The alternative pathway is a branch of the complement network, which is generally recognized as an important conservator to recognize and eliminate the pathogens through direct killing or stimulation of phagocytosis. Besides the immunoregulatory functions, complement system has been elaborated on the pathogenic role of ischemic injury, inflammatory, and autoimmune diseases.
The alternative pathway is an independent defense mechanism of the immune response, and it plays an indispensable role in the defense against infections, especially in the early stage while specific antibodies have not been produced. In the physical circumstances, this pathway is slowly activated by spontaneous hydrolysis of the internal C3 thioester bond. When the foreign excitant (e.g. various proteins, lipids and carbohydrate structures on microorganisms) contact with C3, alternative pathway is amplified quickly.
Components of Alternative Pathway
Compared with classical pathway and lectin pathway, the common components are C3, C5-C9, while the unique components are:
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Factor B
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Factor D
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Factor P (properdin)
Aided by factor B/factor D-targeted transgenic mice, investigators demonstrated that all of them are required for efficient alternative pathway activation by zymosan.
Activation Mechanisms of Alternative Pathway
In contrast to classical and lectin pathway, the alternative pathway is capable of autoactivation because of a process termed “tickover” of C3. A conformationally altered C3, designated C3(H2O) is the production of tickover. Normally, the rate of spontaneously tickover is extremely low to 1% of total C3. C3(H2O) has the capability to bind factor B, which can be cleaved into Ba and Bb followed by the constitutively active serum protease factor D. Bb remains bound to C3(H2O) to form C3(H2O)Bb, the alternative pathway C3-convertase, which has the serine protease activity to cleave multiple C3 into C3b to generate more C3 convertase in a powerful amplification loop, resulting in the full activation of the complement system. C3bBb is unstable until it binds properdin to form the complex C3bBbP, a stable form which can bind an additional C3b to form C5-convertase, (C3b)2BbP. Then the alternative pathway follows the same path as the classical or lectin pathway. C5-convertase cleaves C5 into C5a and C5b. C5b recruits C6, C7, C8 C9 to form membrane attack complex (MAC) inducing cell lysis.
Fig. 1 The illustration of activation mechanisms of the alternative pathway.1
The Regulation of Alternative Pathway
Because of the spontaneous activating capabilities, the C3 convertase amplification loop in alternative pathway requires rigorous control to prevent inadvertent inflammation and damage.
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Complement Factor I (CFI): it is a plasma protease, which prevents the reassembles of the C3 convertase by proteolytic inactivation of C3b to iC3b (inactive C3b).
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Complement Factor H (CFH): it plays important regulatory functions via several ways. It inhibits the formation of the C3 convertase by competing with factor B for binding to C3b, and accelerates the dissociation of the C3bBb convertase complex. Moreover, it acts as a cofactor in the cleavage of C3b to iC3b.
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Complement Factor H-Related protein (CFHR): it plays control action by competing with CFH for binding to C3b. CFHR5 is demonstrated as a cofactor for CFI.
Fig 2. The regulation of alternative pathway. (De, et al. 2015)
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Reference
1. From Wikipedia: By Rantes, oringinally at pl.wikipedia, CC BY-SA 3.0 https://commons.wikimedia.org/wiki/File:Droga_klasyczna.png.
2. De Vriese, An S., et al. "Kidney disease caused by dysregulation of the complement alternative pathway: an etiologic approach." Journal of the American Society of Nephrology: JASN 26.12 (2015): 2917.
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Questions & Answer
A: Initiation of the classical pathway occurs through the binding of antigen-antibody complexes to C1q proteins. The initiation of the alternative pathway occurs through the binding of C3b to a foreign surface, whereas the initiation of the lectin pathway occurs through the lectin that binds mannose. Thus, this is the main difference between the classical, alternative and lectin pathways.
A: The alternative complement pathway plays a key role in the production of pro-inflammatory complement activation products in vivo, and in most cases plays an important role. All three activation pathways require the involvement of alternative pathways in order to cause tissue damage in vivo. Lupus nephritis, rheumatoid arthritis, age-related macular degeneration, and others have all been studied in which the alternative pathway has been found to play an important role.
A: Despite the benefits demonstrated in a variety of complement-mediated diseases, there are limitations to the use of inhibitors targeting the classical/agglutinin and terminal pathways. The exploration of alternative pathway-targeted therapies has led to new approaches for the treatment of many complement-mediated diseases. Some drugs can be highly selective for alternative pathways, leaving the classical and lectin pathways intact, which can reduce the risk of infection compared to C3 and terminal complement inhibitors.
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