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The complement system, also known as complement cascade, is a part of the humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane.^[1] Despite being part of the innate immune system, the complement system can be recruited and brought into action by antibodies generated by the adaptive immune system.

The complement system consists of a number of small, inactive, liver synthesized protein precursors circulating in the blood. 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 complement activation or complement fixation cascade is stimulation of phagocytes to clear foreign and damaged material, inflammation to attract additional phagocytes, and activation of the cell-killing membrane attack complex. About 50 proteins and protein fragments make up the complement system, including plasma proteins, and cell membrane receptors. They account for about 10% of the globulin fraction of blood serum.^[2]

Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the lectin pathway.^[3] The alternative pathway accounts for the majority of terminal pathway activation and so therapeutic efforts in disease have revolved around its inhibition.^[4]

History

In 1888, George Nuttall found that sheep blood serum had mild killing activity against the bacterium that causes anthrax.^[5] The killing activity disappeared when he heated the blood.^[6] In 1891, Hans Ernst August Buchner, noting the same property of blood in his experiments, named the killing property "alexin", which means "to ward off" in Greek.^[7]^[8] By 1894, several laboratories had demonstrated that serum from guinea pigs that had recovered from cholera killed the cholera bacterium in vitro. Heating the serum destroyed its killing activity. Nevertheless, the heat-inactivated serum, when injected into guinea pigs exposed to the cholera bacteria, maintained its ability to protect the animals from illness. Jules Bordet, a young Belgian scientist in Paris at the Pasteur Institute, concluded that this principle has two components, one that maintained a "sensitizing" effect after being heated and one (alexin) whose toxic effect was lost after being heated.^[9] The heat-stable component was responsible for immunity against specific microorganisms, whereas the heat-sensitive component was responsible for the non-specific antimicrobial activity conferred by all normal sera. In 1899, Paul Ehrlich renamed the heat-sensitive component "complement".^[10]^[6]

Ehrlich introduced the term "complement" as part of his larger theory of the immune system.^[11] 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. Those receptors, which we now call "antibodies", were called by Ehrlich "amboceptors" to emphasise their bifunctional binding capacity: They recognise and bind to a specific antigen, but they also recognise 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.^{[citation needed]}

Functions

Complement triggers the following immune functions:^[12]

Membrane attack – by rupturing the cell wall of bacteria. (classical complement pathway)
Phagocytosis – by opsonizing antigens. C3b has most important opsonizing activity. (alternative complement pathway)
Inflammation – by attracting macrophages and neutrophils. (lectin pathway)

Overview

Most of the proteins and glycoproteins that constitute the complement system are synthesized by hepatocytes. But significant amounts are also produced by tissue macrophages, blood monocytes, and epithelial cells of the genitourinary system and gastrointestinal tract. The three pathways of activation all generate homologous variants of the protease C3-convertase. The classical complement pathway typically requires antigen-antibody complexes for activation (specific immune response), whereas the alternative pathway can be activated by spontaneous complement component 3 (C3) hydrolysis, foreign material, pathogens, or damaged cells. The mannose-binding lectin pathway can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causes a cascade of further cleavage and activation events. C3b binds to the surface of pathogens, leading to greater internalization by phagocytic cells by opsonization.^{[citation needed]}

In the alternative pathway, C3b binds to Factor B. Factor D releases Factor Ba from Factor B bound to C3b. The complex of C3b(2)Bb is a protease which cleaves C5 into C5b and C5a. C5 convertase is also formed by the classical pathway when C3b binds C4b and C2b. C5a is an important chemotactic protein, helping recruit inflammatory cells. C3a is the precursor of an important cytokine (adipokine) named ASP (although this is not universally accepted ^[13]) and is usually rapidly cleaved by carboxypeptidase B. Both C3a and C5a have anaphylatoxin activity, directly triggering degranulation of mast cells as well as increasing vascular permeability and smooth muscle contraction.^[13] C5b initiates the membrane attack pathway, which results in the membrane attack complex (MAC), consisting of C5b, C6, C7, C8, and polymeric C9.^[14] 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.^{[citation needed]}

Classical pathway

The classical and alternative complement pathways

The classical pathway is triggered by activation of the C1-complex. The C1-complex is composed of 1 molecule of C1q, 2 molecules of C1r and 2 molecules of C1s, or C1qr²s². This occurs when C1q binds to IgM or IgG complexed with antigens. A single pentameric IgM can initiate the pathway, while several, ideally six, IgGs are needed. This also occurs 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 molecules. C1r is a serine protease. They then cleave C1s (another serine protease). The C1r²s² component now splits C4 and then C2, producing C4a, C4b, C2a, and C2b (historically, the larger fragment of C2 was called C2a but is now referred to as C2b). C4b and C2b bind to form the classical pathway C3-convertase (C4b2b complex), which promotes cleavage of C3 into C3a and C3b. C3b later joins with C4b2b to make C5 convertase (C4b2b3b complex).^[15]

Alternative pathway

The alternative pathway is continuously activated at a low level, analogous to a car engine at idle, as a result of spontaneous C3 hydrolysis due to the breakdown of the internal thioester bond (C3 is mildly unstable in aqueous environment). The alternative pathway does not rely on pathogen-binding antibodies like the other pathways.^[3] C3b that is generated from C3 by a C3 convertase enzyme complex in the fluid phase is rapidly inactivated by factor H and factor I, as is the C3b-like C3 that is the product of spontaneous cleavage of the internal thioester. In contrast, when the internal thioester of C3 reacts with a hydroxyl or amino group of a molecule on the surface of a cell or pathogen, the C3b that is now covalently bound to the surface is protected from factor H-mediated inactivation. The surface-bound C3b may now bind factor B to form C3bB. This complex in the presence of factor D will be cleaved into Ba and Bb. Bb will remain associated with C3b to form C3bBb, which is the alternative pathway C3 convertase.^[16]

The C3bBb complex is stabilized by binding oligomers of factor P (properdin). The stabilized C3 convertase, C3bBbP, then acts enzymatically to cleave much more C3, some of which becomes covalently attached to the same surface as C3b. This newly bound C3b recruits more B, D and P activity and greatly amplifies the complement activation. When complement is activated on a cell surface, the activation is limited by endogenous complement regulatory proteins, which include CD35, CD46, CD55 and CD59, depending on the cell. Pathogens, in general, don't have complement regulatory proteins (there are many exceptions, which reflect adaptation of microbial pathogens to vertebrate immune defenses). Thus, the alternative complement pathway is able to distinguish self from non-self on the basis of the surface expression of complement regulatory proteins. Host cells don't accumulate cell surface C3b (and the proteolytic fragment of C3b called iC3b) because this is prevented by the complement regulatory proteins, while foreign cells, pathogens and abnormal surfaces may be heavily decorated with C3b and iC3b. Accordingly, the alternative complement pathway is one element of innate immunity.^{[citation needed]}

Once the alternative C3 convertase enzyme is formed on a pathogen or cell surface, it may bind covalently another C3b, to form C3bBbC3bP, the C5 convertase. This enzyme then cleaves C5 to C5a, a potent anaphylatoxin, and C5b. The C5b then recruits and assembles C6, C7, C8 and multiple C9 molecules to assemble the membrane attack complex. This creates a hole or pore in the membrane that can kill or damage the pathogen or cell.^[1]

Lectin pathway

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 of MBL 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 C2b then bind together to form the classical C3-convertase, as in the classical pathway. Ficolins are homologous to MBL and function via MASP in a similar way. Several single-nucleotide polymorphisms have been described in M-ficolin in humans, with effect on ligand-binding ability and serum levels. Historically, the larger fragment of C2 was named C2a, but it is now referred to as C2b.^[17] 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.^{[citation needed]}

Complement protein fragment nomenclature

Immunology textbooks have used different naming assignments for the smaller and larger fragments of C2 as C2a and C2b. The preferred assignment appears to be that the smaller fragment be designated as C2a: as early as 1994, a well known textbook recommended that the larger fragment of C2 should be designated C2b.^[18] However, this was amplified in their 1999 4th edition, to say that:^[19] "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 lectin pathways the C3 convertase enzyme is formed from membrane-bound C4b with C2b."^[19]

This nomenclature is used in another literature:^[20] The assignment is mixed in the latter literature, though. Some sources designate the larger and smaller fragments as C2a and C2b respectively^[21]^[22]^[23]^[24]^[25]^[26]^[27]^[28]^[29] while other sources apply the converse.^[18]^[19]^[30]^[31]^[32] However, due to the widely established convention, C2b here is the larger fragment, which, in the classical pathway, forms C4b2b (classically C4b2a). It may be noteworthy that, in a series of editions of Janeway's book, 1st to 7th, in the latest edition^[28] they withdraw the stance to indicate the larger fragment of C2 as C2b.

Viral inhibition

Fixation of the MBL protein on viral surfaces has also been shown to enhance neutralization of viral pathogens.^[33]

Review

Activation pathway	Classic	Alternative	Lectin
Activator	Ag–Ab Complex	spontaneous hydrolysis of C3	MBL-Mannose Complex
C3-convertase	C4b2b	C3bBb	C4b2b
C5-convertase	C4b2b3b	C3bBbC3b	C4b2b3b
MAC development	C5b+C6+C7+C8+C9

Activation of complements by antigen-associated antibody

In the classical pathway, C1 binds with its C1q subunits to Fc fragments (made of CH2 region) of IgG or IgM, which has formed a complex with antigens. C4b and C3b are also able to bind to antigen-associated IgG or IgM, to its Fc portion.^[20]^[25]^[28]

Such immunoglobulin-mediated binding of the complement may be interpreted as that the complement uses the ability of the immunoglobulin to detect and bind to non-self antigens as its guiding stick. The complement itself can bind non-self pathogens after detecting their pathogen-associated molecular patterns (PAMPs),^[28] however, utilizing specificity of the antibody, complements can detect non-self targets much more specifically.^{[citation needed]}

Some components have a variety of binding sites. In the classical pathway, C4 binds to Ig-associated C1q and C1r²s² enzyme cleaves C4 to C4b and 4a. C4b binds to C1q, antigen-associated Ig (specifically to its Fc portion), and even to the microbe surface. C3b binds to antigen-associated Ig and to the microbe surface. Ability of C3b to bind to antigen-associated Ig would work effectively against antigen-antibody complexes to make them soluble.^{[citation needed]}

Regulation

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 blood plasma and host cell membrane.^[34] 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 polymerization during the formation of the membrane attack complex. The classical pathway is inhibited by C1-inhibitor, which binds to C1 to prevent its activation.^[35] Another example, is a plasma protein called, Factor H (FH), which has a key role in down-regulating the alternative pathway.^[36] Factor H, along with another protein called Factor I, inactivates C3b, the active form of C3. This process prevents the formation of C3 convertase and halts the progression of the complement cascade. C3-convertase also can be inhibited by decay accelerating factor (DAF), which is bound to erythrocyte plasma membranes via a GPI anchor.^[35]

Role in disease

Complement deficiency

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, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome and ischemia-reperfusion injuries,^[37]^[38] and rejection of transplanted organs.^[39]

Complement regulation is suggested to play a role in pregnancy. Improper alternative complement pathway activation may mediate recurrent immune-mediated fetal loss.^[40]^[41]

The complement system is also becoming increasingly implicated in diseases of the central nervous system such as Alzheimer's disease and other neurodegenerative conditions such as spinal cord injuries.^[42]^[43]^[44]

Deficiencies of the terminal pathway predispose to both autoimmune disease and infections (particularly Neisseria meningitidis, due to the role that the membrane attack complex ("MAC") plays in attacking Gram-negative bacteria).^[45]

Infections with N. meningitidis and N. gonorrhoeae are the only conditions known to be associated with deficiencies in the MAC components of complement.^[46] 40–50% of those with MAC deficiencies experience recurrent infections with N. meningitidis.^[47]

Deficiencies in complement regulators

Mutations in the genes of complement regulators, especially factor H, have been associated with atypical hemolytic uremic syndrome,^[4]^[48]^[49] and C3 glomerulopathy.^[4] Both of these disorders are currently thought to be due to complement overactivation either on the surface of host cells or in plasma, with the molecular location of genetic variation in complement proteins providing clues into the underlying disease processes.^[4] Moreover, several single nucleotide polymorphisms and mutations in the complement factor H gene (the most common of which results in the protein change p.Y402H) have been associated with the common eye disease age-related macular degeneration.^[4] Polymorphisms of complement component 3, complement factor B, and complement factor I, as well as deletion of complement factor H-related 3 and complement factor H-related 1, also affect a person's risk of developing age-related macular degeneration.^[4]^[50]

Mutations in the C1 inhibitor gene can cause hereditary angioedema, a genetic condition resulting from reduced regulation of bradykinin by C1-INH.^{[citation needed]}

Paroxysmal nocturnal hemoglobinuria is caused by complement breakdown of RBCs due to an inability to make GPI. Thus the RBCs are not protected by GPI anchored proteins such as DAF.^[51]

Diagnostic tools

Diagnostic tools to measure complement activity include the total complement activity test.^[52]

The presence or absence of complement fixation upon a challenge can indicate whether particular antigens or antibodies are present in the blood. This is the principle of the complement fixation test.^{[citation needed]}

Modulation of the body by complement with infection

Excessive complement activity contributes to severe Covid-19 symptoms and disease.^[53] Although complement is intended to protect the body systems, under stress there can be more damage than protection. Research has suggested that the complement system is manipulated during HIV/AIDS, in a way that further damages the body.^[54]

Role in the brain

Research from over the last decade has shown that complement proteins of the classical complement pathway have an important role in synaptic pruning in the brain during early development.^[55]^[56]

