Classical complement pathway: Difference between revisions

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The '''classical complement pathway''' is one of three pathways which activate the [[complement system]], which is part of the [[immune system]]. The classical complement pathway is initiated by [[antigen-antibody complex]]es with the antibody isotypes [[Immunoglobulin G|IgG]] and [[Immunoglobulin M|IgM]].<ref name="Overview of Complement" /><ref name="Complement in disease" />

Following activation, a series of [[protein]]s are recruited to generate [[C3-convertase|C3 convertase]] (C4bC2aC4bC2b), which cleaves the [[Complement component 3|C3]] protein. The [[C3b]] component of the cleaved C3 binds to C3 convertase (C4bC2aC4bC2b) to generate [[C5-convertase|C5 convertase]] (C4bC2aC3bC4bC2bC3b), which cleaves the [[complement component 5|C5]] protein. The cleaved products attract phagocytes to the site of infection and tags target cells for elimination by phagocytosis. In addition, the C5 convertase initiates the terminal phase of the complement system, leading to the assembly of the membrane attack complex ([[Complement membrane attack complex|MAC]]). The membrane attack complex creates a pore on the target cell's membrane, inducing cell lysis and death.<ref name="Complement in disease" /><ref name="Complement history" />

The classical complement pathway can also be activated by apoptotic cells, necrotic cells, and acute phase proteins.<ref name="Overview of Complement">{{cite journal|last1=Noris|first1=Marina|last2=Remuzzi|first2=Giuseppe|title=Overview of Complement Activation and Regulation|journal=Seminars in Nephrology|date=November 2013|volume=33|issue=6|pages=479–492|doi=10.1016/j.semnephrol.2013.08.001|pmc=3820029|pmid=24161035}}</ref><ref name="Complement history">{{cite journal|last1=Nesargikar|first1=Prabhu|last2=Spiller|first2=B.|last3=Chavez|first3=R.|title=The complement system: History, pathways, cascade and inhibitors|journal=European Journal of Microbiology and Immunology|date=June 2012|volume=2|issue=2|pages=103–111|doi=10.1556/EuJMI.2.2012.2.2|pmc=3956958|pmid=24672678}}</ref><ref name="C1q">{{cite journal|last1=Thielens|first1=Nicole M.|last2=Tedesco|first2=Francesco|last3=Bohlson|first3=Suzanne S.|last4=Gaboriaud|first4=Christine|last5=Tenner|first5=Andrea J.|date=June 2017|title=C1q: A fresh look upon an old molecule|journal=Molecular Immunology|doi=10.1016/j.molimm.2017.05.025|volume=89|pages=73–83}}</ref>

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=== Formation of C3 convertase ===

The binding of C1q leads to conformational changes and the activation of the serine protease C1r. The activated C1r then cleaves and activates the serine protease C1s.<ref name="Complement history" /><ref name="C1q" /> The activated C1s cleaves C4 into C4a and C4b, and C2 into C2a and C2b.<ref>{{Cite journal|last = Krych-Goldberg|first = M.|last2 = Atkinson|first2 = J. P.|date = 2001-04-01|title = Structure-function relationships of complement receptor type 1|journal = Immunological Reviews|volume = 180|pages = 112–122|issn = 0105-2896|pmid = 11414353|doi=10.1034/j.1600-065x.2001.1800110.x}}</ref> The larger and active fragments, C4b and C2aC2b form C4bC2aC4bC2b, a C3 convertase.<ref name="Complement in disease" /> C3 convertase then cleaves C3 into C3a and C3b. While the anaphylatoxin C3a interacts with its C3a receptor (C3aR) to recruit leukocytes, C3b contributes to further downstream complement activation.<ref name="Overview of Complement" /><ref name="Complement history" />

===Formation of C5 convertase and MAC===

C3b binds to the C3 convertase (C4bC2aC4bC2b), to form C5 convertase (C4bC2aC3bC4bC2baC3b). C5 convertase then cleaves C5 into C5a and C5b.<ref name="Complement history" /> Like C3a, C5a is also an anaphylatoxin with interacts with its cognate C5a receptor (C5aR) to attract leukocytes.<ref name="Overview of Complement" /> Subsequent interactions between C5b and other terminal components C6, C7, C8, and C9 form the membrane attack complex or the C5b-9 complex which forms pores on the target cell membranes to lysing.<ref name="Rus 103–112">{{Cite journal| last = Rus| first = Horea| last2 = Cudrici| first2 = Cornelia| last3 = Niculescu| first3 = Florin| date = 2005-11-01| title = The role of the complement system in innate immunity| url = https://link.springer.com/article/10.1385/IR%3A33%3A2%3A103| journal = Immunologic Research| language = en| volume = 33| issue = 2| pages = 103–112| doi = 10.1385/IR:33:2:103| issn = 0257-277X| pmid=16234578}}</ref>

== Clinical significance ==