Functions of Complement
This section of the article will cover:
- Membrane Attack Complex (MAC) Formation
- Viral and Toxin Neutralisation
- Activating Cells of the Immune System
1. MAC Formation
- All three pathways of complement activation converge to form the MAC by cleaving C5 in the complement cascade.
- In the classical and lectin pathways this cleavage is mediated by C2a4b3b whereas the C5 convertase of the alternative pathway is the agglomeration of C3bBbP3b.
- C5b binds with C6 and C7 which exposes a hydrophobic surface on C7, allowing it to insert into the targeted membrane.
- Once attached to the membrane, C8 binds to the complex and inserts through the bi-layer allowing C9 to bind, unfold into the membrane and polymerise to form the MAC.
- 12 to 18 C9 proteins are required to form a pore through the membrane, allowing influx of extracellular material into the cell; which ultimately results in lysis of the targeted cell.
- The release of C3a, C4a and C5a from the site of complement activation into the circulation creates chemotactic gradients along which cells expressing the appropriate receptors can travel; thus recruiting them to the site of inflammation.
- Neutrophils, macrophages and monocytes express receptors that actively bind these proteins.
- The C3a receptor (C3aR) is able to bind both C3a and C4a, and the C5a receptor (C5aR) binds to C5a.
- As with chemokine receptors, which are also involved in chemotaxis, these receptors are part of the G-protein coupled receptor (GPCR) family.
- GCPRs have 7 trans-membrane spanning domains, of which the extracellular loops and amino-termini of the receptor associate with complement anaphylatoxins. The intracellular carboxy-terminus associate with the hetero-trimeric G-protein.
- Signalling through these receptors recruits inflammatory cells to the site of inflammation, and increases permeability of local vasculature and adhesion molecule expression
- Complement proteins, (C3b) that become associated with pathogenic cells, immune complexes and apoptotic cells, label these cells for phagocytosis.
- Complement receptors (CR) are expressed on the surface of phagocytic cells, to aid the interaction with the complement labelled cell, and enhance the engulfing process.
- CR3 and CR4 are expressed on a wide range of phagocytic cells and are heavily involved in the clearance of C3b opsonised cells and immune complexes.
- This function is important in providing a link between the innate and adaptive immune systems by activating the professional antigen presenting cells (pAPCs) required to activate T and B cells
4. Virus and Toxin Neutralisation
- Binding of complement molecules to toxins and viruses can neutralise them by blocking vital receptors
5. Activating Cells of the Immune System
- C3a and C5a, acting through C3aR and C5aR respectively, have been indicated in mast cell and basophil degranulation.
- Mast cells and basophils contain preformed granules rich in histamine and heparin; both of which are potent activators of inflammation indicated in allergic responses.
- In each case, C5a is a much more potent initiator of degranulation with a potency of around 50 times that of C3a.
- B cell receptors bound to pathogens coated in C3d are able to recruit CR2 that associates with membrane proteins CD19 and CD81.
- The threshold for B cell activation is significantly reduced leading to proliferation, cytokine release and differentiation into Ab secreting plasma cells.
- Other APC express complement receptors in some situations.
- Dunkelberger, J. R. & Song, W. C. (2009) Complement and its role in innate and adaptive immune responses. Cell Research. 20 (1), 34-50.