References

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^ Glovsky MM (9 November 2019). Talavera F, Dreskin SC, Kaliner MA (eds.). "Complement-Related Disorders: Background, Pathophysiology, Activation". Medscape.
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^ Nuttall G (1888). "Experimente über die bakterien feindlichen Einflüsse des tierischen Körpers" [Experiments on the antibacterial influences of animal substances]. Zeitschrift für Hygiene (in German). 4: 353–394.English translation here
^ ^a ^b Chaplin H (2020). "Review: the burgeoning history of the complement system 1888-2005". Immunohematology. 21 (3): 85–93. doi:10.21307/immunohematology-2019-398. PMID 16178664.
^
Buchner named "alexin" during an address to a meeting of the Medical Society (Aerztlichen Verein) in Munich, Germany on 3 June 1891. Buchner's address was published in: Buchner H (23 June 1891). "Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe" [Brief overview of the development of bacteriology since Naegeli's involvement in it]. Münchener Medizinische Wochenschrift (in German). 38 (25): 435–437, (26): 454–456. From p. 437: "Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die mit irgend welchen bisher bekannten sich nicht identificieren lassen, und die man am besten deshalb mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet." (So it's a matter of protein of a new type, which cannot be identified with any [protein] which [has been] known until now, and which one therefore designates best with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)
- Buchner's address was reprinted in condensed form in: Buchner H (1891). "Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe". Centralblatt für Bakteriologie und Parasitenkunde (in German). 10: 349–352. From p. 350: "Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die besonders durch grosse Labilität ausgezeichnet sind (bei 50-55°C erlischt rasch die Wirksamkeit), und die am besten mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet werden könnten." (So it's a matter of protein of a new type, which is especially distinguished by great lability (at 50-55°C its efficacy suddenly ceases to exist), and which can best be designated with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)
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^ Thurman, Joshua M.; Holers, V. Michael (2006-02-01). "The Central Role of the Alternative Complement Pathway in Human Disease". The Journal of Immunology. 176 (3): 1305–1310. doi:10.4049/jimmunol.176.3.1305. ISSN 0022-1767. PMID 16424154.
^ Mellor, Andrew L.; Sivakumar, Jayabalan; Chandler, Phillip; Smith, Kimberly; Molina, Hector; Mao, Dailing; Munn, David H. (January 2001). "Prevention of T cell–driven complement activation and inflammation by tryptophan catabolism during pregnancy". Nature Immunology. 2 (1): 64–68. doi:10.1038/83183. ISSN 1529-2908.
^ Galvan MD, Luchetti S, Burgos AM, Nguyen HX, Hooshmand MJ, Hamers FP, Anderson AJ (December 2008). "Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury". The Journal of Neuroscience. 28 (51): 13876–88. doi:10.1523/JNEUROSCI.2823-08.2008. PMC 2680920. PMID 19091977.
^ Nguyen HX, Galvan MD, Anderson AJ (June 2008). "Characterization of early and terminal complement proteins associated with polymorphonuclear leukocytes in vitro and in vivo after spinal cord injury". Journal of Neuroinflammation. 5: 26. doi:10.1186/1742-2094-5-26. PMC 2443364. PMID 18578885.
^ Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ (February 2010). "Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment". Brain. 133 (Pt 2): 433–47. doi:10.1093/brain/awp322. PMC 2858013. PMID 20085927.
^ Brown EJ (1985). "Interaction of Gram-Positive Microorganisms with Complement". Bacteria and Complement. Current Topics in Microbiology and Immunology. Vol. 121. Springer, Berlin, Heidelberg. pp. 159–187. doi:10.1007/978-3-642-45604-6_8. ISBN 9783642456060. PMID 3936681.
^ Ram S, Lewis LA, Rice PA (October 2010). "Infections of people with complement deficiencies and patients who have undergone splenectomy". Clinical Microbiology Reviews. 23 (4): 740–80. doi:10.1128/CMR.00048-09. PMC 2952982. PMID 20930072.
^ Lewis LA, Ram S (January 2014). "Meningococcal disease and the complement system". Virulence. 5 (1): 98–126. doi:10.4161/viru.26515. PMC 3916388. PMID 24104403.
^ Dragon-Durey MA, Frémeaux-Bacchi V (November 2005). "Atypical haemolytic uraemic syndrome and mutations in complement regulator genes". Springer Seminars in Immunopathology. 27 (3): 359–74. doi:10.1007/s00281-005-0003-2. PMID 16189652. S2CID 6330326.
^ Zipfel PF, Misselwitz J, Licht C, Skerka C (March 2006). "The role of defective complement control in hemolytic uremic syndrome". Seminars in Thrombosis and Hemostasis. 32 (2): 146–54. doi:10.1055/s-2006-939770. PMID 16575689. S2CID 260316508.
^ Bradley DT, Zipfel PF, Hughes AE (June 2011). "Complement in age-related macular degeneration: a focus on function". Eye. 25 (6): 683–93. doi:10.1038/eye.2011.37. PMC 3178140. PMID 21394116.
^ Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, et al. (December 2005). "Diagnosis and management of paroxysmal nocturnal hemoglobinuria". Blood. 106 (12): 3699–709. doi:10.1182/blood-2005-04-1717. PMC 1895106. PMID 16051736.
^ "Complement Deficiencies Workup: Laboratory Studies, Imaging Studies, Other Tests". emedicine.medscape.com. Retrieved 2018-04-26.
^ Afzali B, Noris M, Lambrecht BN, Kemper C (February 2022). "The state of complement in COVID-19". Nature Reviews. Immunology. 22 (2): 77–84. doi:10.1038/s41577-021-00665-1. PMC 8672651. PMID 34912108.
^ Datta PK, Rappaport J (November 2006). "HIV and complement: hijacking an immune defense". Biomedicine & Pharmacotherapy. 60 (9): 561–568. doi:10.1016/j.biopha.2006.07.087. PMID 16978830.
^ Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. (May 2012). "Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner". Neuron. 74 (4): 691–705. doi:10.1016/j.neuron.2012.03.026. PMC 3528177. PMID 22632727.
^ Gomez-Arboledas A, Acharya MM, Tenner AJ (September 2021). "The Role of Complement in Synaptic Pruning and Neurodegeneration". ImmunoTargets and Therapy. 10: 373–386. doi:10.2147/ITT.S305420. PMC 8478425. PMID 34595138.

External links

Media related to Complement system at Wikimedia Commons

[:1-1] Janeway Jr CA, Travers P, Walport M, Shlomchik MJ (2001). "The complement system and innate immunity". Immunobiology: The Immune System in Health and Disease. New York: Garland Science. Retrieved 25 February 2013.

[2] Glovsky MM (9 November 2019). Talavera F, Dreskin SC, Kaliner MA (eds.). "Complement-Related Disorders: Background, Pathophysiology, Activation". Medscape.

[Abbas_2010-3] Abbas AK, Lichtman AH, Pillai S (2010). Cellular and Molecular Immunology (6th ed.). Elsevier. pp. 272–288. ISBN 978-1-4160-3123-9.

[:0-4] ^ ^a ^b ^c ^d ^e ^f Tzoumas N, Hallam D, Harris CL, Lako M, Kavanagh D, Steel DH (November 2020). "Revisiting the role of factor H in age-related macular degeneration: Insights from complement-mediated renal disease and rare genetic variants". Survey of Ophthalmology. 66 (2): 378–401. doi:10.1016/j.survophthal.2020.10.008. PMID 33157112. S2CID 226274874.

[5] Nuttall G (1888). "Experimente über die bakterien feindlichen Einflüsse des tierischen Körpers" [Experiments on the antibacterial influences of animal substances]. Zeitschrift für Hygiene (in German). 4: 353–394.English translation here

[Chaplin2005-6] Chaplin H (2020). "Review: the burgeoning history of the complement system 1888-2005". Immunohematology. 21 (3): 85–93. doi:10.21307/immunohematology-2019-398. PMID 16178664.

[7] Buchner named "alexin" during an address to a meeting of the Medical Society (Aerztlichen Verein) in Munich, Germany on 3 June 1891. Buchner's address was published in: Buchner H (23 June 1891). "Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe" [Brief overview of the development of bacteriology since Naegeli's involvement in it]. Münchener Medizinische Wochenschrift (in German). 38 (25): 435–437, (26): 454–456. From p. 437: "Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die mit irgend welchen bisher bekannten sich nicht identificieren lassen, und die man am besten deshalb mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet." (So it's a matter of protein of a new type, which cannot be identified with any [protein] which [has been] known until now, and which one therefore designates best with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)
Buchner's address was reprinted in condensed form in: Buchner H (1891). "Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe". Centralblatt für Bakteriologie und Parasitenkunde (in German). 10: 349–352. From p. 350: "Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die besonders durch grosse Labilität ausgezeichnet sind (bei 50-55°C erlischt rasch die Wirksamkeit), und die am besten mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet werden könnten." (So it's a matter of protein of a new type, which is especially distinguished by great lability (at 50-55°C its efficacy suddenly ceases to exist), and which can best be designated with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)

[8] Buchner's address was reprinted in condensed form in: Buchner H (1891). "Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe". Centralblatt für Bakteriologie und Parasitenkunde (in German). 10: 349–352. From p. 350: "Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die besonders durch grosse Labilität ausgezeichnet sind (bei 50-55°C erlischt rasch die Wirksamkeit), und die am besten mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet werden könnten." (So it's a matter of protein of a new type, which is especially distinguished by great lability (at 50-55°C its efficacy suddenly ceases to exist), and which can best be designated with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)

[Nesargikar2012-8] Nesargikar PN, Spiller B, Chavez R (June 2012). "The complement system: history, pathways, cascade and inhibitors". European Journal of Microbiology & Immunology. 2 (2): 103–11. doi:10.1556/EuJMI.2.2012.2.2. PMC 3956958. PMID 24672678.

[9] Bordet J (1895). "Les leucocytes et les propriétés actives du sérum chez les vaccinés" [Leucocytes and the active properties of serum in vaccinated [animals]]. Annales de l'Institut Pasteur (in French). 9: 462–506.

[10] Ehrlich P, Morgenroth J (29 May 1899). "Ueber Haemolysine" [On hemolysin]. Berliner klinische Wochenschrift (in German). 36 (22): 481–486. From p. 483: "Es sprechen diese Versuche nach unseren früheren Erfahrungen dafür, dass auch hier in dem Serum ein Analogon des Immunkörpers, ein mit zwei haptophoren Gruppen versehener Complex, der als Zwischenkörper bezeichnet werde, und ein Addiment, das wir im Folgenden mit dem allgemeineren Ausdruck Complement bezeichnen wollen, besteht, und dass von den Blutkörperchen vorweigend der Zwischenkörper gebunden worden ist." (According to our earlier experiences, these experiments indicate (1) that here too there exists in the serum an analog of the immune bodies — a complex [that's] provided with two haptophoric groups, [one of] which may be designated as an "intermediate body" and [the other, as] an addiment [i.e., a component of a hemolysin that's induced by an antigen (see p. 481)], which we will designate in the following with the more general term "complement" — and (2) that the intermediate body has been bound mainly by the blood cells.)

[11] Kaufmann SH (July 2008). "Immunology's foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff". Nature Immunology. 9 (7): 705–12. doi:10.1038/ni0708-705. PMID 18563076. S2CID 205359637.

[12] Murphy K, Weaver C (2017). "Innate Immunity: the First Lines of Defense". Janeway's Immunobiology (9th ed.). Garland Science. p. 49. ISBN 978-0-8153-4505-3.

[pmid=_23383423-13] Klos A, Wende E, Wareham KJ, Monk PN (January 2013). "International Union of Basic and Clinical Pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors". Pharmacological Reviews. 65 (1): 500–43. doi:10.1124/pr.111.005223. PMID 23383423.

[Baron-14] Goldman AS, Prabhakar BS (1996). "The Complement System". In Baron S, et al. (eds.). Baron's Medical Microbiology (4th ed.). Univ of Texas Medical Branch. ISBN 978-0-9631172-1-2. PMID 21413267.

[15] "Classical Pathway (CP)". www.complementsystem.se. Euro Diagnostica. Archived from the original on 2 June 2016. Retrieved 6 June 2022.

[16] Rooijakkers SH, Wu J, Ruyken M, van Domselaar R, Planken KL, Tzekou A, et al. (July 2009). "Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor". Nature Immunology. 10 (7): 721–7. doi:10.1038/ni.1756. PMC 2729104. PMID 19503103.

[17] Ammitzbøll CG, Kjær TR, Steffensen R, Stengaard-Pedersen K, Nielsen HJ, Thiel S, et al. (2012). "Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin". PLOS ONE. 7 (11): e50585. Bibcode:2012PLoSO...750585A. doi:10.1371/journal.pone.0050585. PMC 3509001. PMID 23209787.

[Janeway1994-18] Janeway C, Travers P (1994). Immunobiology: The Immune System in Health and Disease. London; San Francisco; New York: Current Biology Limited, Garland Publishing. Inc. ISBN 0-8153-1691-7.^{[page needed]}

[janeway1999-19] Janeway CA, Travers P, Walport M, Capra JD (1999). Immunobiology: The Immune System in Health and Disease (4th ed.). New York: Garland Publishing, Inc. ISBN 0-8153-3217-3.^{[page needed]}

[abbas-20] Abbas AK, Lichtman AH (May 2015). Cellular and Molecular Immunology (5th ed.). Philadelphia: Saunders. p. 332. ISBN 978-0-7216-0008-6. Note that, in older texts, the smaller fragment is often called C2b, and the larger one is called C2a for historical reasons.

[Peakman-21] Peakman M, Vergani D (1997). Basic and Clinical Immunology. New York: Churchill Livingstone. ISBN 0-443-04672-7.^{[page needed]}

[22] Paul WE, ed. (1999). Fundamental Immunology (4th ed.). Philadelphia: Lippincott-Raven. ISBN 0-7817-1412-5.^{[page needed]}

[Sims-23] Sims PJ, Wiedmer T (2000). "Complement biology". In Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P (eds.). Hematology: Basic Principles and Practic (3rd ed.). New York; Edinburgh: Churchill-Livingstone. pp. 651–667. ISBN 0-443-07954-4.

