Alternative pathway of complement activation

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... 

Figure 5. Alternative pathway of complement activation amplification loop. Schematic outline of the alternative pathway and the positive feedback loop initiated by C3b. Because of the uncertainty over whether all activating substances utilize the same initial steps, these steps have not been included.

Gotze O, Miiller-Eberhard HJ (1971) The C3-activation system An alternate pathway of complement activation. J Exp Med 134 905-1085... 

Figure 5.4 The Alternative Pathway of Complement Activation. C3 is spontaneously hydrolysed without cleavage of C3a, to become C3b (like). This has the ability to cleave factor B. Combination of C3b (like) with Bb forms a C3 convertase capable of cleaving further C3 into C3b and the anaphylotoxin C3a. Fluid phase C3b is unstable and rapidly inactivated by control proteins, but the availability of a suitable protective surface serves to bind and stabilise the C3b. Stabilisation results in activation of the alternative pathway and constitutes recognition of the protective surface as foreign. C3b can then cleave more factor B to form the true C3 convertase C3bBbP, itself stabilised by the enhancing control protein Properdin (P).

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-... 

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). 

Recently, other reports have appeared (31). as well as our own studies (32). showing that cotton dust activates the alternate pathway of complement. Previous studies in this laboratory (33.34). showed that antibodies to water extracts of cotton dust, cotton bract, and a highly purified fraction of dust elicited positive immunological responses in rabbits. 

The activation of complement occurs exclusively on the microbial cell membrane, where it is triggered either by bound antibody or microbial envelope polysaccharides, both of which activate early complement components. Two sets of early components belong to two distinct pathways of complement activation Cl, C2, and C4 belong to the pathway that is triggered by antibody binding factors B and D belong to the alternative pathway that is triggered by micro-... 

The presence of edema and increased skin fragility (often the site of entrance of bacteria) are among the causes of increased risk of infections in nephrotic syndrome. Losses of immunoglobulin G and factor B (from the alternative pathway of the activation of complement) into the urine weaken the ability of the defense system to respond mainly to encapsulated microbes like pneumococci. The function of lymphocytes can be further weakened as a consequence of losses of zinc and transferrin into the urine. Weakening of the phagocytic function of macrophages has been described as well. 

It is also a well established fact that dextran sulfate modulates the immune response with effects on macrophages [119], proliferation of B-lymphocytes [120], and helper T-lymphocytes [121], It has been implicated as an activator of C3 via the alternative pathway of complement [122]. Numerous reports claim that dextran sulfate is a potent inhibitor of human immunodeficiency virus (HIV), Herpes simplex virus (HSV) and other pathogens [123-125]. 

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. 

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. 

Henry SP, Giclas PC, Leeds J, Pangburn M, Auletta C, Levin AA, Kornbrust DJ. Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide potential mechanism of action. J Pharmacol Exp Therapeut 1997 281(2) 810-6. 

The principal pathway of complement activation, which is part of the innate immunity of the organism, is the alternative pathway. The designation of this pathway as alternative reflects order of discovery and acceptance, not... 

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. 

Both subclasses of serum IgA in aggregated form weakly activate the alternate pathway of complement but the structural basis for this function is not understood at the present time. Cell surface Fc receptors for IgA have been reported [83,84],... 

In a number of cases, the drug may also trigger the inflammatory cells also responsible for true allergic reactions by different mechanisms than those involving antibodies or sensitized cells. This is the case, for example, of the direct nonim-munological activation of mast cells (Stanworth 1980) or of the activation of the alternate pathway of complement (Haensch et al. 1980 Voigtlaender et al. 

The plot of CL intensity versus time presented in figure 6 shows the effect of varying the quantity of fresh autologous serum used as the source of complement. Zymosan, a boiled, proteolytically digested preparation of yeast cells, was used as the particle to be phagocytosed. Zymosan is well established as an activator of the alternative pathway of complement. Each vial contained an equivalent quantity of zymosan. The differences in the curves of CL therefore reflect the quantity of serum used for opsonification. 

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