Herpes Simplex Virus Vaccines and the Viral Strategies Used to Evade Host Immunity
Marie Studahl, Paola Cinque, Tomas Bergström in Herpes Simplex Viruses, 2017
Activation of complement occurs by one of three mechanisms: the classical, lectin, or alternative complement pathways (Fig. 1). The classical complement pathway is initiated upon the binding of antibody to the surface of pathogens or in an antibody-independent manner when C1q, the first component of the complement cascade, binds directly to targets. These targets include bacterial lipopolysaccharide, nucleic acids, polyanionic compounds, myelin, and some viruses. The lectin complement pathway recognizes mannose and N-acetyl glucosamine residues on bacteria, while the alternative complement pathway recognizes foreign surfaces. Together, these three pathways are able to recognize and activate the complement system against a diverse range of microbial pathogens.
The complement system in health and disease
Gabriel Virella in Medical Immunology, 2019
The classical complement pathway is predominantly initiated by antibody-dependent mechanisms, although a number of other antibody-independent mechanisms have been described (Tables 9.1 and 9.2). Immunoglobulins and native complement components are normally found in the serum and in the lymph, but these molecules do not interact with each other until the antibodies interact with their corresponding antigens and undergo the necessary secondary and tertiary conformational changes (Figure 9.2). These immunoglobulin conformational changes are required and the basis for specific activation of the very powerful classical complement pathway. While antibodies are central to this activation, not all immunoglobulin activate complement equally. The general order of complement-activating activity is IgM > IgG3 > IgG1 > IgG2 >> IgG4. IgA can activate the alternative pathway, and IgE generally has no complement fixing activity except under unusual inflammatory situations. For immunoglobulins to promote complement fixation, IgM and IgG are required to bind to antigen, and this binding induces conformational changes in the antibody that facilitate binding of the first complement component, C1.
The humoral response to lung transplantation
Wickii T. Vigneswaran, Edward R. Garrity, John A. Odell in LUNG Transplantation, 2016
Binding of an anti-HLA donor-specific antibody (DSA) with its cognate HLA ligand on the lung allograft triggers a potentially deleterious immune response that results in allograft injury and dysfunction. Amplification of the immune response is dependent on activation of the complement system via the classical pathway. It is now understood that not all DSAs are complement-fixing antibodies; specifically, not all anti-HLA antibodies activate the complement system after binding with HLA molecules. The role of non–complement-fixing antibodies in AMR remains controversial, but an evolving consensus suggests that they are less likely to be alloreactive. The C1q assay aims to distinguish complement-fixing from non–complement-fixing antibodies by identifying only antibodies that can bind to C1q, the first step of the classical complement pathway. C1q-positive anti-HLA DSAs have been shown to be associated with poor outcomes in heart transplantation.14,15 A landmark paper by Loupy and colleagues16 demonstrated that following kidney transplantation, patients with CIq-positive DSAs experienced greater graft loss than did patients with DSAs that were C1q negative. Of note, stratification of patients before transplantation according to C1q positivity did not predict subsequent poor outcomes. Equivalent studies in lung transplantation are awaited.
Multi-functional antibody profiling for malaria vaccine development and evaluation
Published in Expert Review of Vaccines, 2021
D. Herbert Opi, Liriye Kurtovic, Jo-Anne Chan, Jessica L. Horton, Gaoqian Feng, James G. Beeson
Complement is an essential arm of the immune system comprising of more than 30 serum proteins, which act in a sequential cascade to mediate various immunological responses [118]. Complement can be activated by antibodies through interactions with complement protein C1q, which initiates the classical complement pathway. C1q-fixation (together with components C1r and C1s) leads to the deposition of complement protein C3 on target cells. Deposited C3 acts as an opsonin that interacts with complement receptors including CR1, CR2, C3, CR4, and CRIg that are expressed on immune cells including macrophages and neutrophils, to facilitate pathogen uptake and degradation via complement-mediated phagocytosis [118]. The terminal step in complement activation is the formation of the membrane attack complex (MAC) that inserts into the target cell membrane and causes cell lysis.
Acute renal failure with need for renal replacement therapy as a complication of zoonotic S. zooepidemicus infection: case report and review of the literature
Published in Acta Clinica Belgica, 2018
Laurens Veldeman, Katrien De Wilde, Dirk Vogelaers, Evelyne Lerut, An Vonck, Dien Mertens, Annelies Koch, Jan Beckers
A renal biopsy is not indicated in children with a typical course of PSGN unless the diagnosis is doubtful, or in the face of rapidly progressive renal insufficiency.1 Histopathology shows a light microscopic pattern of acute exudative glomerulonephritis with diffuse endocapillary proliferation and infiltration of different immunocompetent cells (mainly neutrophils, but also macrophages and T-lymphocyts).4,11 Typical immunofluorescence shows mostly granular C3 and IgG glomerular staining in mesangium and basement membrane (a ‘starry sky’ pattern).12 Subepithelial electron dense depositions, ‘humps’, are seen on electron microscopy, (with or without intramembranous, mesangial, and subendothelial deposits).11 These immune depositions are shown to consist of IgG, C3, properdin, and C5, components of the alternative complement pathway, and never consist of classical complement pathway components such as C1q or C4. This observation led to the hypothesis that the alternative complement pathway is essential in disease activity.1,13,14
Effects of terminal galactose residues in mannose α1-6 arm of Fc-glycan on the effector functions of therapeutic monoclonal antibodies
Published in mAbs, 2019
Michihiko Aoyama, Noritaka Hashii, Wataru Tsukimura, Kenji Osumi, Akira Harazono, Minoru Tada, Masato Kiyoshi, Akio Matsuda, Akiko Ishii-Watabe
Activation of the classical complement pathway, which is the mechanism of CDC, is triggered by the binding of the C1 complex, formed by the recognition molecule C1q and serine proteases C1r and C1s, to the antigen–antibody complex.35 In this study, we demonstrated that the terminal Gal residue on the Man α1-6 arm of Fc-glycans is more critical for modulating C1q-binding and CDC activities than those on the Man α1-3 arm. Although it was reported that the galactosylation level of N-glycan affects the CDC activity of mAbs,13,15 we demonstrated that the mono-galactosylated glycan isomers (G1aF and G1bF) have different CDC activities. In addition, we evaluated the FcγR-binding activities of four glycoengineered mAbs. Although previous studies showed inconsistent results about the effect of Fc-galactosylation on FcγRIIIa binding affinity,13,14,36,37 our results clearly demonstrated that the galactosylation on the Man α1-6 arm of Fc-glycans increased the FcγRIIIa binding and activation property. One reason for the previous inconsistent results could be that mixtures with differences in the ratio of G1aF and G1bF mAbs were used as typical G1F mAb samples in each study. We also revealed that the FcγRIIa, FcγRIIb, and FcγRIIIb binding activities were increased depending on the galactosylation of the Man α1-6 arm of Fc-glycans (Supplementary Figure S3). These findings were supported by several reports.37–39 In light of these data, enhancements of FcγRs binding activities could be commonly dependent on the galactosylation of the Man α1-6 arm of Fc-glycans.
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