[24] Frank K, Atkinson JP (2001). "Complement system". In Austen KF, Frank K, Atkinson JP, Cantor H (eds.). Samter's Immunologic Diseases. Vol. 1 (6th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 281–298. ISBN 0-7817-2120-2.

[Roitt-25] Roitt I, Brostoff J, Male D (2001). Immunology (6th ed.). St. Louis: Mosby. ISBN 0-7234-3189-2.^{[page needed]}

[anderson2003-26] Anderson DM (2003). Dorland's Illustrated Medical Dictionary (30th ed.). Philadelphia: W.B. Saunders. ISBN 0-7216-0146-4.^{[page needed]}

[Parham-27] Parham P (2005). The Immune System. New York: Garland. ISBN 0-8153-4093-1.^{[page needed]}

[murphy2008-28] Murphy K, Travers P, Walport M, Ehrenstein M (2008). Janeway's Immunobiology (7th ed.). New York: Garland Science. ISBN 978-0-8153-4123-9.^{[page needed]}

[Atkinson-29] Atkinson JP (2009). "Complement system". In Firestein GS, Budd RC, Harris Jr ED, McInnes IB, Ruddy S, Sergent JS (eds.). Kelley's Textbook of Rheumatology. Philadelphia, PA: Saunders/Elsevier. pp. 323–336. ISBN 978-1-4160-3285-4.

[Janeway_2001-30] Janeway Jr CA, Travers P, Walport M, Shlomchik MJ (2001). "The complement system and innate immunity". Immunobiology (5th ed.). Garland Publishing. ISBN 978-0-8153-3642-6.

[doan2007-31] Doan T, Melvold R, Viselli S, Waltenbaugh C (2007). Lippincott's Illustrated Reviews: Immunology, 320p. Lippincott Williams & Wilkins^{[page needed]}

[DeFranco-32] DeFranco AL, Locksley RM, Robertson M (2007). Immunity : The Immune Response in Infectious and Inflammatory Disease. London; Sunderland, MA: New Science Press; Sinauer Associates. ISBN 978-0-9539181-0-2.^{[page needed]}

[33] Stoermer KA, Morrison TE (March 2011). "Complement and viral pathogenesis". Virology. 411 (2): 362–73. doi:10.1016/j.virol.2010.12.045. PMC 3073741. PMID 21292294.

[34] Zewde N, Gorham RD, Dorado A, Morikis D (2016-03-31). "Quantitative Modeling of the Alternative Pathway of the Complement System". PLOS ONE. 11 (3): e0152337. Bibcode:2016PLoSO..1152337Z. doi:10.1371/journal.pone.0152337. PMC 4816337. PMID 27031863.

[:2-35] Bajic G, Degn SE, Thiel S, Andersen GR (November 2015). "Complement activation, regulation, and molecular basis for complement-related diseases". The EMBO Journal. 34 (22): 2735–2757. doi:10.15252/embj.201591881. PMC 4682646. PMID 26489954.

[36] Zhang Y, Ghiringhelli Borsa N, Shao D, Dopler A, Jones MB, Meyer NC, et al. (2020-12-15). "Factor H Autoantibodies and Complement-Mediated Diseases". Frontiers in Immunology. 11: 607211. doi:10.3389/fimmu.2020.607211. PMC 7770156. PMID 33384694.

[pmid_15087815-37] Arumugam TV, Shiels IA, Woodruff TM, Granger DN, Taylor SM (May 2004). "The role of the complement system in ischemia-reperfusion injury". Shock. 21 (5): 401–9. doi:10.1097/00024382-200405000-00002. PMID 15087815. S2CID 36655599.

[pmid19443638-38] Naesens M, Li L, Ying L, Sansanwal P, Sigdel TK, Hsieh SC, et al. (August 2009). "Expression of complement components differs between kidney allografts from living and deceased donors". Journal of the American Society of Nephrology. 20 (8): 1839–51. doi:10.1681/ASN.2008111145. PMC 2723986. PMID 19443638.

[pmid_14499254-39] Sacks SH, Chowdhury P, Zhou W (October 2003). "Role of the complement system in rejection". Current Opinion in Immunology. 15 (5): 487–92. doi:10.1016/S0952-7915(03)00100-6. PMID 14499254.

[40] Thurman, Joshua M.; Holers, V. Michael (2006-02-01). "The Central Role of the Alternative Complement Pathway in Human Disease". The Journal of Immunology. 176 (3): 1305–1310. doi:10.4049/jimmunol.176.3.1305. ISSN 0022-1767. PMID 16424154.

[41] Mellor, Andrew L.; Sivakumar, Jayabalan; Chandler, Phillip; Smith, Kimberly; Molina, Hector; Mao, Dailing; Munn, David H. (January 2001). "Prevention of T cell–driven complement activation and inflammation by tryptophan catabolism during pregnancy". Nature Immunology. 2 (1): 64–68. doi:10.1038/83183. ISSN 1529-2908.

[42] Galvan MD, Luchetti S, Burgos AM, Nguyen HX, Hooshmand MJ, Hamers FP, Anderson AJ (December 2008). "Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury". The Journal of Neuroscience. 28 (51): 13876–88. doi:10.1523/JNEUROSCI.2823-08.2008. PMC 2680920. PMID 19091977.

[43] Nguyen HX, Galvan MD, Anderson AJ (June 2008). "Characterization of early and terminal complement proteins associated with polymorphonuclear leukocytes in vitro and in vivo after spinal cord injury". Journal of Neuroinflammation. 5: 26. doi:10.1186/1742-2094-5-26. PMC 2443364. PMID 18578885.

[44] Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ (February 2010). "Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment". Brain. 133 (Pt 2): 433–47. doi:10.1093/brain/awp322. PMC 2858013. PMID 20085927.

[45] Brown EJ (1985). "Interaction of Gram-Positive Microorganisms with Complement". Bacteria and Complement. Current Topics in Microbiology and Immunology. Vol. 121. Springer, Berlin, Heidelberg. pp. 159–187. doi:10.1007/978-3-642-45604-6_8. ISBN 9783642456060. PMID 3936681.

[Ram2010-46] Ram S, Lewis LA, Rice PA (October 2010). "Infections of people with complement deficiencies and patients who have undergone splenectomy". Clinical Microbiology Reviews. 23 (4): 740–80. doi:10.1128/CMR.00048-09. PMC 2952982. PMID 20930072.

[Lewis2014-47] Lewis LA, Ram S (January 2014). "Meningococcal disease and the complement system". Virulence. 5 (1): 98–126. doi:10.4161/viru.26515. PMC 3916388. PMID 24104403.

[pmid16189652-48] Dragon-Durey MA, Frémeaux-Bacchi V (November 2005). "Atypical haemolytic uraemic syndrome and mutations in complement regulator genes". Springer Seminars in Immunopathology. 27 (3): 359–74. doi:10.1007/s00281-005-0003-2. PMID 16189652. S2CID 6330326.

[pmid16575689-49] Zipfel PF, Misselwitz J, Licht C, Skerka C (March 2006). "The role of defective complement control in hemolytic uremic syndrome". Seminars in Thrombosis and Hemostasis. 32 (2): 146–54. doi:10.1055/s-2006-939770. PMID 16575689. S2CID 260316508.

[BradleyDT2011-50] Bradley DT, Zipfel PF, Hughes AE (June 2011). "Complement in age-related macular degeneration: a focus on function". Eye. 25 (6): 683–93. doi:10.1038/eye.2011.37. PMC 3178140. PMID 21394116.

[51] Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, et al. (December 2005). "Diagnosis and management of paroxysmal nocturnal hemoglobinuria". Blood. 106 (12): 3699–709. doi:10.1182/blood-2005-04-1717. PMC 1895106. PMID 16051736.

[52] "Complement Deficiencies Workup: Laboratory Studies, Imaging Studies, Other Tests". emedicine.medscape.com. Retrieved 2018-04-26.

[53] Afzali B, Noris M, Lambrecht BN, Kemper C (February 2022). "The state of complement in COVID-19". Nature Reviews. Immunology. 22 (2): 77–84. doi:10.1038/s41577-021-00665-1. PMC 8672651. PMID 34912108.

[54] Datta PK, Rappaport J (November 2006). "HIV and complement: hijacking an immune defense". Biomedicine & Pharmacotherapy. 60 (9): 561–568. doi:10.1016/j.biopha.2006.07.087. PMID 16978830.

[55] Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. (May 2012). "Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner". Neuron. 74 (4): 691–705. doi:10.1016/j.neuron.2012.03.026. PMC 3528177. PMID 22632727.

[56] Gomez-Arboledas A, Acharya MM, Tenner AJ (September 2021). "The Role of Complement in Synaptic Pruning and Neurodegeneration". ImmunoTargets and Therapy. 10: 373–386. doi:10.2147/ITT.S305420. PMC 8478425. PMID 34595138.

