Wikipedia

Complement system

This article is about an aspect of the immune system. For other uses, seeComplement.

Thecomplement system,also known ascomplement cascade,is a part of thehumoral,innate immune systemand enhances (complements) the ability ofantibodiesandphagocytic cellsto clearmicrobesand damaged cells from an organism, promoteinflammation,and attack thepathogen'scell membrane.[1]Despite being part of the innate immune system, the complement system can be recruited and brought into action by antibodies generated by theadaptive immune system.

Scheme of the complement system

The complement system consists of a number of small, inactive, liver synthesizedprotein precursorscirculating in theblood.When stimulated by one of several triggers,proteasesin the systemcleave specific proteinsto releasecytokinesand initiate an amplifying cascade of further cleavages. The end result of thiscomplement activationorcomplement fixationcascade is stimulation ofphagocytesto clear foreign and damaged material,inflammationto attract additional phagocytes, andactivationof the cell-killingmembrane attack complex.About 50 proteins and protein fragments make up the complement system, includingplasma proteins,andcell membrane receptors.They account for about 10% of theglobulinfraction of blood serum.[2]

Three biochemical pathways activate the complement system: theclassical complement pathway,thealternative complement pathway,and thelectin 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

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In 1888,George Nuttallfound that sheep bloodserumhad mild killing activity against thebacteriumthat causesanthrax.[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 fromcholerakilled the cholera bacteriumin 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 youngBelgianscientist inParisat thePasteur 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 Ehrlichrenamed 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 recognizeantigens.Upon immunization with anantigen,more of these receptors are formed, and they are then shed from the cells to circulate in the blood. Thosereceptors,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

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Membrane attack complex (Terminal Complement Complex C5b-9)

Complement triggers the following immune functions:[12]

  1. Membrane attack– by rupturing thecell wallofbacteria.(classical complement pathway)
  2. Phagocytosis– byopsonizingantigens. C3b has most important opsonizing activity. (alternative complement pathway)
  3. Inflammation– by attractingmacrophagesandneutrophils.(lectin pathway)

Overview

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Most of theproteinsandglycoproteinsthat constitute the complement system are synthesized byhepatocytes.But significant amounts are also produced by tissuemacrophages,bloodmonocytes,andepithelial cellsof thegenitourinary systemandgastrointestinal tract.The three pathways of activation all generate homologous variants of theproteaseC3-convertase.The classical complement pathway typically requiresantigen-antibody complexesfor activation (specific immune response), whereas the alternative pathway can be activated by spontaneouscomplement component 3(C3) hydrolysis, foreign material, pathogens, or damaged cells. Themannose-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 byphagocytic cellsbyopsonization.[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 convertaseis also formed by the classical pathway when C3b binds C4b and C2b.C5ais an importantchemotactic protein,helping recruit inflammatory cells. C3a is the precursor of an importantcytokine(adipokine) namedASP(although this is not universally accepted[13]) and is usually rapidly cleaved bycarboxypeptidase B.Both C3a and C5a haveanaphylatoxinactivity, directly triggeringdegranulationofmast cellsas well as increasing vascular permeability andsmooth musclecontraction.[13]C5b initiates themembrane attack pathway,which results in themembrane attack complex(MAC), consisting of C5b,C6,C7,C8,and polymericC9.[14]MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causesosmoticlysis of the target cell.Kupffer cellsand 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 theprotostomehorseshoe crabspecies, putting the origins of the system back further than was previously thought.[citation needed]

Reaction cascade of the complement system: classical, alternative, and lectin pathways, amplification loop, terminal pathway, and membrane attack complex.

Classical pathway

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Main article:Classical complement pathway
The classical and alternative complement pathways

Theclassical pathwayis triggered by activation of the C1-complex. TheC1-complexis composed of 1 molecule ofC1q,2 molecules of C1r and 2 molecules of C1s, orC1qr2s2.This occurs when C1q binds toIgMorIgGcomplexed withantigens.A single pentameric IgM can initiate the pathway, while several, ideally six, IgGs are needed. This also occurs whenC1qbinds directly to the surface of the pathogen. Such binding leads to conformational changes in the C1q molecule, which leads to the activation of twoC1rmolecules. C1r is a serine protease. They then cleaveC1s(another serine protease). The C1r2s2component now splitsC4and thenC2,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

