IMMUNOLOGY: The complement system
¹Kwakye Sylvester, ²Obiri Darko Stella, ³Sackey Lyanne
Complement proteins were discovered as heat-labile components of normal plasma that augment the opsonization of bacteria by antibodies and allow antibodies to kill some bacteria. This activity was said to ‘complement’ the antibacterial activity of the antibody, hence the name. Although first discovered as an effector arm of the antibody response, complement can also be activated early in infection in the absence of antibodies. Indeed, it now seems clear that complement first evolved as part of the innate immune system where it still plays an important role.
The complement system is made up of a large number of distinct plasma proteins that react with one another to opsonize pathogens and induce a series of inflammatory responses that help to fight infection.
There are three (3) distinct pathways through which complements can be activated on pathogen surfaces. These pathways depend on different molecules for their initiation, but they converge to generate the same set of effector molecules.
There are three ways in which the complement system protects against infection.
First, it generates large numbers of activated complement proteins that bind covalently to pathogens, opsonizing them for engulfment by phagocytes bearing receptors for complement.
Second, the small fragments of some complement proteins act as chemoattractants to recruit more phagocytes to the site of complement activation, and also to activate these phagocytes.
Third, the terminal complement components damage certain bacteria by creating pores in the bacterial membrane.
In the early phases of an infection, the complement cascade can be activated on the surface of a pathogen through any one, or more, of the three pathways. The classical pathway can be initiated by the binding of C1q, the first protein in the complement cascade, directly to the pathogen surface. It can also be activated during an adaptive immune response by the binding of C1q to antibody:antigen complexes, and is thus a key link between the effector mechanisms of innate and adaptive immunity. The mannose-binding pathway (MB-lectin pathway) is initiated by binding of the mannan-binding lectin, a serum protein, to mannose-containing carbohydrates on bacteria or viruses. Finally, the alternative pathway can be initiated when a spontaneously activated complement component binds to the surface of a pathogen. Each pathway follows a sequence of reactions to generate a protease called a C3-convertase. These reactions are known as the ‘early’ events of complement activation, and consist of triggered-enzyme cascades in which inactive complement zymogens are successively cleaved to yield two fragments, the larger of which is an active serine protease. The active protease is retained at the pathogen surface, and this ensures that the next complement zymogen in the pathway is also cleaved and activated at the pathogen surface. By contrast, the small peptide fragment is released from the site of the reaction and can act as a soluble mediator.
This pathway involves complement components C1, C2 and C4. The pathway is triggered by antibody-antigen complexes binding to C1, which itself has three subcomponents C1q, C1r and C1s. The pathway forms a C3 convertase, C4b2a, which splits C3 into two fragments; the large fragment, C3b, can covalently attach to the surface of microbial pathogens and opsonise them; the small fragment, C3a, activates mast cells, causing the release of vasoactive mediators such as histamine.
This pathway involves various factors, B, D, H & I, which interact with each other, and with C3b, to form a C3 convertase, C3bBb, that can activate more C3, hence the pathway is sometimes called ‘the amplification loop’. Activation of the loop is promoted in the presence of bacterial and fungal cell walls, but is inhibited by molecules on the surface of normal mammalian cells.
Mannose-binding Lectin Pathway
This pathway is activated by the binding of mannose-binding lectin (MBL) to mannose residues on the pathogen surface. This, in turn, activates the MBL-associated serine proteases, MASP-1 and MASP-2, which activate C4 and C2, to form the C3 convertase, C4b2a.
Membrane Attack Complex (MAC)
The MAC is initiated by the splitting of C5, and attachment of C5b to a target. C6, C7, C8 and C9 unite with C5b, and this membrane-attack complex (MAC), when inserted into the outer membrane of some bacteria, can contribute to their death by lysis.
The small complement fragments C3a, C4a, and C5a act on specific receptors to produce local inflammatory responses. When produced in large amounts or injected systemically, they induce a generalized circulatory collapse, producing a shock-like syndrome similar to that seen in a systemic allergic reaction involving IgE antibodies. Such a reaction is termed anaphylactic shock and these small fragments of complement are therefore often referred to as anaphylatoxins.
British Society for Immunology
Immunobiology: The Immune System in Health and Disease. 5th edition.