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Systemic Lupus Erythematosus
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Vaneet K. Sandhu, Neha V. Chiruvolu, Daniel J. Wallace
The complement system plays a key role in lupus pathophysiology, demonstrating consumption by way of reduced complement levels during disease flares. Either a genetic complement deficiency or a functional defect (i.e., antibodies targeting) in C1q, the initiator of the classical pathway and an opsonin, can lead to SLE. C1q not only is an opsonin but is also involved in removal of apoptotic cells without assembly of an inflammasome. Hence, any defect in C1q leading to decreased clearance of apoptotic cells can result in immune dysregulation. Other complements of the classical pathway including C1r, C1s, C4, and C2 have also been implicated, but to a lesser extent than C1q. Mutations in complement inhibitors such as FH and CD46 have been linked to lupus nephritis. Similarly, by amplifying the effect of C1q-driven immune complexes in kidneys, antibodies to C1q have become a predictive marker for lupus nephritis.39
Dermal filler complications and management
Published in Michael Parker, Charlie James, Fundamentals for Cosmetic Practice, 2022
The cascading nature of complement protein activation allows for rapid amplification of a signal, and therefore a trace amount of pathogenic material can result in a large and coordinated immune response. There are three main ways in which the complement cascade can be activated: The classical pathway occurs when IgG or IgM antibodies bind to and form a complex with microbial antigens with resultant phagocytosis, cytolysis and inflammation.The alternative pathway does not rely on antibodies but instead is triggered by interactions between lipid-carbohydrate complexes on the surface of microbes.The lectin pathway is initiated when macrophages digest microbes and release chemicals which stimulate the liver to produce proteins called lec-tins which bind to carbohydrates on the surface of microbes. All three of the preceding pathways can initiate the complement cascade; however, they are not independent entities and all three may be activated independently of one another at various stages of the immune response to infection.
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).
Ravulizumab for the treatment of myasthenia gravis
Published in Expert Opinion on Biological Therapy, 2023
Fiammetta Vanoli, Renato Mantegazza
The main pathogenic mechanism of AChR-antibody-mediated damage is complement activation. AChR antibodies are of IgG1 and IgG3 subclass, and thus activate the complement cascade through the classical pathway which leads to the formation of the C5 convertase and ultimately to the formation of the membrane attack complex (MAC). The MAC complex is constituted by C5b, C6, C7, C8 and polymeric C9, which together form a lytic pore on the post-synaptic membrane, which leads to the disruption of the postsynaptic folds and subsequent impairment of the neuromuscular transmission [24,25]. Ravulizumab is a humanized recombinant mAb IgG2/4 K that specifically binds C5 with high affinity, thus blocking the terminal pathway and preventing MAC formation (Figure 1). Ravulizumab spares the early components of the complement cascade that are fundamental for the opsonization of microorganisms and clearance of immunocomplexes [26].
The role of bactericidal and opsonic activity in immunity against Bordetella pertussis
Published in Expert Review of Vaccines, 2022
Pascal Blanc, Yuanqing Liu, Nathalie Reveneau, Breeze Cavell, Andrew Gorringe, Geneviève Renauld-Mongénie
The complement system consists of over 30 plasma and surface proteins able to induce three different enzymatic cascades, namely the classical (CP), alternative (AP) and mannan-binding lectin (MBL) pathways as reviewed in Geurtsen et al. [15,16]. The classical pathway is activated when C1q protein binds to the Fc region of antibodies complexed with an antigen. The alternative pathway is activated by spontaneous hydrolysis of C3 protein leading to covalent binding of C3b in association with factor B to the hydroxyl groups of carbohydrates and proteins on pathogen-surface. Pathogen specificity is tightly regulated by proteins such as factor H (FH), which prevent the activation of alternative pathway against the host cells. The MBL pathway is activated by binding of MBL to specific patterns of mannose or other sugar residues on a pathogen’s surface. All three pathways lead to the opsonization of target pathogens with the C3 component derivative C3b, and the release of inflammatory mediators, the anaphylatoxins C3a, C4a and C5a. The subsequent formation of membrane attack complex via the mobilization of the terminal complement components C5 to C9 on the target Gram negative bacterial surface results in lysis.
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.