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Specific Host Restance: The Effector Mechanisms
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Complement activation induces inflammation, attracts leukocytes from the circulation to the site of inflammation, facilitates phagocytosis of parasites, facilitates clearing of dangerous immune complexes from the circulation, and produces membrane attack complexes. All of these processes are mediated by complement components (Table 9.2). , , and stimulate inflammation and are called anaphylatoxins. Anaphylatoxins trigger the release of histamine from platelets, mast cells, and basophils. Histamine causes vasodilation, increases capillary permeability, and constriction of bronchial smooth muscle. These changes in the capillaries cause edema, the accumulation of plasma in the inflamed site. The plasma contains additional antibodies and complement thereby accelerating the elimination of the pathogens.
Sensory and Inflammatory Peptide Receptors in Airways
Published in Devendra K. Agrawal, Robert G. Townley, Inflammatory Cells and Mediators in Bronchial Asthma, 2020
These anaphylatoxins are generated following activation of the complement pathway by both the classical and alternative pathways. The complete amino acid sequences of anaphylatoxins have now been elucidated. C3a has 77 amino acids, and C5a has 74 amino acids. The carboxy-terminal pentapeptide sequence appears to be the active site of each molecule, but the remainder of the molecule is necessary for binding to the receptors.
Immune Function in Exercise-Induced Injuries
Published in Ronald R. Watson, Marianne Eisinger, Exercise and Disease, 2020
Louis C. Almekinders, Sally V. Almekinders
One of the first systems to be activated is the complement system. This cascade of twenty plasma proteins can be activated through the “classical” or “alternative” pathways.14 The classical pathway can be activated by several inflammatory mediators such as proteases, immune complexes, and polyanions. This pathway requires proteins Cl, C2, and C4 before activating C3. The alternative pathway can be stimulated by damaged host cells and results in a direct binding of C3. The final common pathway is the formation of active anaphylatoxins and a membrane attack complex that can induce cell lysis. The functions of the anaphylatoxins are multiple and include increased vascular permeability directly or through basophil and mastcell degranulation. They also modulate immune function by acting as chemotactic factors for leukocytes. Finally, they can activate arachidonic acid metabolite formation which can further enhance the increase in vascular permeability.
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.
Sepsis target validation for repurposing and combining complement and immune checkpoint inhibition therapeutics
Published in Expert Opinion on Drug Discovery, 2021
Patrícia R.S. Rodrigues, Noemi Picco, B Paul Morgan, Peter Ghazal
Sepsis is at the same time one of the best known yet most poorly understood medical diseases. It is a common and lethal condition, and even though outcomes have improved, mortality remains high. There is evidence in sepsis, that activation of the complement system results in excessive production of anaphylatoxins, which prompt a series of events leading to septic shock, multiorgan failure, and lethality. Activation of sepsis in non-human primate models has been shown to occur in a biphasic pattern, the initial phase mediated by the bacteria and the later phase mediated by an endogenous mechanism possibly involving PRMs [129]. Increase of complement activation during the first phase of sepsis may relate to bacterial opsonization and is thus beneficial to the host defense response [52]. Conversely, complement activation during the second stage of sepsis via CRP, MBL or other PRMs could be a major contributor to tissue injury and death [69]. Whilst the complement system is the initial driver, immune checkpoint regulation is the ‘master switch’ in charge of the immune response in sepsis; development of a personalized therapeutic strategy capable of targeting patients suffering from a dysregulation of either of these two mechanisms in a timely fashion would likely lead to an improvement in the chances of survival.
Complement activation and coagulopathy - an ominous duo in COVID19
Published in Expert Review of Hematology, 2021
Sojit Tomo, Kiran Pvsn Kumar, Dipayan Roy, Shrimanjunath Sankanagoudar, Purvi Purohit, Dharamveer Yadav, Mithu Banerjee, Praveen Sharma, Sanjeev Misra
The complement system regulates host defense by activating certain plasma proteins upon sensing danger signals by one of the following three pathways: 1) the alternative pathway activated by host–pathogen interaction; 2) the classical pathway triggered by antigen-antibody complexes, and 3) the lectin pathway by binding of polysaccharides on antigen surfaces to host cell. C3 is the central component of each of the pathways, as activation of any of the pathways results in the cleavage of inactive C3 into its functional fragments – C3a and C3b [18]. Complement-derived anaphylatoxins not only aid in the elimination of pathogens by phagocytosis, but also help in programmed cellular death (apoptosis) as part of normal cellular homeostasis [19]. Hemostasis, on the other hand, is the continuous, stepwise combination of processes, leading to a tightly regulated system of clot formation (coagulation) and resolution (fibrinolysis).