Complement activation regulation

Historical aspects of immunology 4.5.3 Regulation of complement activity... 

The alternative pathway may become activated by lipopolysaccharides, endotoxin (sepsis), virus, fungi, immunoglobulin A-antigen (IgA-Ag) immunocom-plexes, and foreign material. These activate C3, after which the common pathway of complement activation takes place (Fig. 4). There are also a number of inhibitors that regulate and control complement activation. The most important are the Cl-esterase inhibitor (Cl-Inh) and the membrane attack complex inhibitor factor (MACIF CD59). In sepsis a relative deficiency of Cl-Inh has been reported. Administration of Cl-Inh to patients with septic shock attenuates complement acti-... 

The procoagulant factors produced by endothelial cells are the coagulation factors von Willebrand factor (WF), F-V, F-VIII, tissue factor (TF), and plasminogen activator inhibitor (PAI), which blocks the activators u-PA and t-PA and counteracts fibrinolysis (G21, FI6). It has been shown that under the influence of complement activation (C9), in response to endotoxin in vitro (C24), in experimental E. coli sepsis in baboons (D30), and after stimulation with TNF (Al, N6), endothelial cells up-regulate the expression of TF, down-regulate TM and inhibit the production of t-PA and PAF. Thus, the balance may shift in the procoagulant direction with a large excess of PAI-1. 

Murthy, K. H., et al. (2001). Crystal structure of a complement control protein that regulates both pathways of complement activation and binds heparan sulfate proteoglycans. Cell 104,301-311. 

RE Edens, RJ Linhardt, JM Weiler. Heparin, not just an anticoagulant anymore six and one-half decades of studies on the ability of heparin to regulate complement activation. Compl Prof 1 96-120, 1993. 

Finally, other factors but the onconeural antibodies may predispose an individual to neuronal damage or contribute to inflammation. We have reported lack of expression of the complement regulator protein CD59 on the surface of Purkinje cells in individuals with PCD, indicating vulnerability to the effects of complement activation [202]. Complement depositis have been found in the brain stem of a patient with paraneoplastic OM [80], Others have found absent or weak complement deposition in postmortem studies of the brain of PEM/SN patients [41, 203, 204], suggesting that... 

In humans, there are five isotypes of antibodies, IgG, IgA, IgD, IgE, and IgM, which are defined by the structures of their heavy chains and their abilities to form multimers (Figure 10.1) [8], IgG is the most abundant isotype present in serum with average serum concentrations ranging from 0.5 to 9mg/ml depending on the IgG subtype. This is followed by IgA (3mg/ml), IgM (1.5mg/ml), IgE (0.05 mg/ml), and IgD (trace). Each antibody isotype has unique functions. Critical functions of IgG include opsonization, complement activation, antibody-dependent cell-mediated cytotoxicity (ADCC), passive immunity, and regulation of B cells. Both IgM and IgD act as antigen receptors on naive B cells, and soluble, multimeric forms of IgM are involved in complement activation. IgA is involved in mucosal and passive neonatal immunity, while IgE is involved in immediate hypersensitivity [8],... 

The significance of exon shuffling to protein evolution, in particular in respect to the development of multicellularity, is signified by a short inventory of processes involving proteins created by modular assembly. Exon shuffling facilitates the construction of proteins involved in regulation of blood coagulation, fibrinolysis, and complement activation, plus most constituents of the extracellular matrix, cell adhesion proteins, and receptor proteins [10, 57]. 

Mold C, Gewurz H, Du Clos TW. Regulation of complement activation by C-reactive protein. Immunopathology 1999 42(l-3) 23 30. 

Enzyme inhibition is one of the ways in which enzyme activity is regulated experimentally or naturally. Most therapeutic drugs function by inhibition of a specific enzyme. Inhibitor studies have contributed much of the available information about enzyme kinetics and mechanisms. In the body, some of the processes controlled by enzyme inhibition are blood coagulation (hemostasis), blood clot dissolution (fibrinolysis), complement activation, connective tissue turnover, and inflammatory reactions. 

Another type of regulation is accomplished by a series of proenzymes in which activation of the initial proenzyme by a biological signal activates the second proenzyme which, in turn, activates the third, and so on. Such an enzyme cascade process provides great amplification in terms of the amount of final product formed. Examples are blood coagulation, the dissolution of blood clots, complement activation, and glycogen breakdown. 

This is a further example of the importance of system balance. Insufficiencies in key components of complement would result in a devastating outcome with regard to certain infectious diseases, despite the use of antibiotics or other chemotherapeutic agents. On the other hand, unrestrained complement activation would cause severe damage to bystander cells. In a healthy body, complement activity is held in check by a variety of regulatory factors, known as regulators of complement activation (RCA).19... 

Identification of serum complement activation with the use of ellipsometry. Activation of the immune complement system in blood, has been described in connection with haemodialysis and leukapheresis It results in various "down stream symptoms" such as transient leukopenia (29-32). Activation of complement on a surface implies sequential activation of several factors. The activation process shows similarity with the clotting system of blood in that restricted proteolysis of some of the factors is one of the main regulation mechanisms and that activation is of the cascade type. C3 is the quantitatively dominating complement protein and has a central position in the complement activation cascade. 

In addition to their direct antimicrobial activity [15] defensins, whose functional overlap with chemokines has recently been confirmed, enhance phagocytosis, promote neutrophil recruitment, boost the production of proinflammatory cytokines and regulate complement activation, thus upregulating innate host inflammatory defenses [15]. They also contribute to adaptive immune responses by selectively attracting immature DCs, CD8+ T cells,... 

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