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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).
Host Defense I: Non-specific Immunity
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Normal serum contains very low concentrations of C3b. This probably arises via the action of serum proteases on circulating C3. Factor B binds C3b yielding the C3bB complex. This is the substrate for factor D. The factor B in the C3bB complex is cleaved yielding Ba and Bb, the complex now being C3bBb. This is a proteolytic complex which cleaves C3 to C3a and C3b analogously to the classical pathway complex C4b2a (it is the C3 convertase of the alternative pathway). The C3bBb complex is highly unstable and loses activity rapidly unless it is further complexed with properdin to give PC3bBb.
The complement system in health and disease
Published in Gabriel Virella, Medical Immunology, 2019
The alternative pathway begins with at least one stable C3b covalently bound to a surface and proceeds with the cleavage of many additional C3 molecules to form more bound C3b and fluid-phase C3a. The nature of the surface to which the C3b binds regulates to a great extent C3b survival time. The absence of a C3b degradation system on the surface to which C3b is bound “allows” bound C3b to remain intact and, consequently, the alternative pathway/amplification loop to be activated. If stable C3bBb is formed on the mammalian cells, it is rapidly inactivated by Factor I, acting in concert with several cofactors present, such as membrane cofactor protein (CD46) and decay accelerating factor (CD55). These cofactors are most effective in binding and regulating C3b that inadvertently binds to bystander host cells (discussed later in the chapter). A lack of regulatory proteins on the microbial surface permits C3b binding and activation of the alternative pathway. Further, another plasma glycoprotein of the alternative pathway, properdin, can bind and associate with C3bBb complex stabilizing the C3 convertase, and forming C3bBbP. Properdin attachment to C3bBb is favored on microbial surfaces as compared to mammalian cells and is thus the only known positive regulator of complement activation. In keeping with the classical pathway, C3 convertase C3b molecules generated by the alternative pathway can bind to the C3bBb complex itself, forming the C3bBbC3b, which functions as the alternative pathway C5 convertase.
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 the alternative pathway in paroxysmal nocturnal hemoglobinuria and emerging treatments
Published in Expert Review of Clinical Pharmacology, 2022
Jong Wook Lee, Robert A. Brodsky, Jun-Ichi Nishimura, Austin G. Kulasekararaj
The complement system functions as a first-line host defense against infection, a bridge between innate and adaptive immunity, and a mechanism of clearance of immune complexes and apoptotic cells [21–23]. Complement signaling occurs via three main activation pathways: the classical pathway, the lectin pathway, and the AP (Figure 1). These three pathways converge at the level of C3 convertase; C3 convertase activates C5 convertases, ultimately resulting in production of the highly inflammatory C5a and formation of C5b-9 or membrane attack complex (MAC) [24]. Proximal complement is important for functions related to microbial opsonization and immune complex clearance (mediated by C3b) [24]. Terminal complement is the effector function of the complement cascade causing cell destruction through the formation of a pore (C5b-9, the MAC) and the potent anaphylatoxin C5a, resulting in activation of inflammatory pathways and platelets, leukocytes, and endothelial cells [8,24]. Chronic IVH in PNH is mediated by uncontrolled terminal complement activation and MAC formation on RBCs, white blood cells, and platelets [2,9].
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.