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-{{Short description|Part of the immune system}}
+{{Short description|Part of the immune system that enhances the ability of antibodies and phagocytic cells}}
 {{About|an aspect of the immune system||Complement (disambiguation){{!}}Complement}}
 [[File:Complement pathway.svg|thumb|lang=en|upright=1.4|Scheme of the complement system]]
-The '''complement system''', also known as '''complement cascade''', is a part of the [[immune system]] that enhances (complements) the ability of [[antibody|antibodies]] and [[phagocytic]] cells to clear [[microbes]] and damaged cells from an organism, promote [[inflammation]], and attack the pathogen's [[cell membrane]]. It is part of the [[innate immune system]],<ref name=":1">{{cite web|url=https://www.ncbi.nlm.nih.gov/books/NBK27100|title=The complement system and innate immunity| vauthors = Janeway CA Jr, Travers P, Walport M |year=2001 |work=Immunobiology: The Immune System in Health and Disease |publisher=Garland Science |access-date=25 February 2013 |location=New York|display-authors=etal}}</ref> which is not adaptable and does not change during an individual's lifetime. The complement system can, however, be recruited and brought into action by antibodies generated by the [[adaptive immune system]].
+The '''complement system''', also known as '''complement cascade''', is a part of the [[humoral]], [[innate immune system]] and enhances (complements) the ability of [[antibodies]] and [[phagocytic cell]]s to clear [[microbes]] and damaged cells from an organism, promote [[inflammation]], and attack the [[pathogen]]'s [[cell membrane]].<ref name=":1">{{Cite book |title=Immunobiology: The Immune System in Health and Disease |vauthors=Janeway Jr CA, Travers P, Walport M, Shlomchik MJ |publisher=Garland Science |year=2001 |location=New York |chapter=The complement system and innate immunity |access-date=25 February 2013 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK27100}}</ref> Despite being part of the innate immune system, the complement system can be recruited and brought into action by antibodies generated by the [[adaptive immune system]].
-The complement system consists of a number of small [[protein]]s that are synthesized by the [[liver]], and circulate in the blood as inactive [[Protein precursor|precursors]]. When stimulated by one of several triggers, [[protease]]s in the system cleave specific proteins to release [[cytokine]]s and initiate an amplifying cascade of further cleavages. The end result of this ''complement activation'' or ''complement fixation'' cascade is stimulation of [[phagocyte]]s to clear foreign and damaged material, [[inflammation]] to attract additional phagocytes, and [[activation]] of the cell-killing [[complement membrane attack complex|membrane attack complex]]. About 50 proteins and protein fragments make up the complement system, including [[blood proteins|serum proteins]], and [[cell surface receptor|cell membrane receptors]]. They account for about 10% of the [[globulin]] fraction of blood serum.<ref>{{Cite journal | vauthors = Glovsky MM | veditors = Talavera F, Dreskin SC, Kaliner MA | date = 9 November 2019 |title=Complement-Related Disorders: Background, Pathophysiology, Activation | journal = Medscape |url=https://emedicine.medscape.com/article/136368-overview}}</ref>
+The complement system consists of a number of small, inactive, liver synthesized [[protein precursor]]s circulating in the [[blood]]. When stimulated by one of several triggers, [[protease]]s in the system [[protease|cleave specific proteins]] to release [[cytokine]]s and initiate an amplifying cascade of further cleavages. The end result of this ''complement activation'' or ''complement fixation'' cascade is stimulation of [[phagocyte]]s to clear foreign and damaged material, [[inflammation]] to attract additional phagocytes, and [[immunologic activation|activation]] of the cell-killing [[membrane attack complex]]. About 50 proteins and protein fragments make up the complement system, including [[plasma protein]]s, and [[cell membrane receptor]]s. They account for about 10% of the [[globulin]] fraction of blood serum.<ref>{{Cite journal |vauthors=Glovsky MM |date=9 November 2019 |title=Complement-Related Disorders: Background, Pathophysiology, Activation |url=https://emedicine.medscape.com/article/136368-overview |journal=Medscape |veditors=Talavera F, Dreskin SC, Kaliner MA}}</ref>
-Three biochemical pathways activate the complement system: the [[classical complement pathway]], the [[alternative complement pathway]], and the [[lectin pathway]].<ref name="Abbas_2010">{{cite book | vauthors = Abbas AK, Lichtman AH, Pillai S | title = Cellular and Molecular Immunology | edition = 6th | publisher = Elsevier | year = 2010 | isbn = 978-1-4160-3123-9 | pages = [https://archive.org/details/cellularmolecula00abba_1/page/272 272–288] | url = https://archive.org/details/cellularmolecula00abba_1/page/272 }}</ref> The alternative pathway accounts for the majority of terminal pathway activation and so therapeutic efforts in disease have revolved around its inhibition.<ref name=":0">{{cite journal | vauthors = Tzoumas N, Hallam D, Harris CL, Lako M, Kavanagh D, Steel DH | title = Revisiting the role of factor H in age-related macular degeneration: Insights from complement-mediated renal disease and rare genetic variants | journal = Survey of Ophthalmology | volume = 66 | issue = 2 | pages = 378–401 | date = November 2020 | pmid = 33157112 | doi = 10.1016/j.survophthal.2020.10.008 | s2cid = 226274874 }}</ref>
+Three biochemical pathways activate the complement system: the [[classical complement pathway]], the [[alternative complement pathway]], and the [[lectin pathway]].<ref name="Abbas_2010">{{Cite book |url=https://archive.org/details/cellularmolecula00abba_1/page/272 |title=Cellular and Molecular Immunology |vauthors=Abbas AK, Lichtman AH, Pillai S |publisher=Elsevier |year=2010 |isbn=978-1-4160-3123-9 |edition=6th |pages=[https://archive.org/details/cellularmolecula00abba_1/page/272 272–288]}}</ref> The alternative pathway accounts for the majority of terminal pathway activation and so therapeutic efforts in disease have revolved around its inhibition.<ref name=":0">{{Cite journal |vauthors=Tzoumas N, Hallam D, Harris CL, Lako M, Kavanagh D, Steel DH |date=November 2020 |title=Revisiting the role of factor H in age-related macular degeneration: Insights from complement-mediated renal disease and rare genetic variants |journal=Survey of Ophthalmology |volume=66 |issue=2 |pages=378–401 |doi=10.1016/j.survophthal.2020.10.008 |pmid=33157112 |s2cid=226274874}}</ref>
 == History ==
-In 1888, [[George Nuttall]] found that sheep blood [[serum (blood)|serum]] had mild killing activity against the [[bacterium]] that causes [[anthrax]].<ref>{{cite journal | vauthors = Nuttall G |title=Experimente über die bakterien feindlichen Einflüsse des tierischen Körpers |journal=Zeitschrift für Hygiene |date=1888 |volume=4 |pages=353–394 |url=https://babel.hathitrust.org/cgi/pt?id=uc1.b3063944&view=1up&seq=361 |trans-title=Experiments on the antibacterial influences of animal substances |language=German}}English translation [https://apps.dtic.mil/sti/pdfs/AD0880296.pdf here]</ref> The killing activity disappeared when he heated the blood.<ref name="Chaplin2005">{{cite journal | vauthors = Chaplin H | title = Review: the burgeoning history of the complement system 1888-2005 | journal = Immunohematology | volume = 21 | issue = 3 | pages = 85–93 | year = 2020 | doi = 10.21307/immunohematology-2019-398 | pmid = 16178664 | doi-access = free }}</ref>  In 1891, [[Hans Ernst August Buchner]], noting the same property of blood in his experiments, named the killing property "alexin", which means "to ward off" in Greek.<ref>Buchner named "alexin" during an address to a meeting of the Medical Society (''Aerztlichen Verein'') in Munich, Germany on 3 June 1891.  Buchner's address was published in: {{cite journal | vauthors = Buchner H |title=Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe |journal=Münchener Medizinische Wochenschrift |date=23 June 1891 |volume=38 |issue=25 |pages=435–437, (26): 454–456 |url=https://babel.hathitrust.org/cgi/pt?id=uc1.c2621491&view=1up&seq=459 |trans-title=Brief overview of the development of bacteriology since Naegeli's involvement in it |language=German}}  From p. 437:  ''"Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die mit irgend welchen bisher bekannten sich nicht identificieren lassen, und die man am besten deshalb mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet."'' (So it's a matter of protein of a new type, which cannot be identified with any [protein] which [has been] known until now, and which one therefore designates best with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)
+In 1888, [[George Nuttall]] found that sheep blood [[serum (blood)|serum]] had mild killing activity against the [[bacterium]] that causes [[anthrax]].<ref>{{Cite journal |vauthors=Nuttall G |date=1888 |title=Experimente über die bakterien feindlichen Einflüsse des tierischen Körpers |trans-title=Experiments on the antibacterial influences of animal substances |url=https://babel.hathitrust.org/cgi/pt?id=uc1.b3063944&view=1up&seq=361 |journal=Zeitschrift für Hygiene |language=German |volume=4 |pages=353–394}}English translation [https://apps.dtic.mil/sti/pdfs/AD0880296.pdf here]</ref> The killing activity disappeared when he heated the blood.<ref name="Chaplin2005">{{Cite journal |vauthors=Chaplin H |year=2020 |title=Review: the burgeoning history of the complement system 1888-2005 |journal=Immunohematology |volume=21 |issue=3 |pages=85–93 |doi=10.21307/immunohematology-2019-398 |pmid=16178664 |doi-access=free}}</ref>  In 1891, [[Hans Ernst August Buchner]], noting the same property of blood in his experiments, named the killing property "alexin", which means "to ward off" in Greek.<ref>Buchner named "alexin" during an address to a meeting of the Medical Society (''Aerztlichen Verein'') in Munich, Germany on 3 June 1891.  Buchner's address was published in: {{Cite journal |vauthors=Buchner H |date=23 June 1891 |title=Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe |trans-title=Brief overview of the development of bacteriology since Naegeli's involvement in it |url=https://babel.hathitrust.org/cgi/pt?id=uc1.c2621491&view=1up&seq=459 |journal=Münchener Medizinische Wochenschrift |language=German |volume=38 |issue=25 |pages=435–437, (26): 454–456}}  From p. 437:  ''"Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die mit irgend welchen bisher bekannten sich nicht identificieren lassen, und die man am besten deshalb mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet."'' (So it's a matter of protein of a new type, which cannot be identified with any [protein] which [has been] known until now, and which one therefore designates best with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)
-* Buchner's address was reprinted in condensed form in:  {{cite journal | vauthors = Buchner H |title=Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe |journal=Centralblatt für Bakteriologie und Parasitenkunde |date=1891 |volume=10 |pages=349–352 |url=https://www.biodiversitylibrary.org/item/210617#page/365/mode/1up |language=German}}  From p. 350:  ''"Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die besonders durch grosse Labilität ausgezeichnet sind (bei 50-55° C erlischt rasch die Wirksamkeit), und die am besten mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet werden könnten."'' (So it's a matter of protein of a new type, which is especially distinguished by great lability (at 50-55° C its efficacy suddenly ceases to exist), and which can best be designated with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)</ref><ref name="Nesargikar2012">{{cite journal | vauthors = Nesargikar PN, Spiller B, Chavez R | title = The complement system: history, pathways, cascade and inhibitors | journal = European Journal of Microbiology & Immunology | volume = 2 | issue = 2 | pages = 103–11 | date = June 2012 | pmid = 24672678 | pmc = 3956958 | doi = 10.1556/EuJMI.2.2012.2.2 }}</ref>  By 1894, several laboratories had demonstrated that serum from guinea pigs that had recovered from [[cholera]] killed the cholera bacterium ''in vitro''.  Heating the serum destroyed its killing activity.  Nevertheless, the heat-inactivated serum, when injected into guinea pigs exposed to the cholera bacteria, maintained its ability to protect the animals from illness.  [[Jules Bordet]], a young [[Belgians|Belgian]] scientist in [[Paris]] at the [[Pasteur Institute]], concluded that this principle has two components, one that maintained a "sensitizing" effect after being heated and one (alexin) whose toxic effect was lost after being heated.<ref>{{cite journal | vauthors = Bordet J |title=Les leucocytes et les propriétés actives du sérum chez les vaccinés |journal=Annales de l'Institut Pasteur |date=1895 |volume=9 |pages=462–506 |url=https://www.biodiversitylibrary.org/item/31494#page/420/mode/1up |trans-title=Leucocytes and the active properties of serum in vaccinated [animals] |language=French}}</ref> The heat-stable component was responsible for immunity against specific microorganisms, whereas the heat-sensitive component was responsible for the non-specific antimicrobial activity conferred by all normal sera. In 1899, [[Paul Ehrlich]] renamed the heat-sensitive component "complement."<ref>{{cite journal | vauthors = Ehrlich P, Morgenroth J |title=Ueber Haemolysine |journal=Berliner klinische Wochenschrift |date=29 May 1899 |volume=36 |issue=22 |pages=481–486 |url=https://babel.hathitrust.org/cgi/pt?id=uc1.c2892587&view=1up&seq=517 |trans-title=On hemolysin |language=German}}  From p. 483:  ''"Es sprechen diese Versuche nach unseren früheren Erfahrungen dafür, dass auch hier in dem Serum ein Analogon des Immunkörpers, ein mit zwei haptophoren Gruppen versehener Complex, der als Zwischenkörper bezeichnet werde, und ein Addiment, das wir im Folgenden mit dem allgemeineren Ausdruck Complement bezeichnen wollen, besteht, und dass von den Blutkörperchen vorweigend der Zwischenkörper gebunden worden ist."''  (According to our earlier experiences, these experiments indicate (1) that here too there exists in the serum an analog of the immune bodies — a complex [that's] provided with two haptophoric groups, [one of] which may be designated as an "intermediate body" and [the other, as] an addiment [i.e., a component of a hemolysin that's induced by an antigen (see p. 481)], which we will designate in the following with the more general term "complement" — and (2) that the intermediate body has been bound mainly by the blood cells.)</ref><ref name="Chaplin2005" />
