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Specific Host Restance: The Effector Mechanisms
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Other regulatory mechanisms include serum or cell-surface proteins of the host. The enzymatic step mediated by C1 is inhibited by a normal serum protein, C1-inhibitor, that binds and causes it to dissociate from , thereby limiting the activation of C2 and C4 and the formation of C3 covertase. C3 convertase can also be inactivated by a serum protein called C4 binding protein or a cell-surface protein called decay-accelerating factor (DAF). The key step in both the classical and alternative pathways is the deposition of on cells. Factor 1 in normal serum is a -inactivator that degrades and unless they are bound to a cell surface. Another normal serum protein, Factor H, enhances the inhibitory action of Factor 1. Protectin is a protein on host cell surfaces that prevents the formation of membrane attack complexes.
The maternal immune system during pregnancy
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Complement is a collection of serum proteins that bind pathogens, leading to immediate destruction, opsonization, or chemotaxis. Once activated, factors remain bound to the pathogen (i.e., factor C3b) or released locally for neutrophil chemotaxis (i.e., factor C3a). Complement is activated through multiple mechanisms resulting in the formation of a “C3 convertase” (Fig. 1): (i) it is activated by antibodies present on pathogens through factor C1q (the “classical” pathway); (ii) it binds directly to the pathogen through factor C3b (the “alternative” pathway), or (iii) it is activated by the terminal mannose of bacterial N-acetyl glucosamine through mannose-binding protein (the “lectin” pathway). The presence of C3b then opsonizes organisms for phagocytosis by neutrophils and macrophages. In some cases, such as with Neisseria sp., complement also forms a multicomponent membrane attack complex (MAC) that leads to direct perforation and lysis of the organism (9,10).
Immunologic Mechanisms in Renal Disease
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Brian D. Schreiber, Gerald C. Groggel
The usual mechanism whereby immune deposits and antibody are thought to initiate injury is through the activation of the complement system (Couser et al., 1985b; Cybulsky et al., 1988). The complement system can be activated by either the classical pathway which is initiated by IgG or IgM, or by the alternative pathway which can be initiated by IgA or nonimmunologically by polysaccharides, bacteria, and other substances (Schreiber and Muller-Eberhard, 1979). Both pathways lead to the formation of a C3 convertase to form C3b (Schreiber and Muller-Eberhard, 1979). This then leads to the formation of a C5 convertase to form C5a and C5b. Generation of C5b from either pathway initiates self-assembly of C5b-9, which is the MAC.
Investigational drugs in clinical trials for macular degeneration
Published in Expert Opinion on Investigational Drugs, 2022
Michael J Tolentino, Andrew J Tolentino
The complement cascade has three predominant activation pathways which converge on the formation of complement factor 3 (C3) convertase which represents the rate limiting step for the amplification and production of C5 and C5-9 the membrane attack complex. The complement pathway can be described in three stages, activation, amplification/inflammation, and lysis/resolution. The activating trigger defines the pathway. The classical and lectin activation pathways require the binding of antibodies or mannose respectively to activate the cascade. The alternative pathway, in contrast, is constitutively activated and is negatively regulated by CFH which prevents the amplification and lysis stages. The Alternative pathway is negatively regulated needs to be turned off with CFH, the Classical and Lectin Pathway need to be turned on [17]. (Figure 2)
THE ROLE OF HUMAN COMPLEMENT PROTEIN FACTOR B AND FACTORP/PROPERDIN IN HIV-ASSOCIATED PRE-ECLAMPSIA
Published in Hypertension in Pregnancy, 2022
Phumelele Kikine, Yazira Pillay, Thajasvarie Naicker
The alternative pathway (AP) is constantly activated at low levels by the spontaneous hydrolysis of C3 (10). Following C3 hydrolysis, a conformational change in C3 occurs resulting in C3(H2O) which binds factor B to form a C3(H2O)B complex. factor D cleaves factor B resulting in the formation of the initiation AP C3 convertase C3(H2O)Bb, which cleaves C3 into C3a and C3b similar to the classical and lectin pathway C3 convertase, C4bC2a (11). C3b emanating from any of the CS pathways may bind to factor B and with the involvement of factor D, produces the AP C3 convertase, C3bBb. Factor P/properdin binds to C3bBb promoting stabilization of the complex. In addition, factor P may induce AP activation via surface AP C3 convertase or microbial antigens (11).
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.