Plasma Protein Function in Hemostasis
Genesio Murano, Rodger L. Bick in Basic Concepts of Hemostasis and Thrombosis, 2019
An alternate route of complement activation (the alternative pathway) involves properdin and other components leading to direct C3 activation.158,159,174,175 Some of the initiators of this pathway are F(ab)′2 fragment of IgG, IgE, IgA, bacterial lipopolysaccharides, inulin, and zymosan. 158,159,176-182 A potent inhibitor of esterase (CI INH), an alpha-2-globulin, controls the activity of this enzyme on C4 and C2 substrates.183 A second inhibitor (C3b Inactivator) controls the activity of C3b.184Figure 27 summarizes the interrelationships of the two pathways of activation. En route, various effects—Chemotaxis of neutrophils into the area of immunologic reaction, enhancement of phagocytosis, elaboration of anaphylatoxin, histamine release, etc.—are mediated.159* Tables 3 and 4 summarize the activities of the various components.
Immunopathology
Constantin A. Bona, Francisco A. Bonilla in Textbook of Immunology, 2019
Harmful effects of complement activation arise by direct lysis of cells to which antibody has bound, and by recruitment of other leukocytes by complement products. The anaphylatoxin C5a is chemotactic for phagocytes, and both C3a and C5a stimulate release of their lysosomal contents. These include proteases which may generate kinins, and others with directly cytotoxic properties. Mast cell and platelet degranulation (releasing vasoactive amines and other mediators of inflammation) are additional indirect effects of complement activation. These processes lead to destruction of tissue to which antibody has bound. Indirect inflammatory effects of complement activation are diagrammed in Figure 12–2.
Pulmonary Immunology
Lourdes R. Laraya-Cuasay, Walter T. Hughes in Interstitial Lung Diseases in Children, 2019
Immune complex mediated reactions (type III) result when complexes containing antigen and antibody are deposited in tissues or vascular endothelium. Such deposition leads to complement activation, anaphylatoxin generation, attraction of neutrophils to the site of inflammation, and tissue destruction. Clinical examples of immune complex mediated tissue injury include serum sickness and lupus nephritis. Rheumatoid lung disease and idiopathic pulmonary fibrosis include pulmonary examples of this type of tissue injury.33 In idiopathic pulmonary fibrosis there is desquamation of alveolar lining cells, increased cellularity of the intra-alveolar spaces, interstitial inflammation, and fibrosis.
HSP90-Mediates Liraglutide Preconditioning-Induced Cardioprotection by Inhibiting C5a and NF-κB
Published in Journal of Investigative Surgery, 2022
Shi-Tao He, Dong-Xiao Wang, Jian-Jun Meng, Xiao-Fang Cheng, Qi Bi, Guo-Qiang Zhong, Rong-Hui Tu
The complement system is prominently involved in myocardial I/R injury pathogenesis [35]. Once activated, C3 and C5a recruit proinflammatory leukocytes, and produce inflammatory cytokines, including IL-1β, TNFα, and ICAM-1, triggering tissue necrosis and inflammation during reperfusion [6,8]. Moreover, production of the C5a anaphylatoxin further activates NF-κB signaling, aggravating the inflammatory response [9,10]. Such inflammatory processes tend to spread, ultimately leading to sustained cardiomyocyte apoptosis and necrosis after I/R injury [36]. Therefore, C5a/NF-κB signaling is a central mediator of myocardial I/R injury. Suppression of C5a via C5a receptor knockout prevents NF-κB activation, secretion of proinflammatory cytokines, and ischemic reperfusion injury [28]. Ischemic preconditioning and postconditioning alleviate myocardial I/R injury by suppressing toll-like receptor 4 (TLR4)/NF-κB signaling [21,37]. However, whether liraglutide exerts a similar effect to preconditioning and postconditioning in terms of suppressing TLR4/NF-κB signaling is unclear. Here, we observed relatively high levels of C5a and NF-κB in the I/R group, and significantly lower levels in the LP group. Treatment with the C5a receptor antagonist, PMX53, further inhibited NF-κB activation, and secretion of TNFα, IL-1β, and ICAM-1, indicating that C5a/NF-κB signaling is involved in LP-induced cardioprotection. The mechanisms underlying these effects require further investigation.
The efficacy and safety of complement C5a inhibitors for patients with severe COVID-19: a systematic review and meta-analysis
Published in Expert Review of Anti-infective Therapy, 2023
Chi-Lun Tsai, Chih-Cheng Lai, Ching-Yi Chen, Ho-Sheng Lee
About possible mechanisms of how C5a inhibitors confer clinical benefits for patients with COVID-19, could be explained by the following evidence. First, anaphylatoxin C5a is a potent proinflammatory mediator with strong chemoattractant properties, and its role in the recruitment of neutrophils and macrophages, which promotes vascular leakage and protein accumulation in the airways, was demonstrated by Garcia et al. using a murine model of influenza A virus infection [42]. In addition, C5a-dependent mechanisms have been previously implicated in the pathogenesis of highly pathogenic viruses with associated acute lung injury, due to exaggerated complement activation and a subsequent cytokine storm [22,43,44]. Furthermore, using a murine model of MERS-CoV infection, Jiang et al. disclosed that blockade of the C5a-C5aR not only decreased tissue damage but also reduced viral replication in lung tissues [44]. Similarly, using the model of African Green Monkeys infected with H7N9 virus, Sun et al. found that anti-complement C5a monoclonal antibodies could reduce the serum plasma levels of inflammatory mediators, including TNF-α, IL-1β, and IL-6, and it also remarkedly reduced lung histopathological injury and decreased the lung infiltration of macrophages and neutrophils [45]. Therefore, it is possible that C5a inhibitors could exhibit similar activities in the treatment of patients with severe COVID-19.
Avacopan for the treatment of ANCA-associated vasculitis
Published in Expert Review of Clinical Immunology, 2021
Mohammed Osman, Jan Willem Cohen Tervaert, Christian Pagnoux
The anaphylatoxin C5a binds to C5aR1 (CD88), but also to CD77 (C5L2), which is a non-signaling C5a receptor [50]. C5a binds with similar affinities to both C5aR1 and CD77 (Kd ~ 2.5 nM). Both receptors belong to the G-protein family of receptors and share approximately 38% sequence homology [50]. Both receptors have similar tissue expression distributions, being both expressed on neutrophils, somatic cells such as skin fibroblasts, vascular smooth muscle cells, neurons, in the heart and lungs. There may be differential expression patterns for C5aR1 and CD77 in the renal tubules, particularly during inflammatory signals [51]. CD77 is a ‘decoy’ receptor for C5a, as numerous studies have suggested that it may not be as important in potentiating inflammatory signals on its own [50]. Also, C5aR1, but not CD77, mRNA expression can be induced by toll-like-receptor (TLR) signals [52], which may precipitate AAV flares [53,54]. Furthermore, CD77 and C5aR1 have distinct sub-cellular localizations, with C5aR1 being present more on the cell surface and CD77 intracellularly, associated with beta-arrestins to dampen inflammatory signals triggered by C5aR1 [50]. Finally, loss of CD77 in AAV animal models exacerbates glomerulonephritis [40]. Hence, there may be a functional dichotomy played by these two C5a receptors whereby C5aR1 may promote ongoing disease activity, while CD77 promotes immunoregulation. These distinctions are important to appreciate, especially as novel therapies such as avacopan (see below) only binds to C5aR1 [55].
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