The alternative pathway is one of three complement pathways thatopsonize and kill pathogens. The pathway is triggered when the C3b protein directly binds amicrobe. It can also be triggered by foreign materials and damaged tissues.
This change in shape allows the binding of plasma proteinFactor B, which allowsFactor 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-phaseC3-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 bindsproperdin, 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 formmembrane attack complex.
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 orCD35) and DAF (decay accelerating factor also known asCD55) 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 calledcomplement 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 orCD46)
Complement factor H can inhibit the formation of the C3 convertase by competing with factor B for binding to C3b;[1] accelerate the decay of the C3 convertase;[2] and act as a cofactor for factor I-mediated cleavage of C3b.[3] 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.[4]
Dysregulation of the complement system has been implicated in several diseases and pathologies, includingatypical 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 retinaltissues.[5] Alternative pathway activation also plays a significant role in complement-mediated renal disorders such as atypical hemolytic uremic syndrome,C3 glomerulopathy, andC3 glomerulonephritis (Dense Deposit Disease or MPGN Type II).[5]
