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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]] (C4b2b, [[Complement system#Complement protein fragment nomenclature|historically]] referred C4b2a), which cleaves the [[Complement component 3|C3]] protein. The [[C3b]] component of the cleaved C3 binds to C3 convertase (
The classical complement pathway can also be activated by [[apoptotic]] cells, necrotic cells, and [[acute phase protein]]s.<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 & 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|pmid=28601358|pmc=5582005|volume=89|pages=73–83}}</ref>
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The classical complement pathway can be initiated by the binding of antigen-antibody complexes to the [[Complement component 1q|C1q]] protein. The globular regions of C1q recognize and bind to the [[Fragment crystallizable region|Fc]] region of antibody isotypes IgG or IgM.<ref name="Complement in disease">{{cite journal|last1=Vignesh|first1=Pandiarajan|last2=Rawat|first2=Amit|last3=Sharma|first3=Madhubala|last4=Singh|first4=Surjit|title=Complement in autoimmune diseases|journal=Clinica Chimica Acta|date=February 2017|volume=465|pages=123–130|doi=10.1016/j.cca.2016.12.017|pmid=28040558}}</ref> These globular regions of C1q can also bind to bacterial and viral surface proteins, apoptotic cells, and acute phase proteins.<ref>{{Cite book| title = Structure and Function of the Complement Receptors, CR1 (CD35) and CR2 (CD21)| journal = Advances in Immunology| last1 = Ahearn| first1 = Joseph M.| last2 = Fearon| first2 = Douglas T.| date = 1989-01-01| editor-last = Dixon| editor-first = Frank J.| volume = 46| pages = 183–219| doi = 10.1016/s0065-2776(08)60654-9| pmid = 2551147| isbn = 9780120224463}}</ref> In the absence of these activation factors, C1q is part of the inactive C1 complex which consists of six molecules of C1q, two molecules of [[C1r]], and two molecules of [[C1s]].<ref name="Overview of Complement" /><ref name="C1q" />
=== Formation of
The binding of C1q with pathogen surface or antigen-antibody immune complex 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" />
=== Regulation of C4b ===
The newly formed C4b cannot stay activated as a highly reactive thioester bond is revealed once C4 has been cleaved. The thioester bond is cleaved by water resulting in it's cleavage permanently deactivating the C4b molecule. As a result of this C4b is restricted to only bind to pathogen surfaces. They would undergo rapid deactivation in the time it took to travel from the orgin of activation where C1q is complexed with an antigen-antibody immune complex(IC) or where C1q is directly attached to the pathogens surface<ref name=":1">{{Cite book |last=Janeway |first=Ca Jr |url=https://www.ncbi.nlm.nih.gov/books/NBK27100/ |title=Immunobiology: The Immune System in Health and Disease |publisher=Garland Science |year=2001 |edition=5th |___location=New York}}</ref>. the pathogen.
=== Formation of C-3 convertase. ===
Surface bound C4b acts as a receptor for the binding of C2<ref name=":1" />. The binding of C2 and C4b results in C2 being cleaved by C1s into C2a and C2b. C2a diffuses into the plasma as a protein inflammatory mediator while C2b remains attached with C4b forming C4bC2b what is known as C3-convertase, The function of the membrane-bound C3-convertase is the cleavage of many many molecules of C3 into C3a and C3b. C3a is a smaller fragment of C3 is a potent inflammatory mediator.
=== C3b function and structure. ===
C3b can act as an opsonin . C3b is very similar to C4 in both structure and function also has a thioester bond that forces it to attach to surface nucleophile of the activator(namely the pathogen or IC). Phagocytes have receptors for C3b and as a result of receptor-ligand binding are able to more easily recognize and engulf pathogen molecules. 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===
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