The alternative pathway of the complement system is an innate component of the immune system's 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 microbe. It can also be triggered by foreign materials and damaged tissues.
Cascade
This change in shape allows the binding of plasma proteinFactor B, which allows Factor D to cleave Factor B into Ba and Bb. Bb remains bound to C3 to form C3Bb. 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 2BbP. After the creation of C5 convertase, the complement system follows the same path regardless of the means of activation. 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 and DAF 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
Complement Factor H can inhibit the formation of the C3 convertase by competing with factor B for binding to C3b; accelerate the decay of the C3 convertase; and act as a cofactor for Factor I-mediated cleavage of C3b. Complement factor H preferentially binds to vertebrate cells, allowing preferential protection of host cells from complement-mediated damage.
CFHR5 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.
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 is now believed to be caused, at least in part, by complement mediated attack on ocular tissues. Alternative pathway activation might also play a significant role in kidney pathology associated with lupus.
