Complement system
The complement system is a biochemical cascade that helps clear pathogens from an organism. It is part of the larger immune system that is not adaptable and does not change over the course of an individual's lifetime; as such it belongs to the innate immune system. However, it can be recruited and brought into action by the adaptive immune system.
The complement system consists of a number of small proteins found in the blood, normally circulating as inactive zymogens. When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. The end-result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex. Over 20 proteins and protein fragments make up the complement system, including serum proteins, serosal proteins, and cell membrane receptors. These proteins are synthesized mainly in the liver, and they account for about 5% of the globulin fraction of blood serum.
Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the mannose-binding lectin pathway.[1]
History
In the late 19th century, blood serum was found to contain a "factor" or "principle" capable of killing bacteria. In 1896, Jules Bordet, a young Belgian scientist in Paris at the Pasteur Institute, demonstrated that this principle could be analyzed into two components: a heat-stable and a heat-labile component. (Heat-labile means that the component loses its effectiveness if the serum is heated.) The heat-stable component was found to confer immunity against specific microorganisms, whereas the heat-labile component was found to be responsible for the non-specific antimicrobial activity conferred by all normal serum. This heat-labile component is what we now call "complement."
The term "complement" was introduced by Paul Ehrlich in the late 1890s, as part of his larger theory of the immune system. According to this theory, the immune system consists of cells that have specific receptors on their surface to recognize antigens. Upon immunization with an antigen, more of these receptors are formed, and they are then shed from the cells to circulate in the blood. These receptors, which we now call "antibodies," were called by Ehrlich "amboceptors" to emphasize their bifunctional binding capacity: They recognize and bind to a specific antigen, but they also recognize and bind to the heat-labile antimicrobial component of fresh serum. Ehrlich, therefore, named this heat-labile component "complement," because it is something in the blood that "complements" the cells of the immune system.
Ehrlich believed that each antigen-specific amboceptor has its own specific complement, whereas Bordet believed that there is only one type of complement. In the early 20th century, this controversy was resolved when it became understood that complement can act in combination with specific antibodies, or on its own in a non-specific way.
Functions of the Complement
The following are the basic functions of the complement
1. Lysis of cells, bacteria and viruses.
2. Opsonization, which promotes phagocytosis of particulate antigens.
3. Binding to specific complement receptors on the cells of the immune system, triggering specific cell functions, inflammation, and certain immunoregulatory molecules.
4. Immune Clearance, which removes immune complexes from immune system and deposits them in the spleen and liver.
Overview
The proteins and glycoproteins that constitute the complement system are synthesized by the liver hepatocytes. But significant amounts are also produced by tissue macrophages, blood monocytes and epithelial cells of genitourinal tract and gastrointestinal tract. The three pathways all generate homologous variants of the protease C3-convertase. The classical complement pathway typically requires antibodies for activation (specific immune response), whereas the alternative and mannose-binding lectin pathways can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, a 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, directly triggering degranulation of mast cells as well as increasing vascular permeability and 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.
Classical pathway
| C2 fragment nomenclature | |
|---|---|
| Different assignment for the fragments C2a and C2b, as to which is larger or smaller, is found below in several current text books in immunology; however, we might safely make assignment that the former is smaller. In a literature below, in the publishing year of as early as 1999, they say that:[3]
"It is also useful to be aware that the larger active fragment of C2 was originally designated C2a, and is still called that in some texts and research papers. Here, for consistency, we shall call all large fragments of complement b, so the larger fragment of C2 will be designated C2b. In the classical and MBLectin pathways the C3 converatase enzyme is formed from membrane-bound C4b with C2a." (p. 341). This nomenclature is used in another literature:[4] "(Note that, in older texts, the smaller fragment is often called C2b, and the larger one is called C2a for historical reason.)" (p. 332). The assignment is mixed in the latter literature, though. | |
| Literature[5] [6] [7] [8] [9] can be found where the larger and smaller fragments are assigned to be C2a and C2b, respectively, and literature[1] [3] [10] can be found where the opposite assignment is made. However, due to the widely established convention, C2a here is the larger fragment which in the classical pathway forms C4b2a. |
The classical pathway is triggered by activation of the C1-complex (C1q, two molecules of C1r, and two molecules of C1s thus forming C1qr2s2), which occurs when C1q binds to IgM or IgG complexed with antigens (a single IgM can initiate the pathway, while multiple IgGs are needed), or when C1q binds directly to the surface of the pathogen. Such binding leads to conformational changes in the C1q molecule, which leads to the activation of two C1r (a serine protease) molecules. They then cleave C1s (another serine protease). The C1r2s2 component now splits C4 and then C2, producing C4a,C4b,C2a,and C2b. C4b and C2a bind to form the classical pathway C3-convertase (C4b2a complex), which promotes cleavage of C3 into C3a and C3b; C3b later joins with C4b2a (the C3 convertase) to make C5 convertase (C4bC2aC3b complex). The inhibition of C1r and C1s is controlled by C1-inhibitor.
C3-convertase can be inhibited by Decay accelerating factor (DAF), which is bound to erythrocyte plasma membranes via a GPI anchor.