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Main article:Alternative complement pathway

Thealternative pathwayis continuously activated at a low level, analogous to a car engine at idle, as a result of spontaneousC3hydrolysis due to the breakdown of the internalthioesterbond (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 byfactor Handfactor 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 bindfactor Bto form C3bB. This complex in the presence offactor Dwill 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 offactor 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 includeCD35,CD46,CD55andCD59,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 ofinnate 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 potentanaphylatoxin,and C5b. The C5b then recruits and assembles C6, C7, C8 and multiple C9 molecules to assemble themembrane attack complex.This creates a hole or pore in the membrane that can kill or damage the pathogen or cell.[1]

Lectin pathway

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Main article:Lectin pathway

Thelectinpathway is homologous to the classical pathway, but with the opsonin,mannose-binding lectin(MBL), andficolins,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. Severalsingle-nucleotide polymorphismshave 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

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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 complementb,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

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Fixation of theMBLprotein on viral surfaces has also been shown to enhance neutralization of viral pathogens.[33]

Review

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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

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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 theirpathogen-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 C1r2s2enzyme 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

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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 bycomplement 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 isCD59,also known as protectin, which inhibits C9 polymerization during the formation of themembrane attack complex.The classical pathway is inhibited byC1-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 calledFactor 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 bydecay accelerating factor(DAF), which is bound to erythrocyte plasma membranes via aGPIanchor.[35]

Role in disease

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Complement deficiency

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Main article:Complement deficiency

It is thought that the complement system might play a role in many diseases with an immune component, such asBarraquer–Simons syndrome,asthma,lupus erythematosus,glomerulonephritis,various forms ofarthritis,autoimmune heart disease,multiple sclerosis,inflammatory bowel disease,paroxysmal nocturnal hemoglobinuria,atypical hemolytic uremic syndromeand 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 asAlzheimer's diseaseand other neurodegenerative conditions such as spinal cord injuries.[42][43][44]

Deficiencies of the terminal pathway predispose to bothautoimmune diseaseandinfections(particularlyNeisseria meningitidis,due to the role that themembrane attack complex( "MAC" ) plays in attackingGram-negativebacteria).[45]

Infections withN. meningitidisandN. gonorrhoeaeare 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 withN. meningitidis.[47]

Deficiencies in complement regulators

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Mutations in the genes of complement regulators, especiallyfactor H,have been associated with atypicalhemolytic 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, severalsingle nucleotide polymorphismsand 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 diseaseage-related macular degeneration.[4]Polymorphisms ofcomplement component 3,complement factor B,andcomplement 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 developingage-related macular degeneration.[4][50]

Mutations in the C1 inhibitor gene can causehereditary angioedema,a genetic condition resulting from reduced regulation ofbradykininby C1-INH.[citation needed]

Paroxysmal nocturnal hemoglobinuriais caused by complement breakdown ofRBCsdue to an inability to make GPI. Thus the RBCs are not protected by GPI anchored proteins such as DAF.[51]

Diagnostic tools

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Diagnostic tools to measure complement activity include thetotal complement activitytest.[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 thecomplement fixation test.[citation needed]

Modulation of the body by complement with infection

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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 duringHIV/AIDS,in a way that further damages the body.[54]

