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==Complement cascade==
[[File:Complement pathway.svg|270px|thumb|The classical complement pathway leading into a complement cascade that is shared with the alternative pathway.]]
The classical pathway is distinct from the other complement pathways in its unique activation triggers and cascade sequence. Activation of the complement pathway through the classical, [[Lectin pathway|lectin]] or [[
===Initiation===
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| last = Ahearn| first = 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 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 fragments C4b and C2a<ref>Overview of Complement Activation and Regulation</ref> form C4b2b (according to old terminology, C2a and C4b2a), a C3 convertase of the classical pathway.<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 (C4b2b), to form C5 convertase (C4b2b3b). C5 convertase then cleaves C5 into C5a and C5b.<ref name="Complement history" /> Like C3a, C5a is also an anaphylatoxin that 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
== Clinical significance ==
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Lack of regulation of the classical complement pathway through the deficiency in [[C1-inhibitor]] results in episodic [[angioedema]].<ref name="Overview of Complement" /> C1-inhibitor defiency can be hereditary or acquired, resulting in hereditary or acquired angioedema.<ref name="angiodema"/> C1-inhibitor plays the role of inactivating C1r and C1s to prevent further downstream classical complement activity.<ref>{{Cite journal|last=Levy|first=Michael|last2=Mealy|first2=Maureen A.|date=2014-06-01|title=Purified human C1-esterase inhibitor is safe in acute relapses of neuromyelitis optica|journal=Neurology: Neuroimmunology & Neuroinflammation|language=en|volume=1|issue=1|pages=e5|doi=10.1212/nxi.0000000000000005|issn=2332-7812|pmid=25340061|pmc=4202676}}</ref><ref name="angiodema">{{Cite journal|last=Cugno|first=Massimo|last2=Zanichelli|first2=Andrea|last3=Foieni|first3=Fabrizio|last4=Caccia|first4=Sonia|last5=Cicardi|first5=Marco|title=C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress|journal=Trends in Molecular Medicine|volume=15|issue=2|pages=69–78|doi=10.1016/j.molmed.2008.12.001|pmid=19162547|year=2009}}</ref> C1-inhibitor controls the processes involved in maintaining vascular permeability. As a result, C1-inhibitor levels of less than 50% of the standard lead to increased vascular permeability, characteristic of angioedema.<ref name="angiodema" /> Cinryze, a human plasma derived C1-esterase inhibitor, has been approved for use in 2008 for the prevention of hereditary angioedema attacks.<ref>{{Cite journal|last=Lunn|first=Michael|date=2010-08-24|title=Cinryze™ as the first approved C1 inhibitor in the USA for the treatment of hereditary angioedema: approval, efficacy and safety|journal=Journal of Blood Medicine|language=English|volume=1|pages=163–70|doi=10.2147/jbm.s9576|pmid=22282695|pmc=3262319}}</ref><ref>{{cite web |url=https://www.fda.gov/biologicsbloodvaccines/bloodbloodproducts/approvedproducts/licensedproductsblas/fractionatedplasmaproducts/ucm150480.htm |title=Approval History, Letters, Reviews and Related Documents - CINRYZE |website= |accessdate=2015-01-21}}</ref>
Deficiency in the [[Complement component 1q|C1q]] protein of the classical complement pathway can lead to development of [[systemic lupus erythematosus]].<ref name="Complement in disease" /><ref>{{Cite journal|last=Stegert|first=Mihaela|last2=Bock|first2=Merete|last3=Trendelenburg|first3=Marten|title=Clinical presentation of human C1q deficiency: How much of a lupus?|journal=Molecular Immunology|volume=67|issue=1|pages=3–11|doi=10.1016/j.molimm.2015.03.007|pmid=25846716|year=2015}}</ref> Among the many functions of C1q, C1q triggers clearance of immune complexes and apoptotic cells by activating the classical pathway and binding directly onto phagocytes.<ref name="Overview of Complement" /><ref>{{Cite journal|last=Taylor|first=Philip R.|last2=Carugati|first2=Anna|last3=Fadok|first3=Valerie A.|last4=Cook|first4=H. Terence|last5=Andrews|first5=Mark|last6=Carroll|first6=Michael C.|last7=Savill|first7=John S.|last8=Henson|first8=Peter M.|last9=Botto|first9=Marina|date=2000-08-07|title=A Hierarchical Role for Classical Pathway Complement Proteins in the Clearance of Apoptotic Cells in Vivo|journal=The Journal of Experimental Medicine|volume=192|issue=3|pages=359–366|issn=0022-1007|pmc=2193213|pmid=10934224|doi=10.1084/jem.192.3.359}}</ref> Consequently, systemic lupus erythematosus from insufficient amounts of C1q
== See also ==
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