+* Buchner's address was reprinted in condensed form in:  {{cite journal | vauthors = Buchner H |title=Kurze Uebersicht über die Entwicklung der Bacterienforschung seit Naegeli's Eingreifen in dieselbe |journal=Centralblatt für Bakteriologie und Parasitenkunde |date=1891 |volume=10 |pages=349–352 |url=https://www.biodiversitylibrary.org/item/210617#page/365/mode/1up |language=German}}  From p. 350:  ''"Es handelt sich demnach um Eiweisskörper einer neuen Kategorie, die besonders durch grosse Labilität ausgezeichnet sind (bei 50-55°C erlischt rasch die Wirksamkeit), und die am besten mit einem neuen Namen, etwa als "Alexine" (d.h. Schutzstoffe, von αλέξειν abwehren, schützen) bezeichnet werden könnten."'' (So it's a matter of protein of a new type, which is especially distinguished by great lability (at 50-55°C its efficacy suddenly ceases to exist), and which can best be designated with a new name, perhaps as "alexine" (i.e., protective stuff, from αλέξειν fight off, defend).)</ref><ref name="Nesargikar2012">{{Cite journal |vauthors=Nesargikar PN, Spiller B, Chavez R |date=June 2012 |title=The complement system: history, pathways, cascade and inhibitors |journal=European Journal of Microbiology & Immunology |volume=2 |issue=2 |pages=103–11 |doi=10.1556/EuJMI.2.2012.2.2 |pmc=3956958 |pmid=24672678}}</ref>  By 1894, several laboratories had demonstrated that serum from guinea pigs that had recovered from [[cholera]] killed the cholera bacterium ''in vitro''.  Heating the serum destroyed its killing activity.  Nevertheless, the heat-inactivated serum, when injected into guinea pigs exposed to the cholera bacteria, maintained its ability to protect the animals from illness.  [[Jules Bordet]], a young [[Belgians|Belgian]] scientist in [[Paris]] at the [[Pasteur Institute]], concluded that this principle has two components, one that maintained a "sensitizing" effect after being heated and one (alexin) whose toxic effect was lost after being heated.<ref>{{Cite journal |vauthors=Bordet J |date=1895 |title=Les leucocytes et les propriétés actives du sérum chez les vaccinés |trans-title=Leucocytes and the active properties of serum in vaccinated [animals] |url=https://www.biodiversitylibrary.org/item/31494#page/420/mode/1up |journal=Annales de l'Institut Pasteur |language=French |volume=9 |pages=462–506}}</ref> The heat-stable component was responsible for immunity against specific microorganisms, whereas the heat-sensitive component was responsible for the non-specific antimicrobial activity conferred by all normal sera. In 1899, [[Paul Ehrlich]] renamed the heat-sensitive component "complement".<ref>{{Cite journal |vauthors=Ehrlich P, Morgenroth J |date=29 May 1899 |title=Ueber Haemolysine |trans-title=On hemolysin |url=https://babel.hathitrust.org/cgi/pt?id=uc1.c2892587&view=1up&seq=517 |journal=Berliner klinische Wochenschrift |language=German |volume=36 |issue=22 |pages=481–486}}  From p. 483:  ''"Es sprechen diese Versuche nach unseren früheren Erfahrungen dafür, dass auch hier in dem Serum ein Analogon des Immunkörpers, ein mit zwei haptophoren Gruppen versehener Complex, der als Zwischenkörper bezeichnet werde, und ein Addiment, das wir im Folgenden mit dem allgemeineren Ausdruck Complement bezeichnen wollen, besteht, und dass von den Blutkörperchen vorweigend der Zwischenkörper gebunden worden ist."''  (According to our earlier experiences, these experiments indicate (1) that here too there exists in the serum an analog of the immune bodies — a complex [that's] provided with two haptophoric groups, [one of] which may be designated as an "intermediate body" and [the other, as] an addiment [i.e., a component of a hemolysin that's induced by an antigen (see p. 481)], which we will designate in the following with the more general term "complement" — and (2) that the intermediate body has been bound mainly by the blood cells.)</ref><ref name="Chaplin2005" />
-Ehrlich introduced the term "complement" as part of his larger theory of the immune system.<ref>{{cite journal | vauthors = Kaufmann SH | title = Immunology's foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff | journal = Nature Immunology | volume = 9 | issue = 7 | pages = 705–12 | date = July 2008 | pmid = 18563076 | doi = 10.1038/ni0708-705 | s2cid = 205359637 }}</ref> 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. Those [[Immune receptor|receptors]], which we now call "[[Antibody|antibodies]]", were called by Ehrlich "amboceptors" to emphasise their bifunctional binding capacity: They recognise and bind to a specific antigen, but they also recognise 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.{{citation needed|date=May 2015}}
+Ehrlich introduced the term "complement" as part of his larger theory of the immune system.<ref>{{Cite journal |vauthors=Kaufmann SH |date=July 2008 |title=Immunology's foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff |journal=Nature Immunology |volume=9 |issue=7 |pages=705–12 |doi=10.1038/ni0708-705 |pmid=18563076 |s2cid=205359637}}</ref> 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. Those [[Immune receptor|receptors]], which we now call "[[Antibody|antibodies]]", were called by Ehrlich "amboceptors" to emphasise their bifunctional binding capacity: They recognise and bind to a specific antigen, but they also recognise 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.{{citation needed|date=May 2015}}
 == Functions ==
-[[File:Membrane Attack Complex (Terminal Complement Complex C5b-9).png|thumb|Membrane Attack Complex (Terminal Complement Complex C5b-9)]]
+[[File:Membrane Attack Complex (Terminal Complement Complex C5b-9).png|thumb|Membrane attack complex (Terminal Complement Complex C5b-9)]]
-Complement triggers the following immune functions:<ref>{{cite book| vauthors = Murphy K, Weaver C |title=Janeway's Immunobiology|date=2017|publisher=Garland Science|isbn=978-0-8153-4505-3|page=49|edition=9th|chapter=Innate Immunity: the First Lines of Defense}}</ref>
+Complement triggers the following immune functions:<ref>{{Cite book |title=Janeway's Immunobiology |vauthors=Murphy K, Weaver C |date=2017 |publisher=Garland Science |isbn=978-0-8153-4505-3 |edition=9th |page=49 |chapter=Innate Immunity: the First Lines of Defense}}</ref>
-# '''[[Complement membrane attack complex|Membrane attack]]''' – by rupturing the [[cell wall]] of [[bacteria]]. ([[Classical Complement Pathway]])
+# '''[[Complement membrane attack complex|Membrane attack]]''' – by rupturing the [[cell wall]] of [[bacteria]]. ([[Classical Complement Pathway|classical complement pathway]])
-# '''[[Phagocytosis]]''' – by [[opsonin|opsonizing]] antigens. C3b has most important opsonizing activity. ([[Alternative complement pathway|Alternative Complement Pathway]])
+# '''[[Phagocytosis]]''' – by [[opsonin|opsonizing]] antigens. C3b has most important opsonizing activity. ([[alternative complement pathway]])
-# '''[[Inflammation]]''' – by attracting [[macrophage]]s and [[neutrophil]]s. ([[Lectin pathway]])
+# '''[[Inflammation]]''' – by attracting [[macrophage]]s and [[neutrophil]]s. ([[lectin pathway]])
 == Overview ==
-Most of the [[protein]]s and [[glycoprotein]]s that constitute the complement system are synthesized by [[hepatocytes]]. But significant amounts are also produced by tissue [[macrophage]]s, blood [[monocyte]]s, and [[epithelial cells]] of the [[genitourinary system]] and [[gastrointestinal tract]]. The three pathways of activation all generate homologous variants of the [[protease]] [[C3-convertase]]. The classical complement pathway typically requires [[antigen-antibody complex]]es for activation (specific immune response), whereas the alternative pathway can be activated by spontaneous [[complement component 3]] (C3) hydrolysis, foreign material, pathogens, or damaged cells. The mannose-binding lectin pathway can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causes a cascade of further cleavage and activation events. C3b binds to the surface of pathogens, leading to greater internalization by [[phagocyte|phagocytic cells]] by [[opsonization]].{{cn}}
+Most of the [[protein]]s and [[glycoprotein]]s that constitute the complement system are synthesized by [[hepatocytes]]. But significant amounts are also produced by tissue [[macrophage]]s, blood [[monocyte]]s, and [[epithelial cells]] of the [[genitourinary system]] and [[gastrointestinal tract]]. The three pathways of activation all generate homologous variants of the [[protease]] [[C3-convertase]]. The classical complement pathway typically requires [[antigen-antibody complex]]es for activation (specific immune response), whereas the alternative pathway can be activated by spontaneous [[complement component 3]] (C3) hydrolysis, foreign material, pathogens, or damaged cells. The [[mannose]]-binding lectin pathway can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causes a cascade of further cleavage and activation events. C3b binds to the surface of pathogens, leading to greater internalization by [[phagocyte|phagocytic cells]] by [[opsonization]].{{citation needed|date=July 2022}}
-In the alternative pathway, C3b binds to Factor B. Factor D releases Factor Ba from Factor B bound to C3b. The complex of C3b(2)Bb is a protease which cleaves C5 into C5b and C5a. [[C5-convertase|C5 convertase]] is also formed by the classical pathway when C3b binds C4b and C2b. [[Complement component 5a|C5a]] is an important [[chemokine|chemotactic protein]], helping recruit inflammatory cells. C3a is the precursor of an important [[cytokine]] (adipokine) named [[Acylation stimulating protein|ASP]] (although this is not universally accepted <ref name="pmid= 23383423">{{cite journal | vauthors = Klos A, Wende E, Wareham KJ, Monk PN | title = International Union of Basic and Clinical Pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors | journal = Pharmacological Reviews | volume = 65 | issue = 1 | pages = 500–43 | date = January 2013 | pmid = 23383423 | doi = 10.1124/pr.111.005223 | doi-access = free }}</ref>) and is usually rapidly cleaved by [[carboxypeptidase B]]. Both C3a and C5a have [[anaphylatoxin]] activity, directly triggering [[degranulation]] of [[mast cell]]s as well as increasing vascular permeability and [[smooth muscle]] contraction.<ref name="pmid= 23383423" /> C5b initiates the [[Complement membrane attack complex|membrane attack pathway]], which results in the [[complement membrane attack complex|membrane attack complex]] (MAC), consisting of C5b, [[Complement component 6|C6]], [[Complement component 7|C7]], [[C8 complex|C8]], and polymeric [[Complement component 9|C9]].<ref name="Baron">{{cite book |vauthors=Goldman AS, Prabhakar BS | chapter = The Complement System |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK7795/#A238 |title=Baron's Medical Microbiology |editor=Baron S| edition = 4th | publisher = Univ of Texas Medical Branch | year = 1996 | pmid = 21413267 | isbn = 978-0-9631172-1-2 |display-editors=etal}}</ref> MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes [[osmosis|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.{{cn}}
+In the alternative pathway, C3b binds to Factor B. Factor D releases Factor Ba from Factor B bound to C3b. The complex of C3b(2)Bb is a protease which cleaves C5 into C5b and C5a. [[C5-convertase|C5 convertase]] is also formed by the classical pathway when C3b binds C4b and C2b. [[Complement component 5a|C5a]] is an important [[chemokine|chemotactic protein]], helping recruit inflammatory cells. C3a is the precursor of an important [[cytokine]] ([[adipokine]]) named [[Acylation stimulating protein|ASP]] (although this is not universally accepted <ref name="pmid= 23383423">{{Cite journal |vauthors=Klos A, Wende E, Wareham KJ, Monk PN |date=January 2013 |title=International Union of Basic and Clinical Pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors |journal=Pharmacological Reviews |volume=65 |issue=1 |pages=500–43 |doi=10.1124/pr.111.005223 |pmid=23383423 |doi-access=free}}</ref>) and is usually rapidly cleaved by [[carboxypeptidase B]]. Both C3a and C5a have [[anaphylatoxin]] activity, directly triggering [[degranulation]] of [[mast cell]]s as well as increasing vascular permeability and [[smooth muscle]] contraction.<ref name="pmid= 23383423" /> C5b initiates the [[Complement membrane attack complex|membrane attack pathway]], which results in the [[complement membrane attack complex|membrane attack complex]] (MAC), consisting of C5b, [[Complement component 6|C6]], [[Complement component 7|C7]], [[C8 complex|C8]], and polymeric [[Complement component 9|C9]].<ref name="Baron">{{Cite book |title=Baron's Medical Microbiology |vauthors=Goldman AS, Prabhakar BS |publisher=Univ of Texas Medical Branch |year=1996 |isbn=978-0-9631172-1-2 |veditors=Baron S |edition=4th |chapter=The Complement System |pmid=21413267 |display-editors=etal |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK7795/#A238}}</ref> MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes [[osmosis|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.{{citation needed|date=July 2022}}
-[[File:09 Hegasy Complement System Wiki EN CCBYSA.png|thumb|Reaction Cascade of the Complement System: Classical, Alternative and Lectin Pathway, Amplification Loop, Terminal Pathway, and Membrane Attack Complex.]]
+[[File:09 Hegasy Complement System Wiki EN CCBYSA.png|thumb|Reaction cascade of the complement system: classical, alternative, and lectin pathways, amplification loop, terminal pathway, and membrane attack complex.]]
 === Classical pathway ===
@@ Line 33: / Line 33: @@
 [[File:Complement-pathways.png|350px|thumb|The classical and alternative complement pathways]]
