Editing Alternative complement pathway

{{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(H<SUB>2</SUB>O) to form C3(H<SUB>2</SUB>O)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)<SUB>2</SUB>BbP (sometimes referred to as C3b<sub>2</sub>Bb). After the creation of C5 convertase (either as (C3b)<SUB>2</SUB>BbP 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]]