Complement activation alternative pathway was discovered by Pillemer and colleagues in 1954 but was recognized universally some years later. The alternative pathway of the complement system is an innate component of the immune system's natural defense against infections. The alternative pathway is one of three complement pathways that opsonize and kill pathogens.This pathway is activated by viruses, fungi, bacteria, parasites, cobra venom, immunoglobulin A, and polysaccharides and forms an important part of the defense mechanism independent of the immune response. Here, C3b binds to factor B that is cleaved by factor D to Bb. C3bBb complex then acts as the C3 convertase and generates more C3b through an amplification loop. Binding of factor H to C3b increases its inactivation by factor I. Properdin stabilizes it, preventing its inactivation by factors H and factor I. The alternate pathway does not result in a truly nonspecific activation of complement because it requires specific types of compounds for activation. It simply does not require specific antigen-antibody interactions for initiation.
Components of the complement system that are unique to the alternative pathway are factor B, factor D, and properdin. Factors B and D have been studied in vivo using specific inhibitors and gene-targeted mice. Serum from these mice has been used to demonstrate that both proteins are required for efficient alternative pathway activation by zymosan.
The classical and lectin pathways are initiated by the binding of recognition proteins to specific targets. The classical pathway is activated by IgM, complement fixing isotypes of IgG, and several other proteins such as C-reactive protein and serum amyloid P protein. The binding of these recognition proteins then allows C1q to be directly bound, initiating the classical pathway activation cascade. The lectin pathway is initiated by the binding of mannose binding lectin to repeating carbohydrate moieties found primarily on the surface of microbial pathogens by another family of lectins designated ficolins, which also recognize pathogens, or by the protein cytokeratin, which is exposed on ischemic endothelial cells.
In contrast to the specific protein : protein or protein : carbohydrate interactions that characterize classical and lectin pathway activation, the alternative pathway is capable of autoactivation because of a process termed "tickover" of C3. Tickover occurs spontaneously at a rate of ~1% of total C3 per hour, generating a conformationally altered C3, designated C3(H2O), that is capable of binding factor B. Once factor B associates with C3(H2O), factor B itself changes conformation and can then be cleaved by the constitutively active serum protease factor D, generating Ba and Bb. The Bb fragment remains associated with the complex and can then, through its own serine protease domain, cleave additional C3 molecules, generating a form designated C3b. Once C3b is generated, it associates with factor B to generate more C3-convertase. This overall series of successive proteolytic steps is enhanced by the serum protein properdin, which stabilizes protein:protein interactions during the process. The alternative pathway can also be initiated as an "amplification loop" when fixed C3b that is generated by classical or lectin pathway activation binds factor B, again resulting in conformational changes in factor B that allow factor D to cleave it similarly to the tickover process.
Carbohydrate composition and its sialic acid content on the cell surface play an important role in the activation of the alternate pathway. Sialic acid blocks activation by favoring the binding of factor H to C3b, which is then inactivated by factor I. Microorganisms lacking sialic acid are killed, whereas human cells covered with glycophorin A, a sialoglycoprotein, are protected.
C3bBb is relatively labile and undergoes spontaneous decay through dissociation of Bb. Properdin is synthesized by monocytes and T lymphocytes. Properdin binds to C3bBb and stabilizes it, preventing its decay. Factor H competes with factor B for binding to C3b and displaces Bb from C3bBb. It accelerates the inactivation of C3b by factor I. Factor I inactivates C3b to iC3b, a molecule that cannot function enzymatically. Complement receptor 1 (CR1) has factor H-like activity, permitting factor I to cleave C3b. Membrane cofactor protein also has factor H-like activity, mainly for alternative C3 convertase.
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2. Matsushita, M, et al. (2000). Cutting edge: complement-activating complex of ficolin and mannose-binding lectin-associated serine protease. J. Immunol. 164: 2281-2284.