imported>OAbot: Open access bot: url-access updated in citation with #oabot.

2025-05-26T03:25:48Z

Open access bot: url-access updated in citation with #oabot.

New page

{{Short description|Type of cascade reaction of the complement system}}
[[Image:Complement pathway.svg|thumb|right|270px|The classical and alternative complement pathways.]]
[[Image:Droga alternatywna.png|thumb|right|270px|Alternative pathway. (Some labels are in Polish.)]]
The '''alternative pathway''' is a type of [[cascade reaction]] of the [[complement system]] and is a component of the [[innate immune system]], a natural defense against infections.

The alternative pathway is one of three complement pathways that [[opsonize]] and kill pathogens. The pathway is triggered when the C3b protein directly binds a [[microorganism|microbe]]. It can also be triggered by foreign materials and damaged tissues.

==Signaling cascade==
This change in shape allows the binding of plasma protein [[Complement factor B|Factor B]], which allows [[Factor D]] to cleave Factor B into Ba and Bb.

Bb remains bound to C3(H2O) to form C3(H2O)Bb. This complex is also known as a fluid-phase [[C3-convertase]]. This convertase, the alternative pathway C3-convertase, although only produced in small amounts, can cleave multiple C3 proteins into C3a and C3b. The complex is believed to be unstable until it binds [[properdin]], a serum protein. The addition of properdin forms the complex C3bBbP, a stable compound which can bind an additional C3b to form alternative pathway C5-convertase.

The C5-convertase of the alternative pathway consists of (C3b)2BbP (sometimes referred to as C3b2Bb). After the creation of C5 convertase (either as (C3b)2BbP or C4b2a3b from the classical pathway), the complement system follows the same path regardless of the means of activation (alternative, classical, or lectin). C5-convertase cleaves C5 into C5a and C5b. C5b binds sequentially to C6, C7, C8 and then to multiple molecules of C9 to form [[membrane attack complex]].

==Regulation==
Since C3b is free and abundant in the plasma, it can bind to either a host cell or a pathogen surface. To prevent complement activation from proceeding on the host cell, there are several different kinds of regulatory proteins that disrupt the complement activation process:
* Complement Receptor 1 (CR1 or [[CD35]]) and DAF ([[decay accelerating factor]] also known as [[CD55]]) compete with Factor B in binding with C3b on the cell surface and can even remove Bb from an already formed C3bBb complex
* The formation of a C3 convertase can also be prevented when a plasma protease called [[complement factor I]] cleaves C3b into its inactive form, iC3b. Factor I requires a C3b-binding protein cofactor such as complement factor H, CR1, or membrane cofactor of proteolysis (MCP or [[CD46]])
* [[Factor H|Complement factor H]] can inhibit the formation of the C3 convertase by competing with factor B for binding to C3b;<ref>{{cite journal | vauthors = Conrad DH, Carlo JR, Ruddy S | title = Interaction of beta1H globulin with cell-bound C3b: quantitative analysis of binding and influence of alternative pathway components on binding | journal = The Journal of Experimental Medicine | volume = 147 | issue = 6 | pages = 1792–1805 | date = June 1978 | pmid = 567241 | pmc = 2184316 | doi = 10.1084/jem.147.6.1792 }}</ref> accelerate the decay of the C3 convertase;<ref>{{cite journal | vauthors = Weiler JM, Daha MR, Austen KF, Fearon DT | title = Control of the amplification convertase of complement by the plasma protein beta1H | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 73 | issue = 9 | pages = 3268–72 | date = September 1976 | pmid = 1067618 | pmc = 431003 | doi = 10.1073/pnas.73.9.3268 | bibcode = 1976PNAS...73.3268W | doi-access = free }}</ref> and act as a cofactor for factor I-mediated cleavage of C3b.<ref>{{cite journal | vauthors = Pangburn MK, Schreiber RD, Müller-Eberhard HJ | title = Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein beta1H for cleavage of C3b and C4b in solution | journal = The Journal of Experimental Medicine | volume = 146 | issue = 1 | pages = 257–70 | date = July 1977 | pmid = 301546 | pmc = 2180748 | doi = 10.1084/jem.146.1.257 }}</ref> Complement factor H preferentially binds to vertebrate cells (because of affinity for sialic acid residues), allowing preferential protection of host (as opposed to bacterial) cells from complement-mediated damage.
* [[CFHR5]] (Complement factor H-Related protein 5) is able to bind to act as a cofactor for factor I, has decay accelerating activity and is able to bind preferentially to C3b at host surfaces.<ref>{{cite journal | vauthors = McRae JL, Duthy TG, Griggs KM, Ormsby RJ, Cowan PJ, Cromer BA, McKinstry WJ, Parker MW, Murphy BF, Gordon DL | title = Human factor H-related protein 5 has cofactor activity, inhibits C3 convertase activity, binds heparin and C-reactive protein, and associates with lipoprotein | journal = Journal of Immunology | volume = 174 | issue = 10 | pages = 6250–6 | date = May 2005 | pmid = 15879123 | doi = 10.4049/jimmunol.174.10.6250 | doi-access = free }}</ref>

==Role in disease==
Dysregulation of the complement system has been implicated in several diseases and pathologies, including [[atypical hemolytic uremic syndrome]] in which kidney function is compromised. [[Age related macular degeneration]] (AMD) is now believed to be caused, at least in part, by complement overactivation in retinal [[Tissue (biology)|tissue]]s.<ref name=":0">{{Cite journal|last1=Tzoumas|first1=Nikolaos|last2=Hallam|first2=Dean|last3=Harris|first3=Claire L.|last4=Lako|first4=Majlinda|last5=Kavanagh|first5=David|last6=Steel|first6=David H.W.|date=November 2020|title=Revisiting the role of factor H in age-related macular degeneration: Insights from complement-mediated renal disease and rare genetic variants|url=https://doi.org/10.1016/j.survophthal.2020.10.008|journal=Survey of Ophthalmology|volume=66|issue=2|pages=378–401|doi=10.1016/j.survophthal.2020.10.008|pmid=33157112|s2cid=226274874|issn=0039-6257|url-access=subscription}}</ref> Alternative pathway activation also plays a significant role in complement-mediated renal disorders such as atypical hemolytic uremic syndrome, [[C3 glomerulopathy]], and [[C3 glomerulonephritis]] (Dense Deposit Disease or MPGN Type II).<ref name=":0" />

== See also ==
* [[Classical complement pathway]]
* [[Lectin pathway]]

== References ==
{{Reflist}}

== Further reading ==
* {{cite book |last1=Janeway |first1=Charles A. |title=Immunobiology : the immune system in health and disease |date=2005 |publisher=Garland Science |location=New York |isbn=978-0-8153-4101-7 |edition= 5th | chapter = The complement system and innate immunity | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK27100/ }}

{{Immune system}}
{{Complement system}}

[[Category:Complement system]]

Alternative complement pathway - Revision history

imported>OAbot: Open access bot: url-access updated in citation with #oabot.