-The [[classical complement pathway|classical pathway]] is triggered by activation of the C1-complex. The '''C1-complex''' is composed of 1 molecule of [[Complement component 1q|C1q]], 2 molecules of C1r and 2 molecules of C1s, or ''C1qr<sup>2</sup>s<sup>2</sup>''. This occurs when C1q binds to [[IgM]] or [[Immunoglobulin G|IgG]] complexed with [[antigen]]s. A single pentameric IgM can initiate the pathway, while several, ideally six, IgGs are needed. This also occurs when [[Complement component 1q|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 [[Complement component 1r|C1r]] molecules. C1r is a serine protease. They then cleave [[Complement component 1s|C1s]] (another serine protease). The C1r<sup>2</sup>s<sup>2</sup> component now splits [[Complement component 4|C4]] and then [[Complement component 2|C2]], producing C4a, C4b, C2a, and C2b (historically, the larger fragment of C2 was called C2a but is now referred to as C2b). C4b and C2b bind to form the classical pathway C3-convertase (C4b2b complex), which promotes cleavage of C3 into C3a and C3b. C3b later joins with C4b2b to make C5 convertase (C4b2b3b complex).<ref>{{cite web |url=http://www.complementsystem.se/classical-pathway |title=Classical Pathway (CP) | publisher = Euro Diagnostica |website=www.complementsystem.se |access-date=6 June 2022 |archive-url=https://web.archive.org/web/20160602151601/http://www.complementsystem.se/classical-pathway |archive-date=2 June 2016 |url-status=dead}}</ref>
+The [[classical complement pathway|classical pathway]] is triggered by activation of the C1-complex. The '''C1-complex''' is composed of 1 molecule of [[Complement component 1q|C1q]], 2 molecules of C1r and 2 molecules of C1s, or ''C1qr<sup>2</sup>s<sup>2</sup>''. This occurs when C1q binds to [[IgM]] or [[Immunoglobulin G|IgG]] complexed with [[antigen]]s. A single pentameric IgM can initiate the pathway, while several, ideally six, IgGs are needed. This also occurs when [[Complement component 1q|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 [[Complement component 1r|C1r]] molecules. C1r is a serine protease. They then cleave [[Complement component 1s|C1s]] (another serine protease). The C1r<sup>2</sup>s<sup>2</sup> component now splits [[Complement component 4|C4]] and then [[Complement component 2|C2]], producing C4a, C4b, C2a, and C2b (historically, the larger fragment of C2 was called C2a but is now referred to as C2b). C4b and C2b bind to form the classical pathway C3-convertase (C4b2b complex), which promotes cleavage of C3 into C3a and C3b. C3b later joins with C4b2b to make C5 convertase (C4b2b3b complex).<ref>{{Cite web |title=Classical Pathway (CP) |url=http://www.complementsystem.se/classical-pathway |url-status=dead |archive-url=https://web.archive.org/web/20160602151601/http://www.complementsystem.se/classical-pathway |archive-date=2 June 2016 |access-date=6 June 2022 |website=www.complementsystem.se |publisher=Euro Diagnostica}}</ref>
 === Alternative pathway ===
 {{Main|Alternative complement pathway}}
-The [[alternate complement pathway|alternative pathway]] is continuously activated at a low level, analogous to a car engine at idle, as a result of spontaneous [[complement component 3|C3]] hydrolysis due to the breakdown of the internal thioester bond (C3 is mildly unstable in aqueous environment). The alternative pathway does not rely on pathogen-binding antibodies like the other pathways.<ref name="Abbas_2010" /> C3b that is generated from C3 by a C3 convertase enzyme complex in the fluid phase is rapidly inactivated by [[factor H]] and [[complement factor I|factor I]], as is the C3b-like C3 that is the product of spontaneous cleavage of the internal thioester. In contrast, when the internal thioester of C3 reacts with a hydroxyl or amino group of a molecule on the surface of a cell or pathogen, the C3b that is now covalently bound to the surface is protected from factor H-mediated inactivation. The surface-bound C3b may now bind [[complement factor B|factor B]] to form C3bB. This complex in the presence of [[factor D]] will be cleaved into Ba and Bb. Bb will remain associated with C3b to form C3bBb, which is the alternative pathway C3 convertase.<ref>{{cite journal | vauthors = Rooijakkers SH, Wu J, Ruyken M, van Domselaar R, Planken KL, Tzekou A, Ricklin D, Lambris JD, Janssen BJ, van Strijp JA, Gros P | display-authors = 6 | title = Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor | journal = Nature Immunology | volume = 10 | issue = 7 | pages = 721–7 | date = July 2009 | pmid = 19503103 | pmc = 2729104 | doi = 10.1038/ni.1756 }}</ref>
+The [[alternate complement pathway|alternative pathway]] is continuously activated at a low level, analogous to a car engine at idle, as a result of spontaneous [[complement component 3|C3]] hydrolysis due to the breakdown of the internal [[thioester]] bond (C3 is mildly unstable in aqueous environment). The alternative pathway does not rely on pathogen-binding antibodies like the other pathways.<ref name="Abbas_2010" /> C3b that is generated from C3 by a C3 convertase enzyme complex in the fluid phase is rapidly inactivated by [[factor H]] and [[complement factor I|factor I]], as is the C3b-like C3 that is the product of spontaneous cleavage of the internal thioester. In contrast, when the internal thioester of C3 reacts with a hydroxyl or amino group of a molecule on the surface of a cell or pathogen, the C3b that is now covalently bound to the surface is protected from factor H-mediated inactivation. The surface-bound C3b may now bind [[complement factor B|factor B]] to form C3bB. This complex in the presence of [[factor D]] will be cleaved into Ba and Bb. Bb will remain associated with C3b to form C3bBb, which is the alternative pathway C3 convertase.<ref>{{Cite journal |display-authors=6 |vauthors=Rooijakkers SH, Wu J, Ruyken M, van Domselaar R, Planken KL, Tzekou A, Ricklin D, Lambris JD, Janssen BJ, van Strijp JA, Gros P |date=July 2009 |title=Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor |journal=Nature Immunology |volume=10 |issue=7 |pages=721–7 |doi=10.1038/ni.1756 |pmc=2729104 |pmid=19503103}}</ref>
 The C3bBb complex is stabilized by binding oligomers of [[properdin|factor P]] (properdin). The stabilized C3 convertase, C3bBbP, then acts enzymatically to cleave much more C3, some of which becomes covalently attached to the same surface as C3b. This newly bound C3b recruits more B, D and P activity and greatly amplifies the complement activation. When complement is activated on a cell surface, the activation is limited by endogenous complement regulatory proteins, which include [[CD35]], [[CD46]], [[CD55]] and [[CD59]], depending on the cell. Pathogens, in general, don't have complement regulatory proteins (there are many exceptions, which reflect adaptation of microbial pathogens to vertebrate immune defenses). Thus, the alternative complement pathway is able to distinguish self from non-self on the basis of the surface expression of complement regulatory proteins. Host cells don't accumulate cell surface C3b (and the proteolytic fragment of C3b called iC3b) because this is prevented by the complement regulatory proteins, while foreign cells, pathogens and abnormal surfaces may be heavily decorated with C3b and iC3b. Accordingly, the alternative complement pathway is one element of [[innate immunity]].{{citation needed|date=May 2015}}
@@ Line 45: / Line 45: @@
 === Lectin pathway ===
 {{Main|Lectin pathway}}
-The [[lectin]] pathway is homologous to the classical pathway, but with the opsonin, [[mannose-binding lectin]] (MBL), and [[ficolin]]s, instead of C1q. This pathway is activated by binding of MBL 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 C2b then bind together to form the classical C3-convertase, as in the classical pathway. Ficolins are homologous to MBL and function via MASP in a similar way. Several single-nucleotide polymorphisms have been described in M-ficolin in humans, with effect on ligand-binding ability and serum levels. Historically, the larger fragment of C2 was named C2a, but it is now referred to as C2b.<ref>{{cite journal | vauthors = Ammitzbøll CG, Kjær TR, Steffensen R, Stengaard-Pedersen K, Nielsen HJ, Thiel S, Bøgsted M, Jensenius JC | display-authors = 6 | title = Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin | journal = PLOS ONE | volume = 7 | issue = 11 | pages = e50585 | year = 2012 | pmid = 23209787 | pmc = 3509001 | doi = 10.1371/journal.pone.0050585 | bibcode = 2012PLoSO...750585A | doi-access = free }}</ref> 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.
+The [[lectin]] pathway is homologous to the classical pathway, but with the opsonin, [[mannose-binding lectin]] (MBL), and [[ficolin]]s, instead of C1q. This pathway is activated by binding of MBL to mannose residues on the pathogen surface, which activates the MBL-associated serine proteases, [[MASP1 (protein)|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 C2b then bind together to form the classical C3-convertase, as in the classical pathway. Ficolins are homologous to MBL and function via MASP in a similar way. Several [[single-nucleotide polymorphism]]s have been described in M-ficolin in humans, with effect on ligand-binding ability and serum levels. Historically, the larger fragment of C2 was named C2a, but it is now referred to as C2b.<ref>{{Cite journal |display-authors=6 |vauthors=Ammitzbøll CG, Kjær TR, Steffensen R, Stengaard-Pedersen K, Nielsen HJ, Thiel S, Bøgsted M, Jensenius JC |year=2012 |title=Non-synonymous polymorphisms in the FCN1 gene determine ligand-binding ability and serum levels of M-ficolin |journal=PLOS ONE |volume=7 |issue=11 |pages=e50585 |bibcode=2012PLoSO...750585A |doi=10.1371/journal.pone.0050585 |pmc=3509001 |pmid=23209787 |doi-access=free}}</ref> 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.{{citation needed|date=July 2022}}
 === Complement protein fragment nomenclature ===
-Immunology textbooks have used different naming assignments for the smaller and larger fragments of C2 as C2a and C2b. The preferred assignment appears to be that the smaller fragment be designated as C2a: as early as 1994, a well known textbook recommended that the larger fragment of C2 should be designated C2b.<ref name="Janeway1994">{{cite book | vauthors = Janeway C, Travers P | date = 1994 | title = Immunobiology: The Immune System in Health and Disease | location = London; San Francisco; New York | publisher =  Current Biology Limited, Garland Publishing. Inc. | isbn = 0-8153-1691-7 }}{{page needed|date=May 2015}}</ref> However, this was amplified in their 1999 4th edition, to say that:<ref name="janeway1999">{{cite book | vauthors = Janeway CA, Travers P, Walport M, Capra JD | date = 1999 | title = Immunobiology: The Immune System in Health and Disease | edition = 4th | location = New York | publisher = Garland Publishing, Inc. | isbn = 0-8153-3217-3}}{{page needed|date=May 2015}}</ref>
+Immunology textbooks have used different naming assignments for the smaller and larger fragments of C2 as C2a and C2b. The preferred assignment appears to be that the smaller fragment be designated as C2a: as early as 1994, a well known textbook recommended that the larger fragment of C2 should be designated C2b.<ref name="Janeway1994">{{Cite book |title=Immunobiology: The Immune System in Health and Disease |vauthors=Janeway C, Travers P |date=1994 |publisher=Current Biology Limited, Garland Publishing. Inc. |isbn=0-8153-1691-7 |location=London; San Francisco; New York}}{{page needed|date=May 2015}}</ref> However, this was amplified in their 1999 4th edition, to say that:<ref name="janeway1999">{{Cite book |title=Immunobiology: The Immune System in Health and Disease |vauthors=Janeway CA, Travers P, Walport M, Capra JD |date=1999 |publisher=Garland Publishing, Inc. |isbn=0-8153-3217-3 |edition=4th |location=New York}}{{page needed|date=May 2015}}</ref>
 "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 lectin pathways the C3 convertase enzyme is formed from membrane-bound C4b with C2b."<ref name="janeway1999" />
-This nomenclature is used in another literature:<ref name="abbas">{{cite book | vauthors = Abbas AK, Lichtman AH | title = Cellular and Molecular Immunology | edition = 5th | location = Philadelphia | publisher = Saunders | isbn = 978-0-7216-0008-6 |date=May 2015 | page = 332 | quote = Note that, in older texts, the smaller fragment is often called C2b, and the larger one is called C2a for historical reasons. }}</ref>
+This nomenclature is used in another literature:<ref name="abbas">{{Cite book |title=Cellular and Molecular Immunology |vauthors=Abbas AK, Lichtman AH |date=May 2015 |publisher=Saunders |isbn=978-0-7216-0008-6 |edition=5th |location=Philadelphia |page=332 |quote=Note that, in older texts, the smaller fragment is often called C2b, and the larger one is called C2a for historical reasons.}}</ref>
 The assignment is mixed in the latter literature, though.
-Some sources designate the larger and smaller fragments as C2a and C2b respectively<ref name="Peakman">{{cite book | vauthors = Peakman M, Vergani D | date = 1997 | title = Basic and Clinical Immunology | location = New York | publisher = Churchill Livingstone | isbn = 0-443-04672-7}}{{page needed|date=May 2015}}</ref><ref>{{cite book | veditors = Paul WE | date = 1999 | title = Fundamental Immunology | edition = 4th | location = Philadelphia | publisher = Lippincott-Raven | isbn = 0-7817-1412-5}}{{page needed|date=May 2015}}</ref><ref name="Sims">{{cite book | vauthors = Sims PJ, Wiedmer T | chapter = Complement biology | veditors = Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P | date = 2000 | title = Hematology: Basic Principles and Practic | edition = 3rd | pages = 651–667 | location = New York; Edinburgh | publisher = Churchill-Livingstone | isbn = 0-443-07954-4}}</ref><ref>{{cite book | vauthors = Frank K, Atkinson JP | date = 2001 | chapter = Complement system | veditors = Austen KF, Frank K, Atkinson JP, Cantor H | title = Samter's Immunologic Diseases | edition = 6th | volume = 1 | pages = 281–298 | location = Philadelphia | publisher = Lippincott Williams & Wilkins | isbn = 0-7817-2120-2}}</ref><ref name="Roitt">{{cite book | vauthors = Roitt I, Brostoff J, Male D | date = 2001 | title = Immunology | edition = 6th | location = St. Louis | publisher = Mosby | isbn = 0-7234-3189-2}}{{page needed|date=May 2015}}</ref><ref name="anderson2003">{{cite book | vauthors = Anderson DM | date = 2003 | title = Dorland's Illustrated Medical Dictionary | edition = 30th | location = Philadelphia | publisher = W.B. Saunders | isbn = 0-7216-0146-4}}{{page needed|date=May 2015}}</ref><ref name="Parham">{{cite book | vauthors = Parham P | date = 2005 | title = The Immune System | location = New York | publisher = Garland | isbn = 0-8153-4093-1}}{{page needed|date=May 2015}}</ref><ref name="murphy2008">{{cite book | vauthors = Murphy K, Travers P, Walport M, Ehrenstein M | date = 2008 | title = Janeway's Immunobiology | edition = 7th | location = New York | publisher = Garland Science | isbn = 978-0-8153-4123-9}}{{page needed|date=May 2015}}</ref><ref name="Atkinson">{{cite book | vauthors = Atkinson JP | chapter = Complement system | veditors = Firestein GS, Budd RC, Harris Jr ED, McInnes IB, Ruddy S, Sergent JS | date = 2009 | title = Kelley's Textbook of Rheumatology | pages = 323–336 | location = Philadelphia, PA | publisher = Saunders/Elsevier | isbn = 978-1-4160-3285-4}}</ref> while other sources apply the converse.<ref name="Janeway1994" /><ref name="janeway1999" /><ref name="Janeway_2001">{{cite book | vauthors = Janeway Jr CA, Travers P, Walport M, Shlomchik MJ |title=Immunobiology |edition=5th |publisher=Garland Publishing |year=2001 |chapter=The complement system and innate immunity |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK27100/ |isbn=978-0-8153-3642-6 |url=https://archive.org/details/immunobiology00char }}</ref><ref name="doan2007">Doan T, Melvold R, Viselli S, Waltenbaugh C (2007). ''Lippincott's Illustrated Reviews: Immunology,'' 320p. Lippincott Williams & Wilkins{{page needed|date=May 2015}}</ref><ref name="DeFranco">{{cite book | vauthors = DeFranco AL, Locksley RM, Robertson M | date = 2007 | title = Immunity : The Immune Response in Infectious and Inflammatory Disease | location = London; Sunderland, MA | publisher = New Science Press; Sinauer Associates | isbn = 978-0-9539181-0-2}}{{page needed|date=May 2015}}</ref> However, due to the widely established convention, C2b here is the larger fragment, which, in the classical pathway, forms C4b2b (classically C4b2a). It may be noteworthy that, in a series of editions of Janeway's book, 1st to 7th, in the latest edition<ref name="murphy2008" /> they withdraw the stance to indicate the larger fragment of C2 as C2b.
