Complement system

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A complement protein attacking an invader.

The complement system is a biochemical cascade of the immune system that helps clear pathogens from an organism, and promote healing. It is derived from many small plasma proteins that work together to form the primary end result of cytolysis by disrupting the target cell's plasma membrane.^[1]

The actions of the complement system affect both innate immunity and acquired immunity.

Activation of this system leads to cytolysis, chemotaxis, opsonization, immune clearance, and inflammation, as well as the marking of pathogens for phagocytosis. The complement system consists of more than 35 soluble and cell-bound proteins, 12 of which are directly involved in the complement pathways. The proteins account for 5% of the serum globulin fraction. Most of these proteins circulate as zymogens, which are inactive until proteolytic cleavage. The complement proteins are synthesized mainly by hepatocytes; however, significant amounts are also produced by monocytes, macrophages, and epithelial cells in the gastrointestinal and genitourinary tracts. The central nervous system is also able to produce complement components.

Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the mannose-binding lectin pathway. Antibodies, in particular the IgG1 class, can also "fix" complement.

1 Overview
2 Role in disease
3 Modulation by infections
4 References

[edit] Overview

The C1 protein, showing subunits C1r, C1s, and the C1q tails.

The three pathways all generate homologous variants of the protease C3-convertase. The classical complement pathway typically requires antibodies for activation (specific immune response), while the alternate pathway can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). C3-convertase cleaves and activates component C3, creating C3a and C3b and causing a cascade of further cleavage and activation events. C3b binds to the surface of pathogens leading to greater internalization by phagocytic cells by opsonization. C5a is an important chemotactic protein, helping recruit inflammatory cells. Both C3a and C5a have anaphylatoxin activity (mast cell degranulation, increased vascular permeability, smooth muscle contraction). C5b initiates the membrane attack pathway, which results in the membrane attack complex (MAC), consisting of C5b, C6, C7, C8, and polymeric C9.^[2] MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes osmotic lysis of the target cell. Kupffer cells and other macrophage cell types help clear complement-coated pathogens. As part of the innate immune system, elements of the complement cascade can be found in species earlier than vertebrates; most recently in the protostome horseshoe crab species, putting the origins of the system back further than was previously thought.

[edit] Classical pathway

The classical and alternative complement pathways.

The classical pathway is triggered by activation of the C1-complex (which consists of one molecule C1q and two molecules C1r and C1s), either by C1q's binding to antibodies from classes M and G, complexed with antigens, or by its binding C1q to the surface of the pathogen. This binding leads to conformational changes in C1q molecule, which leads to the activation of two C1r (serine protease) molecules. Then they cleave C1s (another serine protease). The C1-complex now binds to and splits C2 and C4, producing C2a and C4b. The inhibition of C1r and C1s is controlled by C1-inhibitor. C4b and C2a bind to form C3-convertase (C4b2a complex: NB the 2a is actually the larger fragment of the two, contrary to conventional nomenclature designating 'b' fragments as the larger). Production of C3-convertase signals the end of the Classical Pathway, but cleavage of C3 by this enzyme brings us to the start of the Alternative Pathway.

[edit] Alternative pathway

The alternative pathway is triggered by C3 hydrolysis directly on the surface of a pathogen. It does not rely on a pathogen-binding protein like the other pathways.^[1] In the alternative pathway, the protein C3 is produced in the liver, and is then cleaved into C3a and C3b by enzymes in the blood. If there is no pathogen in the blood, the C3a and C3b protein fragments will be deactivated. However, if there is a nearby pathogen, some of the C3b is bound to the plasma membrane of the pathogen. Then, it will bind to factor B. This complex will then be cleaved by factor D into Ba and the alternative pathway C3-convertase, Bb.

The C3bBb complex, which is "hooked" onto the surface of the pathogen, will then act like a "chain saw", catalyzing the hydrolysis of C3 in the blood into C3a and C3b, which positively effects the number of C3bBb hooked onto a pathogen.

After hydrolysis of C3, C3b complexes to become C3bBbC3b, which cleaves C5 into C5a and C5b. C5a and C3a are known to trigger mast cell degranulation. C5b with C6, C7, C8, and C9 (C5b6789) complex to form the membrane attack complex, also known as MAC, which is inserted into the cell membrane, "punches a hole", and initiates cell lysis.

[edit] Lectin pathway (MBL - MASP)

The lectin pathway is homologous to the classical pathway, but with the opsonin, mannan-binding lectin (MBL) and ficolins, instead of C1q. This pathway is activated by binding mannan-binding lectin to mannose residues on the pathogen surface, which activates the MBL-associated serine proteases, MASP-1, MASP-2, MASP-3, which can then split C4 into C4a and C4b and C2 into C2a and C2b. C4b and C2a then bind together to form C3-convertase, as in the classical pathway. Ficolins are homologous to MBL and function via MASP in a similar way. In non-vertebrates without an adaptive immune system, ficolins are expanded and their binding specificities diversified to compensate for the lack of pathogen-specific recognition molecules.

[edit] Regulation of the Complement System

The complement system has the potential to be extremely damaging to host tissues meaning its activation must be tightly regulated. The complement system is regulated by complement control proteins, which are present at a higher concentration in the blood plasma than the complement proteins themselves. Some complement control proteins are present on the membranes of self-cells preventing them being targeted by complement. One example is CD59, which inhibits C9 polymerasiation during the formation of the membrane attack complex.

[edit] Role in disease

It is thought that the complement system might play a role in many diseases with an immune component, such as Barraquer-Simons Syndrome, asthma, lupus erythematosus, various forms of arthritis, autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, and ischemia-reperfusion injuries. The complement system is also becoming increasingly implicated in diseases of the central nervous system such as Alzheimer's disease, and other neurodegenerative conditions.

Deficiencies of the terminal pathway predispose to both autoimmune disease and infections (particularly meningitis).

[edit] Modulation by infections

Recent research has suggested that the complement system is manipulated during HIV/AIDS to further damage the body.^[3]^[4]

[edit] References

^ ^a ^b Janeway CA Jr., Travers P, Walport M, Shlomchik MJ (2001). Immunobiology., 5th ed., Garland Publishing. (via NCBI Bookshelf) ISBN 0-8153-3642-X.
^ Goldman AS, Prabhakar BS (1996). The Complement System. in: Baron's Medical Microbiology (Baron S et al, eds.), 4th ed., Univ of Texas Medical Branch. (via NCBI Bookshelf) ISBN 0-9631172-1-1.
^ Bolger MS, Ross DS, Jiang H, Frank MM, Ghio AJ, Schwartz DA, Wright JR, Complement Levels and Activity in the Normal and LPS-Injured Lung, American Journal of Physiology: Lung Cellular and Molecular Physiology. 2006 Oct 27; PMID 17071722
^ Datta PK, Rappaport J, HIV and Complement: Hijacking an immune defence, Biomedicine and Pharmacotherapy, 2006 Nov; 60(9):561-568 PMID 16978830