Complement activation alternative pathway

Complement can be activated by two pathways, the classical pathway and the alternative pathway (Fig. 14.4). 

The complement cascade may become activated via two pathways the classical pathway or the alternative pathway. 

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. 

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-... 

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

CH50 determinations can be used to analyze the total serum complement and are useful for monitoring immune complex diseases (Sullivan, 1989) activation of complement (Table 15.13) in the presence of autoantibodies is indicative of immune complex diseases and autoimmunity. The various components of the complement system (C3, C4) can also be measured to assess the integrity of the system. For instance, low serum concentrations of C3 and C4, with a concomitant decrease in CH50 may indicate activation of complement, while a low C4 alone is a sensitive indicator of reduced activation of the complement system. Since C3 is used as an alternate complement pathway, it usually measures high. Therefore, a low C3 with a normal C4 may indicate an alternate pathway of activation. 

The complement system comprises twenty plasma proteins present in the blood and in most bodily fluids. They are normally present in an inactive form but become activated via two separate pathways the classical pathway, which requires antibody, and the alternative pathway, which does not. Once the initial components of complement are activated, a cascade reac-... 

Activation of complement via the alternative pathway requires no antibody-antigen complexes. It may be activated by endotoxin (LPS) on the surface of many Gram-negative organisms, by zymosan of the cell walls of many yeasts or by aggregated IgA. 

Figure 1.15. Complement activation via the alternative pathway. Always present in serum are trace amounts of C3b, which may attach to recognition sites on, for example, yeast cell walls. C3b may combine with serum factor B to form C3bB, and this complex is acted upon by factor D to form C3bBb. This latter complex is a C3 convertase and may act upon C3 to form more C3b to amplify the process. The C3bBb-coated particles may activate other complement components (C4-C9) or be recognised by complement receptors on neutrophils.

Upon activation of complement (by either the classical or alternative pathways), C3 binds covalently to the target, and an internal thioester bond in C3 is rearranged to yield a free sulphydryl group on C3 and an ester link between C3 and a hydroxyl group on the target (Fig. 3.8). The resulting co-... 

Complement A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed components of complement and are designated by the symbols... 

Figure 5.25 Complement cascade. The classical pathway requires antigen antibody (Ag Ab) interaction to activate Cl, the alternative pathway is antigen independent...

Cotton dust activates complement vitro by both the classical (antibody dependent) and alternative (antibody independent) pathways (12,47,48). It is proposed that endotoxins may be the agents responsible for complement activation (49). Cotton dust extractions maximizing endotoxin content are 10 times more potent than other extracts in activating complement (12). Activation of complement via the alternative pathway has also been... 

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). 

There are two parallel, but entirely independent pathways leading to activation of the terminal, biologically important portion of the complement sequence. These mechanisms of activation, termed the classical and alternative pathways, are triggered by different substances. The two pathways converge at C3 (midpoint) while the remainder of the reaction sequence, involving the reactions of C5 through C9, is common to both pathways. 

In vitro studies indicate that cotton mill dust extracts do activate complement by the alternative pathway. Kutz et al. (36) proposed that endotoxin is not the only agent responsible for complement activation, as microgram rather than nanogram quantities of purified endotoxin are required to induce the degree of complement activation observed with crude cotton dust extract. Several investigators (36, 37) have thus proposed endotoxin... 

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. 

Complement Some microorganisms produce proteins that bind to and inactivate components of the complement system and hence decrease activation of the cascade, e.g. the vaccinia virus secretes a protein that inhibits activation of both the classical and alternative pathways. Some bacteria produce a protein that mimics the action of an acceleration factor, which increases the rate of destruction of the active convertase this factor is normally produced by the host when the complement response is no longer required. 

The reactions that take place in the complement system can be initiated in several ways. During the early phase of infection, lipopoly-saccharides and other structures on the surface of the pathogens trigger the alternative pathway (right). If antibodies against the pathogens become available later, the antigen-antibody complexes formed activate the classic pathway (left). Acute-phase proteins (see p. 276) are also able to start the complement cascade lectin pathway, not shown). 

LPS are known to activate complement via the alternative pathway. Regression of subcutaneous MH134 tumor in C3H/He mice was shown to implicate the complement as part of the antitumoral effect of LPS [62] but this effect has not been since documented. 

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. 

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-... 

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