Activation of complement involves sequential proteolysis of proteins to generate enzyme complexes with proteolytic activity. Proteolytic cascades allow tremendous amplification because each enzyme molecule activated at one step can generate multiple activated enzyme molecules at the next step.
The products of complement activation become covalently attached to microbial cell surfaces, antibodies bound to microbes, other antigens & apoptotic bodies.
Activation of complement cascade takes place through any of the following three pathways:
- The classical pathway
- The alternative pathway
- The lectin pathway
Complement system is activated by microbes and by antibodies that are attached to microbes and other antigens.
- Classical pathway is activated by certain isotypes of antibodies bound to antigens
- Alternative pathway is activated by microbial cell surfaces in the absence of antibody
- Lectin pathway is activated by a plasma lectin that binds to mannose residues on microbes.
Alternative and lectin pathways play important role in innate immunity of the host. These two are also more important when the human host is infected by a microorganism for the first time as they can be activated by microbial cell surface or lectin component while classical pathway requires antibody to trigger/activate which is not present in first infection.
Although the pathways of complement activation differ in how they are initiated, all of them result in the generation of enzyme complexes that are able to cleave the most abundant complement protein, C3 and leads up to the formation of membrane attack complex (MAC). Final steps that leads to formation of membrane attack complex are same in all the pathways. Formation of MAC is also termed as termination pathway.
The central event in complement activation is proteolysis of the complement protein C3 to generate biologically active products and the subsequent covalent attachment of a product of C3 called C3b to microbial cell surfaces or to antibody bound to antigen.
Complement activation depends on the generation of two proteolytic complexes:
- C3 convertase that cleaves C3 into two proteolytic fragments called C3a and C3b
- C5 convertase that cleaves C5 into C5a and C5b.
As all three activation pathways lead to activation of C3 resulting in the production of C3b, C3b is considered as the central molecule in the activation of the complement cascade.
The initiating pathways have several things in common. They are triggered by
- A cascade of enzyme activation.
- The binding of one of their components to the activator.
- Generation of biological effects.
Each initiating pathway is triggered by a different type of activator usually a cell, microbe, or molecular aggregate that presents charge patterns that are recognized by components of the individual initiating pathway. Each complement pathway has unique proteins for the initiating step, but shares the same or related proteins for the intermediate steps & uses the same components in the last step culminating in the same activities.
Complement activation represents the dynamic interplay among the different pathways, the control processes, other protein systems & cells in the local environment.
Complement activation promotes phagocytosis as C3b becomes covalently linked to microbes, and phagocytes (neutrophils and macrophages) express receptors for C3b. Peptides produced by proteolysis of C3 (and other complement proteins) stimulate inflammation.
C5 convertase assembles after the prior generation of C3b, and this convertase contributes both to inflammation (by generation of the C5a fragment) and to the formation of pores in the membranes of microbial targets. The pathways of complement activation differ in how C3b is produced but follow a common sequence of reactions after the cleavage of C5.
Complement activation is inhibited by regulatory proteins that are present on normal host cells and absent from microbes. The regulatory proteins are an adaptation of normal cells that minimize complement mediated damage to host cells. Microbes lack these regulatory proteins, which allows complement activation to occur on microbial surfaces.