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Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
In some disorders the attachment of the particles of microorganisms to neutrophils or mononuclear phagocytes is inadequate due to an abnormalitity in the complement system or to lack of antibodies. Low serum levels of C3 or failure of activation of C3 to C3b is connected with recurrent infections. Defective serum opsonic activity has been described in newborns with low C3 and C5 levels and in patients with hepatic cirrhosis, acute glomerulonephritis, systemic lupus erythematosus, postsplenectomy, and increased catabolism of C3 component.442 In these cases, usually very virulent bacteria such as Streptococci, Pneumococci, and Haemophilus influenzae are responsible for the recurrent infection.
Inflammation and immunology
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Christopher Bellamy, Stephen J. Jenkins, Henry J. McSorley, David A. Dorward, Timothy J. Kendall
The complement system consists of more than 20 components circulating within the plasma (Figure 4.3). It is a major defence mechanism, critical in the initiation of acute inflammation. There are three pathways for the activation of complement: the classical, mannose-binding lectin (MBL), and alternative pathways of complement activation. The classical pathway of complement activation is dependent on antibody−antigen complex activation of complement component C1 and thus will be described further in the adaptive immunity section. The MBL pathway is dependent on the MBL component of the complement pathway. MBL is activated on binding to certain polysaccharides such as mannose, which do not exist in the extracellular spaces of a healthy body but are produced in large quantities by certain bacteria. Therefore, MBL can be regarded as a soluble PRR. Finally, the alternative pathway of complement activation occurs when complement component C3 spontaneously hydrolyses into C3a and C3b. C3b can then mediate further amplify complement activation by all three pathways and is required for activation of all later complement components. C3b binds to any nearby plasma membranes, which will usually be the body's own cells, which contain multiple pathways of complement control, preventing further complement activation. Bacterial cells lack these complement control components, allowing further complement activation.
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.
Monoclonal antibodies for treatment of cold agglutinin disease
Published in Expert Opinion on Biological Therapy, 2023
Georg Gelbenegger, Sigbjørn Berentsen, Bernd Jilma
Following autoantibody binding to the I antigen on the RBC surface and ensuing RBC agglutination, the IgM-antigen complex induces potent complement activation via the classical complement pathway [27] (Figure 1). Bound cold agglutinins fix and activate C1, which in turn cleaves C2 and C4 into C2a, C2b and C4a, C4b, respectively. C4b and C2a combine to form C3 convertase [15,27], which catalyzes C3 proteolysis into C3a and C3b. C3b triggers opsonization and extravascular hemolysis of RBCs in the liver [28]. RBC surface-bound C3b additionally binds C3 convertase, forming C5 convertase with subsequent production of C5a and C5b. C5b binds C6, C7, C8, and C9 to form the membrane attack complex (MAC), leading to intravascular hemolysis. C3b on surviving RBCs is converted into C3d, which is left unrecognized by phagocytes but can be identified for diagnostic purposes in the direct antiglobulin test (DAT, or direct Coombs test). Extravascular hemolysis is the predominant form of hemolysis in CAD; intravascular hemolysis occurs mainly secondarily as it is tightly regulated by CD55 and CD59 [29] but may become life-threatening. Aberrant hemolysis results in anemia, which can range from mild forms all the way to transfusion dependency [6,12,13]. Concomitant symptoms include fatigue, pallor, and dyspnea. Around 50% of CAD patients have a history of transfusion [12,13].
Immune Cell Status and Cytokines Profiles in Patients with Acute Retinal Necrosis
Published in Ocular Immunology and Inflammation, 2021
Peijun Zhang, Shixue Liu, Zhujian Wang, Min Zhou, Rui Jiang, Gezhi Xu, Qing Chang
Consistent with previous studies17, we did not identify a severe immune deficiency in terms of the expression levels of systemic immunoglobins and immune cells in ARN patients. The average level of leukocytes and complement C3 and C4 remain in the normal range. However, the C3 serum levels in the 4 out of 17 ARN patients were below the normal range. The mean value of C3 serum level in ARN patients was reduced when compared to the mean value of the normal range (105.42 ± 15.25 vs 135.00 ± 22.50). As the most abundant component of complement, C3 deficiency is rare and always marked by severe recurrent infections.18 We speculate that ARN is a systematic disease that innate immune system is persistently activated, and the persistent activation of the immune system consumes C3 in the serum, though in the normal range of reference value. Few studies have evaluated C3 level in the condition of viral infection in the eyes. Additionally, previous studies that focus on ARN and included large cohorts did not show complement levels in the serum.19 We did not measure serum and humoral C3a, C3b, and C3d levels in this study because of which we could not fully understand the mechanism of C3 decrease in a systemic scope, which may also be helpful to interpretate the slightly reduction of C3. Further studies should investigate if C3 consumption is intrinsic to the patient with ARN (mutation or overactivation) or ARN patients are susceptible to C3 consumption.
C3 Gene Functional Polymorphisms and C3 Serum Levels in Patients with Rheumatoid Arthritis
Published in Immunological Investigations, 2021
Leia Sena, Camila F. Oliveira-Toré, Thelma Skare, Iara Jose de Messias-Reason, Fabiana Antunes Andrade
Common polymorphisms in C3 gene, such as rs2230199:C > G [p.Arg102Gly] (C3S/F allotypes for slow/fast migration in electrophoresis) and rs1047286:C > T [p.Pro314Leu] have been described to affect C3b function, impacting on complement activation (Abrera-Abeleda et al. 2011; Botto et al. 1990; Heurich et al. 2011; Rodriguez et al. 2015). The amino acid substitution in p.Arg102Gly was reported to decrease overall positive charge in C3b, promoting changes in interdomain arrangements that reduces its affinity to factor H (FH), the main fluid phase complement regulator (Andrade et al., 2017; Heurich et al. 2011; Rodriguez et al. 2015). Similarly, the p.Pro314Leu substitution was predicted to be probably damaging, with an effect on C3b function (Abrera-Abeleda et al. 2011), possibly increasing its affinity to factor B (FB) and thus promoting the C3 convertase formation of the alternative pathway (Abrera-Abeleda et al. 2011). The rs2230199:C > G and rs1047286:C > T polymorphisms have already been associated with diverse complement-related diseases including Age Related Macular Degeneration (Paun et al. 2016; Zhang et al. 2015), type 1 Diabetes (Törn et al. 2016), cognitive impairment in Multiple Sclerosis (Roostaei et al. 2019) and Dense Deposit Disease (Abrera-Abeleda et al. 2011). However, the impact of these polymorphisms on RA has not yet been reported. In this context, the present study aimed to evaluate the association of C3 gene functional polymorphisms with the susceptibility and clinical presentation of RA in a Brazilian cohort.