Classical pathway of complement activation

FIGURE 6.9 The classical pathway of complement activation is initiated by binding of Clq to antibody on a surface such as a bacterial surface. Multiple molecules of IgG bound on the surface of a pathogen allow the binding of a single molecule of Clq to two or more Fc pieces. The binding of Clq activates the associated Clr, which becomes an active enzyme that cleaves the proenzyme Cls, generating a serine protease that initiates the classical complement cascade. 

This pathway of complement activation, which starts when antibody has bound to antigen on the microbe surface, is called the classical pathway. An alternative pathway of activation also exists which is activated directly by polysaccharides in the cell wall of microorganisms even in the absence of antibody. The alternative pathway therefore defends the body against attack in the early stages before an immune response can occur and also augments the effects of the classical pathway of complement activation when the immune response has occurred. 

The classical pathway of complement activation is closely linked to acquired immunity because it is initiated by antigen-antibody complexes binding to Cl, the first component of this pathway. Antigen-antibody complexes that... 

Although more completely understood mechanistically, the classical pathway of complement activation is as complex as... 

Classical pathway of complement activity Genetic polymorphism without clinical abnormalities... 

Fig.l. Classical pathway of complement activation. A bar over the number or letter of a factor indicates that the factor is activated (i.e. proteoly-tically active). Activation by proteolysis occurs near to the /V-terminus, producing a small (a) and a large (b) cleavage product, e.g. C3- C3a -t C3b. 

Kaplan A Mechanisms of activation of the classical pathway of complement by Hageman factor frag- 91 ment. J Chn Invest 1983 71 1450-1456. 

Rufifet E, Pires R, Pillot J, Bouvet JP Activation of the classical pathway of complement by non-immune complexes of immunoglobulins with human protein Fv (Fv fragment-binding protein). Scand J Immunol 1994 40 359-362. 

The total ethanolic extract of the stem bark and its main constituent esculin (1) were found practically non-toxic. They inhibited the classical pathway and alternative pathway of complement activation. The total extract and 1 displayed antiinflammatory activity in both zymosan- and carrageenan-induced paw edema in mice. The extract exhibited a pronounced antioxidative activity and caused intense wound epithelization. The antimicrobial and photodynamic damage prevention properties of the extract and its fractions were dependable on their... 

Guided by the complement activity two phloroglucinol derivatives, multifidol (34) (or (2-methylbutyryl)phloroglucinol) and multifidol glucoside (35) were isolated from the latex of Jathropa multifida L. (Euphorbiaceae) [24]. Both compounds inhibited the classical pathway of complement. Multifidol affected a practically complete inhibition at a concentration of 298 xM multifidol glucoside showed 100% inhibition at a much higher concentration, i.e. 1.3 xM. 

Plicatic acid (41), a lignan isolated from the heartwood of Western red cedar Thuja plicata D. Don) (Coniferae) was found to activate the classical pathway of complement. The mechanism by which this activation occurred was not completely defined at the molecular level, but appeared to involve interference with the control of active Cls in serum by Cl-In. By virtue of its ability to interfere with Cl-In in its inactivation of active Cl, plicatic acid might act as a protector of active Cl [26]. 

The classical pathway can become activated by immune complexes, bacteria, viruses, and F-XIIa. Binding occurs to the complement C1 q, a part of complement factor 1 (Cl). This initiates a cascade of activations, first of Clr, Cls, then of C4. This C4 activates C2, after which C3 becomes activated. Activated C3 initiates a cascade of activations, which are in common with the alternative pathway and which end up in activated C5-9, a membrane attack complex that lyses the target. 

Fig. 4. The classical and alternative pathway cascade of complement activation. activation Cl-inh., Cl-esterase inhibitor MACIF, membrane attack complex inhibiting factor (—CD59).

Figure 1.14. Complement activation via the classical pathway. The sequential activation of complement following antibody deposition onto a surface is shown. C9 forms a pore in the membrane, eventually leading to cell death by osmotic lysis. See text for details.

Prevalence of byssinosis correlates better with airborne endotoxin concentration than with total dust (65). Also, gramnegative bacteria levels in the mill correlate well with disease (66). It has been hypothesized that endotoxins elicit symptoms of byssinosis by activation of both the classical and the alternative pathway of complement with subsequent release of anaphylatoxins, which lead to airway narrowing, and chemotaxins, which cause the influx of PMNs followed by release of lysosomal enzymes and, ultimately, tissue damage. In experiments with guinea pigs using bract, cotton, and gin mill trash extracts, there is a strong correlation between number of PMNs recruited to airways and level of endotoxin (67). 

The complement system is a humoral effector of inflammation which is activated by a cascade mechanism through the classical and/or alternative pathway [62]. Activation of the system is normally beneficial for the host. However, excessive activation may evoke pathological reaction in a variety of immunological and degenerative diseases and hyperacute rejection in transplantation. Therefore, the modulation of complement activity should be useful in the therapy of inflammatory diseases. 

Impaired function of phagocytes and deficiency of early components of the classic pathway of the complement system result in increased apoptotic waste. This waste, including nucleosomes and other autoantigens, is formed and altered by the protease of apoptotic cells. They are expressed on the surface of apoptotic blebs and activate bystander dendritic cells. Subsequently the dendritic cells activate helper T cells, which then help B cells to generate high-affinity autoantibodies (Fig. 1). 

Once deposited, there are multiple mechanisms by which an immune complex initiates an inflammatory reaction (Fig. 2). Foremost among these is activation of the complement system. Immune complexes can activate the classical complement pathway as well as, indirectly or directly, the alternative complement pathway. The biologic activities of complement activation which are relevant to tissue inflammation include the generation of anaphylatoxins C5a and C3a (H29) and chemotactic peptide C5a (H29, T6), direct and indirect membrane lysis by the terminal complement components C56789 (T17), leukocytosis by C3e (G8), macrophage activation by Bb (G12), immune complex solubilization by C3b (C21), and immune adherence, the binding and activation of cells bearing complement receptors. 

Chonn, A., Cullis, PR., and Devine, D.V. (1991) The role of surface charge in the activation of the classical and alternative pathways of complement by liposomes. Journal of Immunology 146 4234-4241. 

In most of 19 renal specimens from autopsies of intravenous diamorphine users there was severe lymphomono-cytic glomerulonephritis as a result of activation of the classical pathway of the complement binding system (40). This could have been a result of diamorphine itself, adulterants, or active hepatitis B and/or C infection. 

Ebanks R, Jaikaran A, Carroll MC, Anderson MJ, Campbell RD, Isenman DE. A single arginine to tryptophan interchange at P-chain residue 458 of human complement component C4 accounts for the defect in the classical pathway C5 convertase activity of allotype C4A6 Implications for the location of a C5 binding site in C4. J Immunol 1992 148 2803-11. 

Ling M, Piddlesden SJ, et al. A component of the medicinal herb ephedra blocks activation in the classical and alternative pathways of complement. Clin Exp Immunol 1995 102 582-8. 

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