+Some sources designate the larger and smaller fragments as C2a and C2b respectively<ref name="Peakman">{{Cite book |title=Basic and Clinical Immunology |vauthors=Peakman M, Vergani D |date=1997 |publisher=Churchill Livingstone |isbn=0-443-04672-7 |location=New York}}{{page needed|date=May 2015}}</ref><ref>{{Cite book |title=Fundamental Immunology |date=1999 |publisher=Lippincott-Raven |isbn=0-7817-1412-5 |veditors=Paul WE |edition=4th |location=Philadelphia}}{{page needed|date=May 2015}}</ref><ref name="Sims">{{Cite book |title=Hematology: Basic Principles and Practic |vauthors=Sims PJ, Wiedmer T |date=2000 |publisher=Churchill-Livingstone |isbn=0-443-07954-4 |veditors=Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P |edition=3rd |location=New York; Edinburgh |pages=651–667 |chapter=Complement biology}}</ref><ref>{{Cite book |title=Samter's Immunologic Diseases |vauthors=Frank K, Atkinson JP |date=2001 |publisher=Lippincott Williams & Wilkins |isbn=0-7817-2120-2 |veditors=Austen KF, Frank K, Atkinson JP, Cantor H |edition=6th |volume=1 |location=Philadelphia |pages=281–298 |chapter=Complement system}}</ref><ref name="Roitt">{{Cite book |title=Immunology |vauthors=Roitt I, Brostoff J, Male D |date=2001 |publisher=Mosby |isbn=0-7234-3189-2 |edition=6th |location=St. Louis}}{{page needed|date=May 2015}}</ref><ref name="anderson2003">{{Cite book |title=Dorland's Illustrated Medical Dictionary |vauthors=Anderson DM |date=2003 |publisher=W.B. Saunders |isbn=0-7216-0146-4 |edition=30th |location=Philadelphia}}{{page needed|date=May 2015}}</ref><ref name="Parham">{{Cite book |title=The Immune System |vauthors=Parham P |date=2005 |publisher=Garland |isbn=0-8153-4093-1 |location=New York}}{{page needed|date=May 2015}}</ref><ref name="murphy2008">{{Cite book |title=Janeway's Immunobiology |vauthors=Murphy K, Travers P, Walport M, Ehrenstein M |date=2008 |publisher=Garland Science |isbn=978-0-8153-4123-9 |edition=7th |location=New York}}{{page needed|date=May 2015}}</ref><ref name="Atkinson">{{Cite book |title=Kelley's Textbook of Rheumatology |vauthors=Atkinson JP |date=2009 |publisher=Saunders/Elsevier |isbn=978-1-4160-3285-4 |veditors=Firestein GS, Budd RC, Harris Jr ED, McInnes IB, Ruddy S, Sergent JS |location=Philadelphia, PA |pages=323–336 |chapter=Complement system}}</ref> while other sources apply the converse.<ref name="Janeway1994" /><ref name="janeway1999" /><ref name="Janeway_2001">{{Cite book |url=https://archive.org/details/immunobiology00char |title=Immunobiology |vauthors=Janeway Jr CA, Travers P, Walport M, Shlomchik MJ |publisher=Garland Publishing |year=2001 |isbn=978-0-8153-3642-6 |edition=5th |chapter=The complement system and innate immunity |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK27100/}}</ref><ref name="doan2007">Doan T, Melvold R, Viselli S, Waltenbaugh C (2007). ''Lippincott's Illustrated Reviews: Immunology,'' 320p. Lippincott Williams & Wilkins{{page needed|date=May 2015}}</ref><ref name="DeFranco">{{Cite book |title=Immunity : The Immune Response in Infectious and Inflammatory Disease |vauthors=DeFranco AL, Locksley RM, Robertson M |date=2007 |publisher=New Science Press; Sinauer Associates |isbn=978-0-9539181-0-2 |location=London; Sunderland, MA}}{{page needed|date=May 2015}}</ref> However, due to the widely established convention, C2b here is the larger fragment, which, in the classical pathway, forms C4b2b (classically C4b2a). It may be noteworthy that, in a series of editions of Janeway's book, 1st to 7th, in the latest edition<ref name="murphy2008" /> they withdraw the stance to indicate the larger fragment of C2 as C2b.
 === Viral inhibition ===
-Fixation of the [[mannan-binding lectin|MBL]] protein on viral surfaces has also been shown to enhance neutralization of viral pathogens.<ref>{{cite journal | vauthors = Stoermer KA, Morrison TE | title = Complement and viral pathogenesis | journal = Virology | volume = 411 | issue = 2 | pages = 362–73 | date = March 2011 | pmid = 21292294 | pmc = 3073741 | doi = 10.1016/j.virol.2010.12.045 }}</ref>
+Fixation of the [[mannan-binding lectin|MBL]] protein on viral surfaces has also been shown to enhance neutralization of viral pathogens.<ref>{{Cite journal |vauthors=Stoermer KA, Morrison TE |date=March 2011 |title=Complement and viral pathogenesis |journal=Virology |volume=411 |issue=2 |pages=362–73 |doi=10.1016/j.virol.2010.12.045 |pmc=3073741 |pmid=21292294}}</ref>
 === Review ===
@@ Line 75: / Line 75: @@
 In the classical pathway, C1 binds with its C1q subunits to Fc fragments (made of CH2 region) of IgG or IgM, which has formed a complex with antigens. C4b and C3b are also able to bind to antigen-associated IgG or IgM, to its Fc portion.<ref name="abbas" /><ref name="Roitt" /><ref name="murphy2008" />
-Such immunoglobulin-mediated binding of the complement may be interpreted as that the complement uses the ability of the immunoglobulin to detect and bind to non-self antigens as its guiding stick. The complement itself can bind non-self pathogens after detecting their [[pathogen-associated molecular patterns]] (PAMPs),<ref name="murphy2008" /> however, utilizing specificity of the antibody, complements can detect non-self targets much more specifically.
+Such immunoglobulin-mediated binding of the complement may be interpreted as that the complement uses the ability of the immunoglobulin to detect and bind to non-self antigens as its guiding stick. The complement itself can bind non-self pathogens after detecting their [[pathogen-associated molecular patterns]] (PAMPs),<ref name="murphy2008" /> however, utilizing specificity of the antibody, complements can detect non-self targets much more specifically.{{citation needed|date=July 2022}}
 Some components have a variety of binding sites. In the classical pathway, C4 binds to Ig-associated C1q and C1r<sup>2</sup>s<sup>2</sup> enzyme cleaves C4 to C4b and 4a. C4b binds to C1q, antigen-associated Ig (specifically to its Fc portion), and even to the microbe surface. C3b binds to antigen-associated Ig and to the microbe surface. Ability of C3b to bind to antigen-associated Ig would work effectively against antigen-antibody complexes to make them soluble.{{citation needed|date=May 2015}}
 == Regulation ==
-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 protein]]s, which are present at blood plasma and host cell membrane.<ref>{{cite journal | vauthors = Zewde N, Gorham RD, Dorado A, Morikis D | title = Quantitative Modeling of the Alternative Pathway of the Complement System | journal = PLOS ONE | volume = 11 | issue = 3 | pages = e0152337 | date = 2016-03-31 | pmid = 27031863 | pmc = 4816337 | doi = 10.1371/journal.pone.0152337 | bibcode = 2016PLoSO..1152337Z | doi-access = free }}</ref> 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 polymerization during the formation of the [[membrane attack complex]]. The classical pathway is inhibited by [[C1-inhibitor]], which binds to C1 to prevent its activation.<ref name=":2">{{cite journal | vauthors = Bajic G, Degn SE, Thiel S, Andersen GR | title = Complement activation, regulation, and molecular basis for complement-related diseases | journal = The EMBO Journal | volume = 34 | issue = 22 | pages = 2735–2757 | date = November 2015 | pmid = 26489954 | pmc = 4682646 | doi = 10.15252/embj.201591881 }}</ref>
+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 protein]]s, which are present at blood plasma and host cell membrane.<ref>{{Cite journal |vauthors=Zewde N, Gorham RD, Dorado A, Morikis D |date=2016-03-31 |title=Quantitative Modeling of the Alternative Pathway of the Complement System |journal=PLOS ONE |volume=11 |issue=3 |pages=e0152337 |bibcode=2016PLoSO..1152337Z |doi=10.1371/journal.pone.0152337 |pmc=4816337 |pmid=27031863 |doi-access=free}}</ref> 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 polymerization during the formation of the [[membrane attack complex]]. The classical pathway is inhibited by [[C1-inhibitor]], which binds to C1 to prevent its activation.<ref name=":2">{{Cite journal |vauthors=Bajic G, Degn SE, Thiel S, Andersen GR |date=November 2015 |title=Complement activation, regulation, and molecular basis for complement-related diseases |journal=The EMBO Journal |volume=34 |issue=22 |pages=2735–2757 |doi=10.15252/embj.201591881 |pmc=4682646 |pmid=26489954}}</ref>  Another example, is a plasma protein called, [[Factor H]] (FH), which has a key role in down-regulating the alternative pathway.<ref>{{Cite journal |display-authors=6 |vauthors=Zhang Y, Ghiringhelli Borsa N, Shao D, Dopler A, Jones MB, Meyer NC, Pitcher GR, Taylor AO, Nester CM, Schmidt CQ, Smith RJ |date=2020-12-15 |title=Factor H Autoantibodies and Complement-Mediated Diseases |journal=Frontiers in Immunology |volume=11 |pages=607211 |doi=10.3389/fimmu.2020.607211 |pmc=7770156 |pmid=33384694 |doi-access=free}}</ref>  Factor H, along with another protein called [[Complement factor I|Factor I]], inactivates C3b, the active form of C3. This process prevents the formation of C3 convertase and halts the progression of the complement cascade. C3-convertase also can be inhibited by [[decay accelerating factor]] (DAF), which is bound to erythrocyte plasma membranes via a [[Glycophosphatidylinositol|GPI]] anchor.<ref name=":2" />
-C3-convertase can be inhibited by [[decay accelerating factor]] (DAF), which is bound to erythrocyte plasma membranes via a [[Glycophosphatidylinositol|GPI]] anchor.<ref name=":2" />
 == Role in disease ==
@@ Line 88: / Line 86: @@
 === Complement deficiency ===
 {{Main|Complement deficiency}}
-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]], [[paroxysmal nocturnal hemoglobinuria]], [[atypical hemolytic uremic syndrome]] and ischemia-reperfusion injuries,<ref name="pmid 15087815">{{cite journal | vauthors = Arumugam TV, Shiels IA, Woodruff TM, Granger DN, Taylor SM | title = The role of the complement system in ischemia-reperfusion injury | journal = Shock | volume = 21 | issue = 5 | pages = 401–9 | date = May 2004 | pmid = 15087815 | doi = 10.1097/00024382-200405000-00002 | s2cid = 36655599 }}</ref><ref name="pmid19443638">{{cite journal | vauthors = Naesens M, Li L, Ying L, Sansanwal P, Sigdel TK, Hsieh SC, Kambham N, Lerut E, Salvatierra O, Butte AJ, Sarwal MM | display-authors = 6 | title = Expression of complement components differs between kidney allografts from living and deceased donors | journal = Journal of the American Society of Nephrology | volume = 20 | issue = 8 | pages = 1839–51 | date = August 2009 | pmid = 19443638 | pmc = 2723986 | doi = 10.1681/ASN.2008111145 }}</ref> and rejection of transplanted organs.<ref name="pmid 14499254">{{cite journal | vauthors = Sacks SH, Chowdhury P, Zhou W | title = Role of the complement system in rejection | journal = Current Opinion in Immunology | volume = 15 | issue = 5 | pages = 487–92 | date = October 2003 | pmid = 14499254 | doi = 10.1016/S0952-7915(03)00100-6 }}</ref>
+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]], [[paroxysmal nocturnal hemoglobinuria]], [[atypical hemolytic uremic syndrome]] and ischemia-reperfusion injuries,<ref name="pmid 15087815">{{Cite journal |vauthors=Arumugam TV, Shiels IA, Woodruff TM, Granger DN, Taylor SM |date=May 2004 |title=The role of the complement system in ischemia-reperfusion injury |journal=Shock |volume=21 |issue=5 |pages=401–9 |doi=10.1097/00024382-200405000-00002 |pmid=15087815 |s2cid=36655599 |doi-access=free}}</ref><ref name="pmid19443638">{{Cite journal |display-authors=6 |vauthors=Naesens M, Li L, Ying L, Sansanwal P, Sigdel TK, Hsieh SC, Kambham N, Lerut E, Salvatierra O, Butte AJ, Sarwal MM |date=August 2009 |title=Expression of complement components differs between kidney allografts from living and deceased donors |journal=Journal of the American Society of Nephrology |volume=20 |issue=8 |pages=1839–51 |doi=10.1681/ASN.2008111145 |pmc=2723986 |pmid=19443638}}</ref> and rejection of transplanted organs.<ref name="pmid 14499254">{{Cite journal |vauthors=Sacks SH, Chowdhury P, Zhou W |date=October 2003 |title=Role of the complement system in rejection |journal=Current Opinion in Immunology |volume=15 |issue=5 |pages=487–92 |doi=10.1016/S0952-7915(03)00100-6 |pmid=14499254}}</ref>
+Complement regulation is suggested to play a role in pregnancy. Improper alternative complement pathway activation may mediate recurrent immune-mediated fetal loss.<ref>{{Cite journal |last1=Thurman |first1=Joshua M. |last2=Holers |first2=V. Michael |date=2006-02-01 |title=The Central Role of the Alternative Complement Pathway in Human Disease |url=https://journals.aai.org/jimmunol/article/176/3/1305/37524/The-Central-Role-of-the-Alternative-Complement |journal=The Journal of Immunology |language=en |volume=176 |issue=3 |pages=1305–1310 |doi=10.4049/jimmunol.176.3.1305 |pmid=16424154 |issn=0022-1767}}</ref><ref>{{Cite journal |last1=Mellor |first1=Andrew L. |last2=Sivakumar |first2=Jayabalan |last3=Chandler |first3=Phillip |last4=Smith |first4=Kimberly |last5=Molina |first5=Hector |last6=Mao |first6=Dailing |last7=Munn |first7=David H. |date=January 2001 |title=Prevention of T cell–driven complement activation and inflammation by tryptophan catabolism during pregnancy |url=https://www.nature.com/articles/ni0101_64 |journal=Nature Immunology |language=en |volume=2 |issue=1 |pages=64–68 |doi=10.1038/83183 |issn=1529-2908}}</ref>
