The Acute Phase Complement Proteins
Andrzej Mackiewicz, Irving Kushner, Heinz Baumann in Acute Phase Proteins, 2020
Complement proteins of the classical and alternative pathways and C5 are synthesized in several cell types. Thus, activation of the cascade through C5 can be accomplished by proteins synthesized at the extrahepatic sites without a requirement for liver-derived proteins. The widespread synthesis of the prominent acute phase complement proteins, C3 and factor B, which have been identified in virtually every cell type studied, suggests that this extrahepatic synthesis provides a source of alternative complement proteins for local host defense before the influx of serum proteins. The synthesis of two other alternative complement proteins, factor D and properdin, at extrahepatic sites is consistent with this conept and because of their distribution with novel potential functions unrelated to host defenses. Mononuclear phagocytes provide the single richest extrahepatic source of complement proteins, with synthesis of all the activator and inhibitor proteins in both activation pathways, with the exception of factor H. Fibroblasts are also a source of complement proteins, synthesizing at least seven effectors and inhibitors of the system. The functional importance of this extrahepatic complement production is supported by the elaborate tissue-specific and developmentally regulated controls of complement gene expression now recognized in several species.
Complement-Mediated Lipopolysaccharide Release
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
The alternative pathway of complement activation involves the interaction of C3 with Factor B, Factor D, and properdin (Fig. 1). C3 is the most abundant complement protein in the blood, and at any given time a fraction of the C3 molecules undergoes metabolic turnover by a spontaneous conformational change that ex poses an intrachain thiolester bond (–S–C=O) between cysteine and glutamyl residues (5,6). The thiolester bond is extremely labile, its half-life measured in μsec, and is subjected to nucleophilic attack by water to form C3(H20) or C3bi. Factor B may bind to C3(H20), and after cleavage of Factor B by Factor D, the C3(H20)Bb complex may serve as a fluid-phase C3 convertase (Fig. 2). However, this complex is susceptible to inactivation by Factors H and I. Factor H accelerates the disassembly of the C3(H20)Bb complex and acts as a cofactor for the serine protease Factor I, which cleaves C3b and renders it inactive in terms of complement activation. In the presence of an activating surface, such as LPS, C3(H20)Bb-derived C3b molecules may form amide or ester linkages with amino or hydroxyl side groups found on the activating surface. The covalent cross-linking of C3b to a surface favors the interaction of C3b with Factor B and properdin (a C3bB stabilizer) and prohibits the binding of Factor H. The subsequent cleavage of C3b-bound Factor B by Factor D produces the C3bBb complex, a stable membrane-bound C3 convertase (half-life measured in min) that will catalytically cleave C3 and produce millions of membrane-bound C3b molecules (1,2,5). Antibody-dependent activation of the alternative pathway has been characterized and probably involves the binding of C3b to carbohydrates on the Fab portion of certain IgG subclasses.
