Editing Complement system (section)

== Overview ==
[[File:Complement Cascade.png|thumb]]

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 |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 pathways, amplification loop, terminal pathway, and membrane attack complex.]]

=== Classical pathway ===
{{Main|Classical complement pathway}}
[[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 |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 |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}}

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.<ref name=":1" />

=== 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, [[MASP1 (protein)|MASP-1]], and [[MASP2 (protein)|MASP-2]] (very similar to [[Complement component 1r|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 |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 |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 |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 |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 ===
{| class="wikitable"
|-
! 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 || colspan="3" | C5b+C6+C7+C8+C9
|}