Classical complement pathway: Difference between revisions

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{{short description|Aspect of the immune system}}

[[File:Complement pathways.png|thumb|393x393px|Classical and alternative pathways shown with their corresponding proteins.]]

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" />

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===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 Volume 46| last1 = Ahearn| first1 = Joseph M.| last2 = Fearon| first2 = Douglas T.| chapter = Structure and Function of the Complement Receptors, CR1 (CD35) and CR2 (CD21)| 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 C4b convertase ===

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=== 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'sits 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 orginorigin 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 |chapter=The complement system and innate immunity |publisher=Garland Science |year=2001 |edition=5th |___location=New York}}</ref>. the pathogen.

=== Formation of CC3-3 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. C2aC2b diffuses into the plasma as a protein inflammatory mediator while C2bC2a remains attached with C4b, forming C4bC2b what is known asthe C3-convertase, (C4b2a). 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===

C3b binds to the C3 convertase (C4b2bC4b2a), 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 ==

Because of its role in the innate immune system classical complement has been implicated in a number of pathogen related disorders. Complement is responsible for immune inflammatory response in adipose tissues which has been implicated in the development of [[obesity]].<ref name=":0">{{Cite journal|title = Alterations of the classic pathway of complement in adipose tissue of obesity and insulin resistance|journal = American Journal of Physiology. Endocrinology and Metabolism|date = 2007-05-01|issn = 0193-1849|pmid = 17244723|pages = E1433–E1440|volume = 292|issue = 5|doi = 10.1152/ajpendo.00664.2006|language = en|first1 = Jinhui|last1 = Zhang|first2 = Wendy|last2 = Wright|first3 = David A.|last3 = Bernlohr|first4 = Samuel W.|last4 = Cushman|first5 = Xiaoli|last5 = Chen}}</ref> Obesity in turn results in an abnormally high level of complement activation via production of the C1 component of the classical pathway, which can lead to tissue inflammation and eventually [[insulin resistance]], however the exact mechanisms that causes this is yet unknown.<ref name=":0"/>

Immunotherapies have been developed to detect and destroy cells infected by the HIV virus via classical complement activation.<ref>{{Cite journal|title = Synthetic immunotherapy induces HIV virus specific Th1 cytotoxic response and death of an HIV-1 infected human cell line through classic complement activation|journal = Virology Journal|date = 2013-04-04|volume = 10|issue = 1|doi = 10.1186/1743-422x-10-107|pmid = 23557359|pmc = 3626621|language = En|first1 = Olga|last1 = Pleguezuelos|first2 = Gregory A|last2 = Stoloff|first3 = Wilson|last3 = Caparrós-Wanderley|pages=107 | doi-access=free }}</ref> This process involves creating synthetic peptides that target conserved regions in HIV specific proteins and induce an antibody specific immune response through IgG antibodies. This is important for targeting the virus in its intracellular phase because the antibodies specific to the synthetic peptides can trigger the classical complement pathway and induce the death of HIV infected cells.

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>

== See also ==

* [[Alternative complement pathway]] – another complement system pathway

* [[Lectin pathway]] – another complement system pathway

== References ==