The Acute Phase Complement Proteins
Andrzej Mackiewicz, Irving Kushner, Heinz Baumann in Acute Phase Proteins, 2020
C4 is a heterotrimeric glycoprotein of approximately 200 kDa.31 The protein is synthesized as a single-chain precurosr (prepro-C4)32 programmed by a 5.5-kb mature mRNA.33 In humans, two genes, C4A and C4B, polymorphic in size and fine structure, encode the C4 transcripts.34-36 Processing prepro-C4 requires proteolytic cleavage by a signal peptidase, excision of two interchain linking peptides, generation of a thiolester bridge, glycosylation of α- and β-chain residues via a dolichol phosphate intermediate, sulfation, and cleavage of a carboxy terminal fragment of the α-chain by an extracellular metalloproteinase.37-39 Processing and secretion of C4 occurs with a half-time of about 60 to 90 min,40 a rate similar to the kinetics of the synthesis, processing, and secretion of C3 and C5 in hepatoma Hep G2 cells.19,41 The mature C4 protein is activated by cleavage of C4a (a weak anaphylotoxin), a 9-kDa NH2 terminal fragment from the α-chain, leaving the remainder, C4b. The latter serves as a subunit of the C3 cleaving enzyme of the classical pathway.
The complement system in health and disease
Gabriel Virella in Medical Immunology, 2019
As native C4 molecules come into contact with the C1-immune complex, they bind and are cleaved by activated C1s into a small fragment, which remains soluble (C4a), and a larger fragment, C4b. As a helpful rule, fragments released into the fluid phase are often designated by the letter a, while those fragments that remain bound to membranes are designated by the letter b. However, the nomenclature of C2 fragments is reversed, i.e., the bound fragment is designated as C2a, and the soluble fragment as C2b. Each activated C1 is able to cleave and convert many C4 molecules to C4a and C4b. The second fragment derived from C4, C4b, has a very short-lived and highly reactive binding site, an acylating group. This active binding site allows C4b to bind covalently to the nearest hydroxy or amino group, which is usually located on the antigenic surface. Antibody-coated viral envelopes or antibody-coated bacterial membranes serve as excellent sites for C4b deposition. Any activated C4b molecules that do not reach the nearby antigenic surface within a few nanoseconds (unable to bind covalently to the antigen) will lose their short-lived active binding site and undergo conformational changes that facilitate binding to a serum factor termed C4-binding protein. Binding of C4b to C4 binding protein causes rapid loss of C4b function and is a very important control mechanism to protect the host's tissues from “bystander attack” by the C4b molecules being formed in areas of infection.
Complement-Mediated Lipopolysaccharide Release
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
Activation of the complement cascade sets in motion a series of events that (1) facilitate the extravasation of mononuclear phagocytes into areas of infection, (2) destroy invading microorganisms by opsonization or by direct MAC-mediated membrane damage, and (3) clear the blood of antigens such as bacteria and bacterial debris by routing C3b-bound antigens to the liver and spleen for ingestion by hepatic and splenic macrophages. Anaphylatoxins, the low molecular weight split products C3a, C4a, and C5a, act on mast cells and basophils to release histamine and other inflammatory mediators, increasing vasopermeability and vasodilation. C5a is also a potent chemotactic agent, facilitating the extravasation of neutrophils into inflamed tissue. Mononuclear phagocytes possess receptors for C3b and C4b and will readily bind, internalize, and degrade microorganisms coated with these complement proteins (9). Human erythrocytes also possess receptors for C3b, and erythrocyte binding to C3b-coated particulate antigens or immune complexes is important in clearing antigen from the bloodstream (1). Finally, as discussed above, under the appropriate circumstances, the MAC mediates direct bacteriolysis. Thus, although the biological properites of activated complement components are legion (Table 1), the proteins are designed to recognize and eliminate infectious agents, foreign particles, or altered self molecules.
Levels of lymphocyte-associated regulators of complement system CD55 and CD59 are changed in schizophrenia patients
Published in International Journal of Psychiatry in Clinical Practice, 2021
Alper Togay, Bilge Togay, Deniz Ozbay Gediz, Sadıka Halide Akbaş, Sadi Köksoy
Genome-wide association studies on schizophrenia detected a strong association with loci in the MHC region (Ripke et al. 2014), which was confirmed by later studies with larger sample sizes (Li et al. 2017; Pardiñas et al. 2018). Further studies demonstrated that this association may be explained by the involvement of the complement system and specifically by the complement factor 4A (C4A) (Sekar et al. 2016). The classical complement cascade is important for the synaptic refinement and pruning in the developing central nervous system, and inhibition of C4 results in reduced synaptic pruning in mice (Sekar et al. 2016). Since synaptic pruning is also altered in schizophrenia (Wang et al. 2019), many studies were conducted to reveal the role of immune system genes in the disease (Li et al. 2017; Sanders et al. 2017; Pardiñas et al. 2018). In a recent study, Sager et al. (2020) reported that CD46 and CD55 were increased in the human prefrontal cortex in the first 5 years of life, suggesting that dysregulation of complement system may predispose the brain to neurodevelopmental disorders such as schizophrenia. However, the involvement of immune system in the disease aetiology and pathology is still not well understood.
Neuroinflammation and oxidative stress in schizophrenia: are these opportunities for repurposing?
Published in Postgraduate Medicine, 2022
Zarrin Ansari, Sudhir Pawar, Rajmohan Seetharaman
The major histocompatibility (MHC) locus located on chromosome 6 has the highest association with SCZ. Incidentally, this region encodes genes that are involved with innate immunity. The complement component 4A (C4A), highly associated with SCZ, is also associated with the innate immunity system that recognizes foreign pathogens and apoptotic cells and leads them to their destruction by macrophages. This complement component also plays an important role in the various stages of brain development, including neurogenesis, cellular migration, and microglia-mediated pruning of the synapses. The above findings may suggest that the complement component may be directly implicated for its impact on SCZ pathology. Also, various genomic studies have implicated alteration of cytokines in SCZ, reflected by alteration in the regulatory functions of interferons and interleukins. All these together simply imply that SCZ and neuroinflammation have a complex genetic association and this needs to be further validated [53].
The correlation of neutrophil-to-lymphocyte ratio with the presence and short-time curative effect of myasthenia gravis in children: a retrospectively study
Published in International Journal of Neuroscience, 2021
Zhi Jiang, Zeshu Ning, Liming Yang, Bo Chen, Jingwen Tang, Jie Zhang, Hongjun Fang, Rong Xu, Feng Guo, Mei Chen, Kaisheng Sun
MG patients have all kinds of Th cells in the body, such as Thl cells mainly the proinflammatory cytokines including IFN-γ, IL-2. IFN-γ is an important cytokine secretion, wherein the Thl cells have been shown to participate in a variety of autoimmune and infectious diseases. MG is associated with Th17 cells and their secreted cytokines. Cytokines such as IL-17A, IL-17F, IL-21, IL-22 and TNF-α induce and maintain inflammatory responses in tissues [3, 7, 23]. Because this study is a retrospective study, and these tests are expensive and have not finished (Our hospital can not test IL-17A, IL-17F, IL-21, IL-22 and other factors). We can’t do any further analysis. Complement system is also involved in the course of MG disease. In MG patients, there is an obvious increase in complement consumption, and slight decrease of C3 and C4 complement systems [22]. After activation of complement system, C3a, C4a and C5a were generated, causing inflammatory reactions as allergic toxins.
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