How is Complement Activated in Alternative Pathway

Introduction of Alternative Pathway

The alternative pathway is one of three complement pathways that lead to activation of the complement cascade. The alternative pathway does not require a specific antibody to begin, so it can be much faster and more efficient than in the case where antibody synthesis is required in the classical pathway. Instead, in the alternative pathway of complement activation, the C3 protein directly binds to microorganisms and only certain types of antigens can activate this pathway. The alternative pathway can be activated by bacteria, viruses, fungi, cobra venom, parasites, IgA immune complexes and polysaccharides and form an important part of the defense mechanism independent of the immune response.

How is Complement Activated in Alternative Pathway

The AP activation occurs on microbial surfaces in the absence of specific antibody. The alternative pathway is activated slowly by the spontaneous hydrolysis of the internal C3 thioester bond and further triggered by contact with various proteins, lipids and carbohydrate structures on microorganisms and other foreign surfaces. Activation of the alternative pathway triggers a cascade involving C3 and factors B and D and properdin, result in cleavage of C5 and formation of the membrane attack complex (MAC), which in its final state creates a pore in the cell wall and causes cell lysis (Fig.1).

Fig. 1 Alternative and classic complement pathways.¹

Alternative pathways of complement activation can be divided into the following phases:

1. Phase 1. Initiation of the spontaneous activation of the AP occurs through spontaneous cleavage of the thioester bond in C3 to form C3(H₂O), which allows the binding of plasma protein Factor B. Factor B binds the C3(H₂O) and is then cleaved by Factor D, generating a distinct C3 convertase (C3bBb). C3 convertase cleaves C3 into C3a and C3b, which sets the stage for the amplification phase of the complement cascade.
2. Phase 2. Amplification of cleavage of C3 into C3a and C3b offers a source of C3b, from which additional C3 convertase is produced during the amplification process. Complement factor H and factor I are important regulators of complement activity, while properdin enhances complement activity.
3. Phase 3. Continuous amplification ultimately leads to the production of C5 convertase and triggering of the complement terminal pathway. C5 convertase cleaves C5 into C5a and C5b. C5a is released to the microenvironment, and C5b binds to C6, C7, C8, and C9 sequentially to form a membrane attack complex (MAC), causing lysis of the cells.

Regulation of Alternative Pathway

To prevent the complement cascade being activated against the body's own cells, there are several different kinds of regulatory proteins that disrupt the complement activation process. These include serum-based and cell-based factors that inactivate C3b when it is produced (Fig.2). Serum-based factors include complement factor H and factor I. The cell-based receptors include CD46 or membrane cofactor protein (MCP) and thrombomodulin. Mutations or loss of all of these regulatory molecules can cause uncontrolled activation of the alternative pathway, which can lead to diseases such as atypical hemolytic uremic syndrome (aHUS).

Each regulatory protein can promote C3b inactivation and prevent further progression of the complement cascade. Factor H binds C3b and works with factor I to inactivate it. MCP can also bind to C3b which has become attached to cells and works with factor l to inactivate it. In addition, thrombomodulin regulates complement by inactivating the pro-inflammatory mediators C3a and C5a and accelerating factor l-mediated C3b inactivation because mutations are associated with aHUS. Thrombomodulin also plays a role in the regulation of local coagulation through interaction with thrombin.

Creative Biolabs offers a range of comprehensive complement-related products and complement testing services, including:

If you have any questions about our complement testing services and products, please feel free to contact us.

Reference

1. From Wikipedia: By Tossh_eng - Tossh_eng (Schematic illustration was made with a drawing application.), CC BY-SA 4.0 https://commons.wikimedia.org/wiki/File:Complement-pathways.png

Related Product

• Complement Activation Definition
• How is Complement Activated in Classical Pathway
• How is Complement Activated in Lectin Pathway
• Serine Proteases of Complement System