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Specific Host Restance: The Effector Mechanisms
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
The classical and alternative pathways are functionally intertwined by their common C3 and C5 convertases. Therefore, the activation of one pathway can amplify the activity of the other through the generation of and .
Complement-Mediated Lipopolysaccharide Release
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
The complement system is comprised of a series of glycoproteins found circulating in the blood in inactive precursor forms. Activation of complement involves a sequential cascade of enzymatic (primarily proteolytic) reactions that produces the active forms of the complement proteins. The general formula for complement activation is X → Xa + Xb, where a is the smaller molecular weight fragment. Initiation of the complement cascade requires the presence of an activating surface that allows the formation of stable enzyme complexes called C3 and C5 convertases. The stable deposition of these multicomponent enzyme complexes on bacterial surfaces may then trigger the assembly of the membrane attack complex (MAC) composed of terminal complement components C5b through C9 (1,2). The MAC is capable of killing some bacteria targeted by complement activation. Killing mechanisms may include the formation of membrane-spanning pores and a detergent-like membrane perturbation effect (3,4). Activating surfaces may require prior coating of the surface with antibody molecules in order to activate complement or may directly “fix” or cross-link complement proteins to the surface, as is the case for some lipopolysaccharide (LPS) molecules found in gram-negative bacterial outer membranes.
Immune system and Innate Immunity
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
In the classical pathway, when IgG or IgM antibody binds to the bacterial antigen, several C1 molecules bind to the Fc region of the antibody and trigger a complement chain reaction on the surface of the bacterium. In the blood and tissues, some complement proteins form a complex called C1, which is not active because it is bound to an inhibitor molecule. When two or more C1 complexes bind to the Fc region of the IgM, a cascade of events results in the formation of C3 convertase. The C3 convertase converts C3 to C3b, which initiates an activation loop that produces more C3b. The C3a fragments cause smooth muscle contraction, histamine release and increased vascular permeability. The MAC pathway is the final common complement pathway that produces C5a and other ‘killer’ molecules. C5 convertase produced by the classical pathways cleaves C5 into a smaller C5a fragment and a larger C5b fragment. C5b binds to C6 and then to C7. The C5b67 complex binds to C8 and C9, forming the MAC that forms holes in cell membranes, resulting in cell lysis and death. Complements C1, C2 and C3 function as opsonins (proteins coating bacteria or foreign particles which enhance phagocytosis). The formation of plasma kinins also depends on complement activation, and these promote phagocytosis. C3a and C5a are responsible for releasing anaphylatoxins that increase vascular permeability, release histamine and contract smooth muscle. C5a and the C1, 4, 2, 3 complexes have chemotactic properties.
The role of complement and complement therapeutics in neuromyelitis optica spectrum disorders
Published in Expert Review of Clinical Immunology, 2022
Panos Stathopoulos, Marinos C Dalakas
The complement system consists of two main functional pathways: the enzymatic cascade generating the initiating molecular elements of the lytic pathway, and the lytic pathway itself leading to the assembly of the C5b-9 membrane attack complex (MAC, C5b-9) [26] (Figure 1). The process of the enzymatic cascade includes the classical, the lectin, and the alternative pathways, which via a series of enzyme activation processes lead to the assembly of the convertases that subsequently drive the complement amplification, as previously elaborated (26). The classical pathway is initiated by antibodies of the IgM and IgG isotypes (of the IgG1, IgG2 and IgG3, but not IgG4, subclasses), which bind to C1q and by changing its conformation initiate an auto-amplification cascade complex of C1r activation and C1s cleavage that lead to the formation of the surface-bound C5 convertase. The lectin pathway is initiated by various carbohydrate molecules and, like the classic pathway, eventually leads to the formation of C5 convertase. The alternative pathway comprises a continuous activation process that leads to the production of abundant C3a and C3b, thereby aiding the formation of the C5 convertase and then production of C5a and C5b. Finally, the lytic pathway is the cascade where the classic, lectin, and alternative pathways converge and, starting with the action of the C5 convertase, leads to the assembly of MAC, which opens osmolytic pores in the target cell membranes leading to cell death. The C3a and C5a also function as anaphylatotoxins that chemotactically attract phagocytes, such as macrophages and neutrophils.
Research Progress of circRNAs in Inflammatory Mechanisms of Diabetic Retinopathy: An Emerging Star with Potential Therapeutic Targets
Published in Current Eye Research, 2022
Shuai He, Chufeng Gu, Tong Su, Qinghua Qiu
The complement system acts as a component of the innate immune system to protect the host from infectious pathogens, which have been proposed to be involved in DR. In the activated complement pathway, the production of C3/C5 convertase promotes the generation of membrane attack complex (MAC) contributing to the damage of host cells and neural degeneration in DR. Furthermore, Dagher et al. reported the observed deposition of C5b-9 in retinal microvasculature of diabetics as an end-product in the complement activation,100 and Gao et al. revealed the increase in complement factor I, as well as alpha-1-antitrypsin, prothrombin and Factor XIII in the vitreous of PDR patients.101 The excessive accumulation of complement factors in diabetes-induced retinal vascular lumen activates MAC generation and thus results in elevated retinal endothelial death and permeability.102 In addition, C3a and C5a are chemotactic factors and are able to stimulate neutrophils, consistent with the evidence of an enhanced number of neutrophils shown in diabetic retinal vessels, leading to high expression levels of plasma constituents in the connective tissue matrix and exacerbated inflammatory processes in DR.103 Moreover, hyperglycemia induces the upregulation of C5aR, which is responsible for the activation of IL-6 and VEGF to increase proliferation and dysfunction in retinal endothelial cells.104
Avacopan for the treatment of ANCA-associated vasculitis
Published in Expert Review of Clinical Immunology, 2021
Mohammed Osman, Jan Willem Cohen Tervaert, Christian Pagnoux
Once a stable C3 convertase complex is formed via the classical/lectin or alternative pathways, it combines with C3b, a cleaved form of C3, to form the C5 convertase which cleaves C5 into its components C5b and C5a. Of note, the activation of any of the pathways leads to augmented alternative complement activation, resulting in turn to an increased global C5 convertase activity. C5b promotes the assembly of C6-C9 to form membrane complexes that promote cell lysis [16,19,20,23]. C5a, on the other hand, acts as a potent anaphylatoxin, which upon binding to its receptor, C5aR1 (CD88), promotes the recruitment of platelets and granulocytes such as neutrophils and eosinophils, degranulation (of both neutrophils and platelets) and the release of DNA neutrophil extracellular traps, or ‘NETs’ [24–26]. All of these mediators, namely neutrophils, platelets and NETs, are known to be important drivers in the pathogenesis of AAV [27,28]. Moreover, neutrophil degranulation and release of NETs may promote the formation of pathogenic ANCA, by providing more antigens, including MPO or proteinase 3 (PR3), that can be recognized by self-reactive T and B cells, further augmenting neutrophil degranulation and complement activation [29] (Figure 2). The release of C5a may also promote the activation of the extrinsic coagulation pathway, via the release of tissue factor by endothelial cells, and subsequent thrombosis or microvascular damage [20]. Thus, aberrant complement activation can have numerous sequelae in AAV.