Alternative pathway
The alternative pathway is triggered by spontaneous C3 hydrolysis directly due to the breakdown of the thioester bond via condensation reaction (C3 is mildly unstable in aquous environment) to form C3a and C3b. It does not rely on a pathogen-binding antibodies like the other pathways.[1]. C3b is then capable of covalently binding to a pathogenic membrane surface if it is near enough. If there is no pathogen in the blood, the C3a and C3b protein fragments will be deactivated by rejoining with each other. Upon binding with a cellular membrane C3b is bound by factor B to form C3bB. This complex in presence of factor D will be cleaved into Ba and Bb. Bb will remain covalently bonded to C3b to form C3bBb which is the alternative pathway C3-convertase. The protein C3 is produced in the liver.
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 affects the number of C3bBb hooked onto a pathogen. After hydrolysis of C3, C3b complexes to become C3bBbC3b, which cleaves C5 into C5a and C5b. 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 cells lysis. C5a and C3a are known to trigger mast cell degranulation.
IgA is associated with activating the alternative path.
Lectin pathway (MBL - MASP)
The lectin pathway is homologous to the classical pathway, but with the opsonin, mannose-binding lectin (MBL), and ficolins, instead of C1q. This pathway is activated by binding mannose-binding lectin to mannose residues on the pathogen surface, which activates the MBL-associated serine proteases, MASP-1, and MASP-2 (very similar to C1r and C1s, respectively),which can then split C4 into C4a and C4b and C2 into C2a and C2b. C4b and C2a then bind together to form the C3-convertase, as in the classical pathway. Ficolins are homologous to MBL and function via MASP in a similar way. In invertebrates without an adaptive immune system, ficolins are expanded and their binding specificities diversified to compensate for the lack of pathogen-specific recognition molecules.
IgA is involved in activating the alternative pathway.
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 from being targeted by complement. One example is CD59, also known as protectin which inhibits C9 polymerisation during the formation of the membrane attack complex.
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, glomerulonephritis, 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 Neisseria meningitis, due to the role that the C56789 complex plays in attacking Gram-negative bacteria).
Mutations in the complement regulators factor H and membrane cofactor protein have been associated with atypical haemolytic uraemic syndrome.[11][12] Moreover, a common single nucleotide polymorphism in factor H (Y402H) has been associated with the common eye disease age-related macular degeneration.[13] Both of these disorders are currently thought to be due to aberrant complement activation on host surfaces.
Modulation by infections
Recent research has suggested that the complement system is manipulated during HIV/AIDS, further weakening the host.[14]
References
- ^ a b c Janeway CA Jr., Travers P, Walport M, Shlomchik MJ (2001). Immunobiology (5th ed. ed.). Garland Publishing. (via NCBI Bookshelf) ISBN 0-8153-3642-X.
{{cite book}}:|edition=has extra text (help)CS1 maint: multiple names: authors list (link) - ^ Goldman AS, Prabhakar BS (1996). The Complement System. in: Baron's Medical Microbiology (Baron S et al, eds.) (4th ed. ed.). Univ of Texas Medical Branch. (via NCBI Bookshelf) ISBN 0-9631172-1-1.
{{cite book}}:|edition=has extra text (help) - ^ a b Janeway CA, Travers P, Walport M, Capra JD (1999) Immunobiology: the immune system in health and disease (4th ed.) 635p. New York: Garland Pub.
- ^ Abbas AK, Lichtman AH (2003) Cellular and molecular immunology (5th ed.) 563p. Philadelphia: Saunders
- ^ William E. Paul (ed.) (1999) Fundamental immunology, 4th ed. 1589p. Philadelphia: Lippincott-Raven
- ^ Frank K, Atkinson JP (2001) Complement system. In Austen KF, Frank K, Atkinson JP, Cantor H. (ed.) "Samter's Immunologic Diseases (6th ed.) Vol. 1", p. 281-298, Philadelphia: Lippincott Williams & Wilkins
- ^ Roitt I, Brostoff J, Male D (2001) Immunology (6th ed.) 480p. St. Louis: Mosby.
- ^ Anderson DM (2003) "Dorland's illustrated medical dictionary", 30th ed. Philadelphia:W.B. Saunders
- ^ Murphy K, Travers P, Walport M, with contributions by Ehrenstein M et al. (2008) "Janeway's immunobiology", 7th ed., New York: Garland Science.
- ^ Doan T, Melvold R, Viselli S, Waltenbaugh C (2007) "Lippincott's Illustrated Reviews: Immunology", 320p. Lippincott Williams & Wilkins
- ^ Dragon-Durey MA, Frémeaux-Bacchi V (2005). "Atypical haemolytic uraemic syndrome and mutations in complement regulator genes". Springer Semin. Immunopathol. 27 (3): 359–74. doi:10.1007/s00281-005-0003-2. PMID 16189652.
- ^ Zipfel PF, Misselwitz J, Licht C, Skerka C (2006). "The role of defective complement control in hemolytic uremic syndrome". Semin. Thromb. Hemost. 32 (2): 146–54. doi:10.1055/s-2006-939770. PMID 16575689.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Mooijaart SP, Koeijvoets KM, Sijbrands EJ, Daha MR, Westendorp RG (2007). "Complement Factor H polymorphism Y402H associates with inflammation, visual acuity, and cardiovascular mortality in the elderly population at large". Experimental Gerontology. 42: 1116. doi:10.1016/j.exger.2007.08.001. PMID 17869048.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Datta PK, Rappaport J, HIV and Complement: Hijacking an immune defence, Biomedicine and Pharmacotherapy, 2006 Nov; 60(9):561-568 PMID 16978830