Cell triggering by activated complement components (original) (raw)
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Complement System Part I – Molecular Mechanisms of Activation and Regulation
Frontiers in Immunology, 2015
Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here, we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical, and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack-complex. We will also discuss the importance of structure-function relationships using the example of atypical hemolytic uremic syndrome. Lastly, we will discuss the development and benefits of therapies using complement inhibitors.
COMPLEMENT RECEPTOR IS AN INHIBITOR OF THE COMPLEMENT CASCADE
1981
Human erythrocytes interact with particles or soluble immune complexes bearing C3b, the major fragment of the third component of complement. This phenomenon is known as immune adherence (1). B lymphocytes (2), neutrophils, macrophages, monocytes (3-5), and epithelial cells of the kidney glomerulus (6) also have membrane receptors for C3b. The C3b receptors function in phagocytosis, facilitating the attachment of the particle to the phagocytes, and, in synergy with the Fc receptors for IgG, promote ingestion of sensitized particles (7, 8). Recently, a glycoprotein of 205,000 mol wt has been isolated from the membrane of human erythrocytes and identified as the C3b receptor (CR1) (9, 10). This protein was characterized as an inhibitor of the alternative pathway C3 convertase (C3b,Bb) and as a cofactor for the cleavage of the a' chain of C3b in the fluid phase by a serum enzyme, C3b/C4b inactivator.
Annals of the New York Academy of Sciences, 1983
The third (C3) and fourth (C4) components of serum complement, and the plasma proteinase inhibitor a,-macroglobulin (a,M), are known to possess an unusual reactivity, in that, once these proteins are activated by limited proteolysis, they develop a short-lived active site through which they can attach themselves covalently to suitable "acceptor" molecules.'-* The physiological roles of the two complement proteins and of a,M do not appear superficially to be closely related, but all three proteins have important roles in clearance of exogenous material from the circulation. q M is known as a proteinase inhibitor of wide specificity and its principal physiological role is likely to be the trapping of cellular and exogenous endopeptidases and removal of these proteins from circulationP Additional actions of a,M and its possible role in modulation of the immune system have been discussed by James." Proteolytic enzymes are thought to be inhibited by a,M mainly via a noncovalent entrapment process that occurs after the proteases have "activated" q M by cleaving it." Although it is now clear that a proportion of the protease molecules become covalently bound to qM,' covalent binding is not required for inhibition of proteases, and the significance of the covalent binding of a,M to proteases is therefore uncertain. It is possible however, that covalent binding of a,M to bystander molecules other than proteases may be of physiological significance.
New insights into the molecular mechanisms of classical complement activation
Molecular Immunology, 2010
C1q, the initiator of the classical complement cascade, is a versatile molecule with numerous ligands and variety of functions. Recent mutagenesis, epitope mapping and structural data brought novel understanding of the molecular mechanisms of C1q binding to target molecules, and subsequent C1 activation. Evidence has emerged suggesting that residues located within the C1q apical surface, and the exposed side surface of the B chain, facilitate the interaction of C1q with the majority of C1q ligands. The binding of C1q to IgG, IgM, CRP, and PTX3 is most likely a contiguous process, developing in different phases. During the initial phase, residues located within the gC1q apex, and shared between the three chains, are involved in the interaction with the ligands. After this initial recognition event, the Ca 2+ ion is attracted by the negatively charged C1q ligand. This loss of the Ca 2+ ion induces a rotation of the globular C1q head, facilitating further ligand binding, and transmitting an activation signal to C1r-C1s. This review summarizes these data, and offers a unifying model for C1 activation by negatively charged gC1q targets.
American Journal of Medical Sciences and Medicine, 2014
The multiple interconnections among complement proteins, immune cells, and mediators provide an excellent mechanism to protect the organism against infections and support the repair of damaged tissues. However, disturbances in this "defense machinery" contribute to the pathogenesis of various diseases. The role of complement in various inflammatory disorders is multifaceted; for example, the activation of complement can significantly contribute to inflammation-mediated tissue damage, whereas inherited or acquired complement deficiencies highly favor the development of autoimmunity. Complement as an essential component of the immune system is of substantial relevance for the destruction of invading microorganisms and for maintaining tissue homeostasis including the protection against autoimmune diseases. The involvement of complement in the pathogenesis of a great number of partly life threatening diseases defines the importance to develop inhibitors which specifically interfere with its deleterious action. Endogenous soluble complement-inhibitors, antibodies or low molecular weight antagonists, either blocking key proteins of the cascade reaction or neutralizing the action of the complementderived anaphylatoxins have successfully been tested in various animal models over the past years.
The activation of complement components by aggregates of antibodies and their fragments
Molecular Immunology, 1979
The relative consumption of the complement components Cl, C2, C3 and C4 from guinea pig serum on addition of rabbit antibody-antigen aggregates, papain digested aggregates, heat aggregated rabbit IgG and Fc has been measured. It has been found that antibody-antigen aggregates are much more efficient with respect to consumption of all four components than heat aggregated IgG which in turn is more efficient than heat aggregated Fc. In the latter two preparations the inefficiency is most marked with C2 and C3 consumption.