Role in the brain

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

References

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  1. ^abJaneway 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.Retrieved25 February2013.
  2. ^Glovsky MM (9 November 2019). Talavera F, Dreskin SC, Kaliner MA (eds.)."Complement-Related Disorders: Background, Pathophysiology, Activation".Medscape.
  3. ^abAbbas AK, Lichtman AH, Pillai S (2010).Cellular and Molecular Immunology(6th ed.). Elsevier. pp.272–288.ISBN978-1-4160-3123-9.
  4. ^abcdefTzoumas 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.PMID33157112.S2CID226274874.
  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 translationhere
  6. ^abChaplin H (2020)."Review: the burgeoning history of the complement system 1888-2005".Immunohematology.21(3): 85–93.doi:10.21307/immunohematology-2019-398.PMID16178664.
  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. ^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.PMC3956958.PMID24672678.
  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.PMID18563076.S2CID205359637.
  12. ^Murphy K, Weaver C (2017). "Innate Immunity: the First Lines of Defense".Janeway's Immunobiology(9th ed.). Garland Science. p. 49.ISBN978-0-8153-4505-3.
  13. ^abKlos 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.PMID23383423.
  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.ISBN978-0-9631172-1-2.PMID21413267.
  15. ^"Classical Pathway (CP)".www.complementsystem.se.Euro Diagnostica. Archived fromthe originalon 2 June 2016.Retrieved6 June2022.
  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.PMC2729104.PMID19503103.
  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.PMC3509001.PMID23209787.
  18. ^abJaneway C, Travers P (1994).Immunobiology: The Immune System in Health and Disease.London; San Francisco; New York: Current Biology Limited, Garland Publishing. Inc.ISBN0-8153-1691-7.[page needed]
  19. ^abcJaneway CA, Travers P, Walport M, Capra JD (1999).Immunobiology: The Immune System in Health and Disease(4th ed.). New York: Garland Publishing, Inc.ISBN0-8153-3217-3.[page needed]
  20. ^abAbbas AK, Lichtman AH (May 2015).Cellular and Molecular Immunology(5th ed.). Philadelphia: Saunders. p. 332.ISBN978-0-7216-0008-6.Note that, in older texts, the smaller fragment is often called C2b, and the larger one is called C2a for historical reasons.
  21. ^Peakman M, Vergani D (1997).Basic and Clinical Immunology.New York: Churchill Livingstone.ISBN0-443-04672-7.[page needed]
  22. ^Paul WE, ed. (1999).Fundamental Immunology(4th ed.). Philadelphia: Lippincott-Raven.ISBN0-7817-1412-5.[page needed]
  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.ISBN0-443-07954-4.
  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.ISBN0-7817-2120-2.
  25. ^abRoitt I, Brostoff J, Male D (2001).Immunology(6th ed.). St. Louis: Mosby.ISBN0-7234-3189-2.[page needed]
  26. ^Anderson DM (2003).Dorland's Illustrated Medical Dictionary(30th ed.). Philadelphia: W.B. Saunders.ISBN0-7216-0146-4.[page needed]
  27. ^Parham P (2005).The Immune System.New York: Garland.ISBN0-8153-4093-1.[page needed]
  28. ^abcdMurphy K, Travers P, Walport M, Ehrenstein M (2008).Janeway's Immunobiology(7th ed.). New York: Garland Science.ISBN978-0-8153-4123-9.[page needed]
  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.ISBN978-1-4160-3285-4.
  30. ^Janeway Jr CA, Travers P, Walport M, Shlomchik MJ (2001)."The complement system and innate immunity".Immunobiology(5th ed.). Garland Publishing.ISBN978-0-8153-3642-6.
  31. ^Doan T, Melvold R, Viselli S, Waltenbaugh C (2007).Lippincott's Illustrated Reviews: Immunology,320p. Lippincott Williams & Wilkins[page needed]
  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.ISBN978-0-9539181-0-2.[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.PMC3073741.PMID21292294.
  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.PMC4816337.PMID27031863.
  35. ^abBajic 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.PMC4682646.PMID26489954.
  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.PMC7770156.PMID33384694.
  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.PMID15087815.S2CID36655599.
  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.PMC2723986.PMID19443638.
  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.PMID14499254.
  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.ISSN0022-1767.PMID16424154.
  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.ISSN1529-2908.
  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.PMC2680920.PMID19091977.
  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.PMC2443364.PMID18578885.
  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.PMC2858013.PMID20085927.
  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.ISBN9783642456060.PMID3936681.
  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.PMC2952982.PMID20930072.
  47. ^Lewis LA, Ram S (January 2014)."Meningococcal disease and the complement system".Virulence.5(1): 98–126.doi:10.4161/viru.26515.PMC3916388.PMID24104403.
  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.PMID16189652.S2CID6330326.
  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.PMID16575689.S2CID260316508.
  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.PMC3178140.PMID21394116.
  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.PMC1895106.PMID16051736.
  52. ^"Complement Deficiencies Workup: Laboratory Studies, Imaging Studies, Other Tests".emedicine.medscape.com.Retrieved2018-04-26.
  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.PMC8672651.PMID34912108.
  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.PMID16978830.
  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.PMC3528177.PMID22632727.
  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.PMC8478425.PMID34595138.
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