complement activation, alternative pathway

Definition

Target type: biologicalprocess

Any process involved in the activation of any of the steps of the alternative pathway of the complement cascade which allows for the direct killing of microbes and the regulation of other immune processes. [GOC:add, ISBN:0781735149]

The alternative pathway of complement activation is a crucial component of the innate immune system, acting as a first line of defense against pathogens. It differs from the classical and lectin pathways in its initiation, relying on spontaneous activation rather than antibody or lectin recognition.

The process begins with the spontaneous hydrolysis of C3, a central complement protein. This hydrolysis exposes a reactive thioester bond on C3, allowing it to bind to a variety of surfaces, including microbial cell walls. This initial binding forms a complex known as C3(H2O), which is unstable and quickly degraded. However, in the presence of certain microbial surfaces, such as lipopolysaccharide (LPS) from gram-negative bacteria, C3(H2O) can interact with Factor B, a serum protein.

Factor B binds to C3(H2O) and undergoes a conformational change that allows it to be cleaved by Factor D, a serine protease present in the serum. This cleavage results in the formation of two fragments: Ba, which is released, and Bb, which remains bound to C3(H2O). This complex, known as C3(H2O)Bb, is the alternative pathway C3 convertase.

The C3 convertase, C3(H2O)Bb, is unstable and rapidly degraded. However, it can bind to another molecule of C3, cleaving it into C3a and C3b. C3b, the larger fragment, can then bind to the surface of the microbial cell, forming a new C3 convertase complex known as C3bBb. This complex is more stable and amplifies the activation process, leading to the deposition of multiple C3b molecules on the target surface.

The deposited C3b can then interact with Factor P (properdin), a stabilizing protein that increases the stability and half-life of the C3 convertase. This further amplifies the complement cascade.

Ultimately, the deposition of C3b on the microbial cell surface leads to the formation of the alternative pathway C5 convertase, composed of C3b2Bb. This enzyme cleaves C5 into C5a and C5b. C5b initiates the formation of the membrane attack complex (MAC), a complex of complement proteins that forms pores in the microbial cell membrane, leading to cell lysis and death.

In addition to its role in microbial killing, the alternative pathway plays a critical role in opsonization, the process by which microbial cells are marked for destruction by phagocytes. The deposited C3b acts as an opsonin, binding to receptors on phagocytes and facilitating the engulfment and destruction of the pathogen.

The alternative pathway is tightly regulated to prevent uncontrolled activation and potential damage to host tissues. Regulatory proteins, such as Factor H and Factor I, bind to C3b, promoting its inactivation and preventing the formation of the C3 convertase. This regulatory mechanism ensures that the complement system is activated only in the presence of pathogens, minimizing the risk of collateral damage to host cells.'
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Proteins (7)

Compounds (7)