-The complement system is also becoming increasingly implicated in diseases of the central nervous system such as [[Alzheimer's disease]] and other neurodegenerative conditions such as spinal cord injuries.<ref>{{cite journal | vauthors = Galvan MD, Luchetti S, Burgos AM, Nguyen HX, Hooshmand MJ, Hamers FP, Anderson AJ | title = Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury | journal = The Journal of Neuroscience | volume = 28 | issue = 51 | pages = 13876–88 | date = December 2008 | pmid = 19091977 | pmc = 2680920 | doi = 10.1523/JNEUROSCI.2823-08.2008 }}</ref><ref>{{cite journal | vauthors = Nguyen HX, Galvan MD, Anderson AJ | title = Characterization of early and terminal complement proteins associated with polymorphonuclear leukocytes in vitro and in vivo after spinal cord injury | journal = Journal of Neuroinflammation | volume = 5 | pages = 26 | date = June 2008 | pmid = 18578885 | pmc = 2443364 | doi = 10.1186/1742-2094-5-26 }}</ref><ref>{{cite journal | vauthors = Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ | title = Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment | journal = Brain | volume = 133 | issue = Pt 2 | pages = 433–47 | date = February 2010 | pmid = 20085927 | pmc = 2858013 | doi = 10.1093/brain/awp322 }}</ref>
+The complement system is also becoming increasingly implicated in diseases of the central nervous system such as [[Alzheimer's disease]] and other neurodegenerative conditions such as spinal cord injuries.<ref>{{Cite journal |vauthors=Galvan MD, Luchetti S, Burgos AM, Nguyen HX, Hooshmand MJ, Hamers FP, Anderson AJ |date=December 2008 |title=Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury |journal=The Journal of Neuroscience |volume=28 |issue=51 |pages=13876–88 |doi=10.1523/JNEUROSCI.2823-08.2008 |pmc=2680920 |pmid=19091977}}</ref><ref>{{Cite journal |vauthors=Nguyen HX, Galvan MD, Anderson AJ |date=June 2008 |title=Characterization of early and terminal complement proteins associated with polymorphonuclear leukocytes in vitro and in vivo after spinal cord injury |journal=Journal of Neuroinflammation |volume=5 |pages=26 |doi=10.1186/1742-2094-5-26 |pmc=2443364 |pmid=18578885 |doi-access=free}}</ref><ref>{{Cite journal |vauthors=Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ |date=February 2010 |title=Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment |journal=Brain |volume=133 |issue=Pt 2 |pages=433–47 |doi=10.1093/brain/awp322 |pmc=2858013 |pmid=20085927}}</ref>
-Deficiencies of the terminal pathway predispose to both [[autoimmune disease]] and [[infection]]s (particularly [[Neisseria meningitidis]], due to the role that the [[membrane attack complex]] ("MAC") plays in attacking [[Gram-negative]] bacteria).<ref>{{Cite book|title=Bacteria and Complement|volume = 121| vauthors = Brown EJ |date=1985|publisher=Springer, Berlin, Heidelberg|isbn=9783642456060|series=Current Topics in Microbiology and Immunology|pages=159–187|language=en|doi=10.1007/978-3-642-45604-6_8|chapter = Interaction of Gram-Positive Microorganisms with Complement|pmid = 3936681}}</ref>
+Deficiencies of the terminal pathway predispose to both [[autoimmune disease]] and [[infection]]s (particularly [[Neisseria meningitidis]], due to the role that the [[membrane attack complex]] ("MAC") plays in attacking [[Gram-negative]] bacteria).<ref>{{Cite book |title=Bacteria and Complement |vauthors=Brown EJ |date=1985 |publisher=Springer, Berlin, Heidelberg |isbn=9783642456060 |series=Current Topics in Microbiology and Immunology |volume=121 |pages=159–187 |language=en |chapter=Interaction of Gram-Positive Microorganisms with Complement |doi=10.1007/978-3-642-45604-6_8 |pmid=3936681}}</ref>
-Infections with ''N. meningitidis'' and ''[[N. gonorrhoeae]]'' are the only conditions known to be associated with deficiencies in the MAC components of complement.<ref name="Ram2010">{{cite journal | vauthors = Ram S, Lewis LA, Rice PA | title = Infections of people with complement deficiencies and patients who have undergone splenectomy | journal = Clinical Microbiology Reviews | volume = 23 | issue = 4 | pages = 740–80 | date = October 2010 | pmid = 20930072 | pmc = 2952982 | doi = 10.1128/CMR.00048-09 }}</ref>  40–50% of those with MAC deficiencies experience recurrent infections with ''N. meningitidis''.<ref name="Lewis2014">{{cite journal | vauthors = Lewis LA, Ram S | title = Meningococcal disease and the complement system | journal = Virulence | volume = 5 | issue = 1 | pages = 98–126 | date = January 2014 | pmid = 24104403 | pmc = 3916388 | doi = 10.4161/viru.26515 }}</ref>
+Infections with ''N. meningitidis'' and ''[[N. gonorrhoeae]]'' are the only conditions known to be associated with deficiencies in the MAC components of complement.<ref name="Ram2010">{{Cite journal |vauthors=Ram S, Lewis LA, Rice PA |date=October 2010 |title=Infections of people with complement deficiencies and patients who have undergone splenectomy |journal=Clinical Microbiology Reviews |volume=23 |issue=4 |pages=740–80 |doi=10.1128/CMR.00048-09 |pmc=2952982 |pmid=20930072}}</ref>  40–50% of those with MAC deficiencies experience recurrent infections with ''N. meningitidis''.<ref name="Lewis2014">{{Cite journal |vauthors=Lewis LA, Ram S |date=January 2014 |title=Meningococcal disease and the complement system |journal=Virulence |volume=5 |issue=1 |pages=98–126 |doi=10.4161/viru.26515 |pmc=3916388 |pmid=24104403}}</ref>
 === Deficiencies in complement regulators ===
-Mutations in the genes of complement regulators, especially [[factor H]], have been associated with atypical [[hemolytic uremic syndrome]],<ref name=":0" /><ref name="pmid16189652">{{cite journal | vauthors = Dragon-Durey MA, Frémeaux-Bacchi V | title = Atypical haemolytic uraemic syndrome and mutations in complement regulator genes | journal = Springer Seminars in Immunopathology | volume = 27 | issue = 3 | pages = 359–74 | date = November 2005 | pmid = 16189652 | doi = 10.1007/s00281-005-0003-2 | s2cid = 6330326 }}</ref><ref name="pmid16575689">{{cite journal | vauthors = Zipfel PF, Misselwitz J, Licht C, Skerka C | title = The role of defective complement control in hemolytic uremic syndrome | journal = Seminars in Thrombosis and Hemostasis | volume = 32 | issue = 2 | pages = 146–54 | date = March 2006 | pmid = 16575689 | doi = 10.1055/s-2006-939770 }}</ref> and C3 glomerulopathy.<ref name=":0" /> Moreover, several [[single nucleotide polymorphism]]s and mutations in the complement factor H gene (the most common of which results in the protein change p.Y402H) have been associated with the common eye disease [[age-related macular degeneration]].<ref name=":0" /> Polymorphisms of [[complement component 3]], [[complement factor B]], and [[complement factor I]], as well as deletion of complement factor H-related 3 and complement factor H-related 1, also affect a person's risk of developing [[age-related macular degeneration]].<ref name=":0" /><ref name="BradleyDT2011">{{cite journal | vauthors = Bradley DT, Zipfel PF, Hughes AE | title = Complement in age-related macular degeneration: a focus on function | journal = Eye | volume = 25 | issue = 6 | pages = 683–93 | date = June 2011 | pmid = 21394116 | pmc = 3178140 | doi = 10.1038/eye.2011.37 }}</ref> Both of these disorders are currently thought to be due to complement overactivation either on the surface of host cells or in plasma, with the molecular location of genetic variation in complement proteins providing clues into the underlying disease processes.<ref name=":0" />
+Mutations in the genes of complement regulators, especially [[factor H]], have been associated with atypical [[hemolytic uremic syndrome]],<ref name=":0" /><ref name="pmid16189652">{{Cite journal |vauthors=Dragon-Durey MA, Frémeaux-Bacchi V |date=November 2005 |title=Atypical haemolytic uraemic syndrome and mutations in complement regulator genes |journal=Springer Seminars in Immunopathology |volume=27 |issue=3 |pages=359–74 |doi=10.1007/s00281-005-0003-2 |pmid=16189652 |s2cid=6330326}}</ref><ref name="pmid16575689">{{Cite journal |vauthors=Zipfel PF, Misselwitz J, Licht C, Skerka C |date=March 2006 |title=The role of defective complement control in hemolytic uremic syndrome |journal=Seminars in Thrombosis and Hemostasis |volume=32 |issue=2 |pages=146–54 |doi=10.1055/s-2006-939770 |pmid=16575689 |s2cid=260316508}}</ref> and C3 glomerulopathy.<ref name=":0" /> Both of these disorders are currently thought to be due to complement overactivation either on the surface of host cells or in plasma, with the molecular location of genetic variation in complement proteins providing clues into the underlying disease processes.<ref name=":0" /> Moreover, several [[single nucleotide polymorphism]]s and mutations in the complement factor H gene (the most common of which results in the protein change p.Y402H) have been associated with the common eye disease [[age-related macular degeneration]].<ref name=":0" /> Polymorphisms of [[complement component 3]], [[complement factor B]], and [[complement factor I]], as well as deletion of complement factor H-related 3 and complement factor H-related 1, also affect a person's risk of developing [[age-related macular degeneration]].<ref name=":0" /><ref name="BradleyDT2011">{{Cite journal |vauthors=Bradley DT, Zipfel PF, Hughes AE |date=June 2011 |title=Complement in age-related macular degeneration: a focus on function |journal=Eye |volume=25 |issue=6 |pages=683–93 |doi=10.1038/eye.2011.37 |pmc=3178140 |pmid=21394116}}</ref>
 Mutations in the C1 inhibitor gene can cause [[hereditary angioedema]], a genetic condition resulting from reduced regulation of [[bradykinin]] by C1-INH.{{citation needed|date=May 2015}}
-[[Paroxysmal nocturnal hemoglobinuria]] is caused by complement breakdown of RBCs due to an inability to make GPI. Thus the RBCs are not protected by GPI anchored proteins such as DAF.<ref>{{cite journal | vauthors = Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socié G | display-authors = 6 | title = Diagnosis and management of paroxysmal nocturnal hemoglobinuria | journal = Blood | volume = 106 | issue = 12 | pages = 3699–709 | date = December 2005 | pmid = 16051736 | pmc = 1895106 | doi = 10.1182/blood-2005-04-1717 }}</ref>
+[[Paroxysmal nocturnal hemoglobinuria]] is caused by complement breakdown of [[Red blood cell|RBC]]s due to an inability to make GPI. Thus the RBCs are not protected by GPI anchored proteins such as DAF.<ref>{{Cite journal |display-authors=6 |vauthors=Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socié G |date=December 2005 |title=Diagnosis and management of paroxysmal nocturnal hemoglobinuria |journal=Blood |volume=106 |issue=12 |pages=3699–709 |doi=10.1182/blood-2005-04-1717 |pmc=1895106 |pmid=16051736}}</ref>
 === Diagnostic tools ===
-Diagnostic tools to measure complement activity include the [[total complement activity]] test.<ref>{{Cite web|url=https://emedicine.medscape.com/article/135478-workup|title=Complement Deficiencies Workup: Laboratory Studies, Imaging Studies, Other Tests|website=emedicine.medscape.com|language=en|access-date=2018-04-26}}</ref>
+Diagnostic tools to measure complement activity include the [[total complement activity]] test.<ref>{{Cite web |title=Complement Deficiencies Workup: Laboratory Studies, Imaging Studies, Other Tests |url=https://emedicine.medscape.com/article/135478-workup |access-date=2018-04-26 |website=emedicine.medscape.com |language=en}}</ref>
+The presence or absence of complement fixation upon a challenge can indicate whether particular antigens or antibodies are present in the blood. This is the principle of the [[complement fixation test]].{{cn|date=July 2024}}
+== Modulation of the body by complement with infection ==
-The presence or absence of complement fixation upon a challenge can indicate whether particular antigens or antibodies are present in the blood. This is the principle of the [[complement fixation test]].
+Excessive complement activity contributes to severe Covid-19 symptoms and disease.<ref>{{Cite journal |vauthors=Afzali B, Noris M, Lambrecht BN, Kemper C |date=February 2022 |title=The state of complement in COVID-19 |journal=Nature Reviews. Immunology |volume=22 |issue=2 |pages=77–84 |doi=10.1038/s41577-021-00665-1 |pmc=8672651 |pmid=34912108}}</ref>  Although complement is intended to protect the body systems, under stress there can be more damage than protection. Research has suggested that the complement system is manipulated during [[Human Immunodeficiency Virus|HIV]]/[[Acquired Immunodeficiency Syndrome|AIDS]], in a way that further damages the body.<ref>{{Cite journal |vauthors=Datta PK, Rappaport J |date=November 2006 |title=HIV and complement: hijacking an immune defense |journal=Biomedicine & Pharmacotherapy |volume=60 |issue=9 |pages=561–568 |doi=10.1016/j.biopha.2006.07.087 |pmid=16978830}}</ref>
-== Modulation by infections ==
+== Role in the brain ==
+Research from over the last decade has shown that complement proteins of the classical complement pathway have an important role in [[synaptic pruning]] in the brain during early development.<ref>{{Cite journal |display-authors=6 |vauthors=Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B |date=May 2012 |title=Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner |journal=Neuron |volume=74 |issue=4 |pages=691–705 |doi=10.1016/j.neuron.2012.03.026 |pmc=3528177 |pmid=22632727}}</ref><ref>{{Cite journal |vauthors=Gomez-Arboledas A, Acharya MM, Tenner AJ |date=September 2021 |title=The Role of Complement in Synaptic Pruning and Neurodegeneration |journal=ImmunoTargets and Therapy |volume=10 |pages=373–386 |doi=10.2147/ITT.S305420 |pmc=8478425 |pmid=34595138 |doi-access=free}}</ref>
-Recent research has suggested that the complement system is manipulated during [[Human Immunodeficiency Virus|HIV]]/[[Acquired Immunodeficiency Syndrome|AIDS]], in a way that further damages the body.<ref>{{cite journal | vauthors = Datta PK, Rappaport J | title = HIV and complement: hijacking an immune defense | journal = Biomedicine & Pharmacotherapy | volume = 60 | issue = 9 | pages = 561–8 | date = November 2006 | pmid = 16978830 | doi = 10.1016/j.biopha.2006.07.087 }}</ref>
 == References ==