Postprocessing of Dialysis Membranes
Sirshendu De, Anirban Roy in Hemodialysis Membranes, 2017
It is important to discuss and understand complement activation in more detail. Complement is a group of 30 plasma proteins acting in cohesion that are responsible for the human body’s defense mechanism, for example, tolerating infection.6,7 Craddock et al.8 first reported complement activation in 1977. It was also reported that severe leukopenia occurred in all patients undergoing hemodialysis.9 Complement activation is a series of reactions brought about by a group of proteins leading to inflammatory responses of the human body. The proteins are named from C1 through C9. Of these, C3 is particularly responsible for inflammatory response as well as phagocytosis. The defense mechanism of the body is triggered only after a specific enzyme called “C3 convertase” is formed. There are two proposed pathways through which the activation of the complex occurs. These are depicted in Figure 6.5a and b, representing the classical and alternative pathways, respectively. The classical pathway consists of protein C1 attaching to the bacterial cell wall, thereby forming an antigen–antibody complex. This complex cleaves C2 into C2a and C2b and C4 into C4a and C4b. C2b and C4b combine to form a protease called C3b convertase. This in turn cleaves C3 to C3a and C3b. In the alternative pathway, C3b binds to factor B, factor D, and properdin forming C3 convertase, which then carries out a function similar to that in the classical pathway of cleaving C3 to C3a and C3b. It can be generalized that whichever pathway is followed for complement activation, the formation of an antigen–antibody complex is vital for triggering complement activation. Kazatchkai and Carreno10 discussed the cleavage of an internal thioester bond of C3 molecule leading free oxygen atoms to undergo a transesterification reaction with an –OH or –NH2 group. This covalent bond causes C3 to attach to the foreign surface, thereby triggering a cascading reaction. The individual roles of C3a and C3b as well as C5 are described in Figure 6.5c and d. A comprehensive review article on the subject is available by Ratnoff, and readers can refer to it for more biological details.11
Ravulizumab in the treatment of paroxysmal nocturnal hemoglobinuria
Published in Expert Opinion on Orphan Drugs, 2020
Factor B (FB), a trypsin-like serine protease, plays an important role in central amplification of C3b production and circulates as a latent zymogen [38]. During alternative pathway activation, FB first binds to C3b [39]. C3b-FB is then cleaved by Factor D (FD), to C3bBb, a C3 convertase with active catalytic Bb subunit of FB. C3bBb amplifies C3b production, positively feeding into the complement cascade. Another unit of C3b binding to C3 convertase generates C3bBbC3b, a C5 convertase complex, which further generates MAC and C5a anaphylatoxin. Factor B and Factor D inhibitors are promising therapies for complement-mediated conditions. A recent publication by Schubart et al. has demonstrated efficacy in vivo with animal studies and ex vivo with human samples, as indicated by the prevention of hemolysis of PNH erythrocytes [38].
Complement inhibition as a therapeutic strategy in retinal disorders
Published in Expert Opinion on Biological Therapy, 2019
Enoch Kassa, Thomas A. Ciulla, Rehan M. Hussain, Pravin U. Dugel
AMD is a polygenic disease with complex etiology and multiple implicated pathways including abnormalities in inflammation, lipid metabolism, autophagy, angiogenesis, and apoptosis. Within the inflammatory pathway, both the complement system and inflammasomes have been implicated. Furthermore, even if the complement system were the main culprit in the pathogenesis of AMD, it may only play a key role early, prior to apoptosis of retinal cellular elements, and thus the timing of intervention would be crucial. Any of these aforementioned factors may partially account for the failed clinical trials of complement factor D inhibition, and C5 inhibition in GA. Although the phase 2 trial of C3 inhibition for GA is promising, the associated increased rate of choroidal neovascularization is concerning. However, results from the DERBY and OAKS phase 3 clinical trials will not be available for several years.
Investigational drugs in clinical trials for macular degeneration
Published in Expert Opinion on Investigational Drugs, 2022
Michael J Tolentino, Andrew J Tolentino
The complement pathway is a complex interplay of serine proteases that requires activation, amplification and lysis. This pathway involves multiple enzymatic processes. The most critical process is the formation of c3 convertase C3bBb. The alternative pathway is regulated by complement factor H which binds to c3b in order to displace Bb and degrade c3 convertase. This critical step is the ideal target for complement pathway inhibition. Complement factor D is important in producing the Bb portion of C3 convertase. While critical and rate limiting, inhibiting mature factor D may not be enough to reduce factor D adequately. Factor D is produced as a pro-enzyme and requires cleavage of 6-amino acid peptide for maturation. This cleavage is under the control of mannose-binding lectin–associated serine protease-3 which is involved in the lectin complement pathway. To inhibit factor D effectively in the majority of patients, inhibition of both factor D and its proenzyme may be necessary. The other possibility is that Factor D may not play such a critical role in the alternative pathway as thought, and may be more critical for the lectin pathway [91].
Related Knowledge Centers
- Adipocyte
- Alternative Complement Pathway
- Chymotrypsin
- Complement Factor B
- Lipolysis
- Protein
- Serine Protease
- Trypsin
- Gene
- Complement System