Classical complement pathway: Difference between revisions

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

C3b binds to the C3 convertase (C4b2a), to form C5 convertase (C4b2b3bC4b2a3b). 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 lysing.<ref name="Rus 103–112">{{Cite journal| last1 = Rus| first1 = Horea| last2 = Cudrici| first2 = Cornelia| last3 = Niculescu| first3 = Florin| date = 2005-11-01| title = The role of the complement system in innate immunity| journal = Immunologic Research| language = en| volume = 33| issue = 2| pages = 103–112| doi = 10.1385/IR:33:2:103| issn = 0257-277X| pmid=16234578| s2cid = 46096567}}</ref>

== Clinical significance ==

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Classical complement activation has also been shown to combat Methicillin-resistant Staphylococcus aureus.<ref>{{Cite journal|title = Complement activation contributes to the anti-methicillin-resistant Staphylococcus aureus effect of natural anti-keratin antibody|journal = Biochemical and Biophysical Research Communications|date = 2015-05-22|pages = 142–147|volume = 461|issue = 1|doi = 10.1016/j.bbrc.2015.03.182|first1 = Jingang|last1 = An|first2 = Zhengxiao|last2 = Li|first3 = Yingying|last3 = Dong|first4 = Jiawen|last4 = Wu|first5 = Jianwen|last5 = Ren|pmid=25862372}}</ref> Certain variants of the IgM antibody were found to bind the Methicillin-resistant ''[[Staphylococcus aureus]]'' these IgM were found to be critical in complement activation through the classical pathway and subsequent destruction of the bacteria. Therapies that utilize classical complement activation have been shown to be effective in targeting and killing cancer cells and destroying tumors.<ref>{{Cite journal|title = Tachyplesin Activates the Classic Complement Pathway to Kill Tumor Cells|url = http://cancerres.aacrjournals.org/content/65/11/4614|journal = Cancer Research|date = 2005-06-01|issn = 0008-5472|pmid = 15930279|pages = 4614–4622|volume = 65|issue = 11|doi = 10.1158/0008-5472.CAN-04-2253|language = en|first1 = Jinguo|last1 = Chen|first2 = Xue-Ming|last2 = Xu|first3 = Charles B.|last3 = Underhill|first4 = Shanmin|last4 = Yang|first5 = Luping|last5 = Wang|first6 = Yixin|last6 = Chen|first7 = Shuigen|last7 = Hong|first8 = Karen|last8 = Creswell|first9 = Lurong|last9 = Zhang|doi-access = free}}</ref> [[Tachyplesin]], a small peptide, has been shown to exhibit these effects. When injected into target tissue encourages recruitment of C1q and activates downstream events, eventually leading to the formation of the C5b-9 complex which damages tumor cells, killing them.

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|last1=Levy|first1=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|last1=Cugno|first1=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 |doi-access=free }}</ref><ref>{{cite web |url=https://www.fda.gov/biologicsbloodvaccines/bloodbloodproducts/approvedproducts/licensedproductsblas/fractionatedplasmaproducts/ucm150480.htm |archive-url=https://web.archive.org/web/20090710040543/http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm150480.htm |url-status=dead |archive-date=July 10, 2009 |title=Approval History, Letters, Reviews and Related Documents - CINRYZE |website= [[Food and Drug Administration]]|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|last1=Stegert|first1=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|last1=Taylor|first1=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 is characterized by the accumulation of autoantibodies and apoptotic cells.<ref name="C1q" /> Studies are being done to look into antibodies against C1q as a diagnostic marker for systemic lupus erythematosus.<ref>{{Cite journal|last1=Chi|first1=Shuhong|last2=Yu|first2=Yunxia|last3=Shi|first3=Juan|last4=Zhang|first4=Yurong|last5=Yang|first5=Jijuan|last6=Yang|first6=Lijuan|last7=Liu|first7=Xiaoming|date=2015|title=Antibodies against C1q Are a Valuable Serological Marker for Identification of Systemic Lupus Erythematosus Patients with Active Lupus Nephritis|journal=Disease Markers|language=en|volume=2015|pages=450351|doi=10.1155/2015/450351|pmid=26549923|pmc=4621353|issn=0278-0240|doi-access=free}}</ref><ref>{{Cite journal|last1=Mahler|first1=Michael|last2=van Schaarenburg|first2=Rosanne|last3=Trouw|first3=Leendert|date=2013|title=Anti-C1q Autoantibodies, Novel Tests, and Clinical Consequences|journal=Frontiers in Immunology|language=English|volume=4|pages=117|doi=10.3389/fimmu.2013.00117|pmid=23717311|pmc=3653116|issn=1664-3224|doi-access=free}}</ref>