns (PAMPs) on the surface of microorganisms.
- In particular, MBL is able to bind to multiple carbohydrate structures to increase the avidity of its interaction with the surface of a pathogen, allowing activation of the serine protease
- MASP-1 and 2 cleave C2 and C4 to form the same C3 convertase as the classical pathway.
- 3. The Alternative Pathway
- The alternative pathway of complement is activated as a result of the inherent instability of the C3 protein.
- Spontaneous hydrolysis of C3 generates a conformational change in the structure of the protein allowing factor B (fB) to bind.
- C3bB is then cleaved by factor D (fD) forming the C3 convertase of the alternative pathway, C3bBb.
- The C3 convertase is able to cleave further C3 and bind additional C3b molecules forming an amplification loop of complement activation.
- fP, or properdin, may also bind to C3bBb to stabilise its structure and further increase its C3 convertase activity.
- An additional C3b can then bind to the C3 convertase, to form the C5 convertase of the alternative pathway, C3bBb3b.
C5 is cleaved into C5a, which is released into the circulation, and C5b. C5b associates with C6, 7, 8 and poly-9 to form the MAC.
6. Further Reading
- Muller-Eberhard, H. J. (1988) Molecular organization and function of the complement system. Annual Review of Biochemistry. 57 (1), 321-347.
- Ricklin, D. & Lambris, J.D., 2013. Complement in immune and inflammatory disorders: therapeutic interventions. Journal of immunology (Baltimore, Md. : 1950), 190(8), p.3839-47. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23564578.
- Mayilyan, K.R., 2012. Complement genetics, deficiencies, and disease associations. Protein & Cell, 3(7), p.487-496.
- Kwan, W.-hong, Touw, W. van der & Heeger, P.S., 2012. Complement regulation of T cell immunity. Immunologic research, 54(1-3), p.247-253.