Alternate pathway complement cascade

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. 

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

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-... 

The complement system which functions as part of the immune response is composed of about twenty proteins which circulate in the blood stream as inactive precursors. The complement cascade is functionally divided into two arms called the classical and alternative pathways, reflecting their different initiating events but which converge at C3. A simplified scheme is shown in Figure 5.25. 

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

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). 

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. 

Antibodies bound to an invading microorganism activate the complement system via the classical pathway. This consists of a cascade of proteolytic reactions leading to the formation of membrane attack complexes on the plasma membrane of the microorganism that cause its lysis. Polysaccharides on the surface of infecting microorganisms can also activate complement directly in the absence of antibody via the alternative pathway. 

Figure 7-2 Control of the alternative complement pathway by activating surfaces. When complement component C3b binds to a surface, there exist two possible outcomes. Under normal conditions, when no activating surface is present (e g., if C3b has contacted normal tissue), sequential addition of blood cofactors H and I converts C3b into C3c, inactivating the complement protein. If an activating surface such as a microbe or damaged tissue is encountered, sequential addition of factors B and D drives the alternative pathway to the normal properdin (P) intermediate, and the complement cascade is triggered. The properdin-containing component (C3bBbP) feeds back to the beginning of the pathway, generating more C3.

Figure 8.3 shows a highly schematized view of the activation cascade for the alternative complement pathway upon a microbial membrane surface. The activation steps in the alternative pathway are also shown in Fig. 8.7, which contrasts with the activation steps in the classical complement pathway involving antibody. 

A complement cascade similar to that of the alternative pathway can be activated through specific antibody-antigen interactions. The antibodies that activate the classical complement pathway are IgM and IgG. 

Figure 20-7 Overview of the complement cascades. Activation via the classical pathway is shown on the left and via the alternative pathway on the right. Continuous tickover by hydrolysis of C3 to C3i is shown at the center top. Direct activation of C3 by neutrophil and plasma proteases also may occur.The control mechanisms are shaded. (Courtesy j.W. Whicher, with modifications.)...

Some of the best known anti-inflammatory triterpenoids have been shown to have inhibitory activity on the complement cascade. A mixture of the aforementioned boswellic acids reduced in a dose-dependent manner the classic pathway activity by as much as 77%, and C3-convertase by 72% [118]. Oleanolic acid showed 85% and 71% inhibition, respectively, in the same tests, at a single dose of 100 jxg/ml [119], and P-glycyrrhetinic acid inhibited the classic human pathway with an IC50 of 35 xM. The component affected was C2. The a form of glycyrrhetinic acid was fairly inactive [120]. None of these three triterpenoids appreciably inhibited the alternative complement pathway. 

Two complement pathways can operate, the classical pathway and the alternative pathway. The classical pathway is analagous to the coagulation cascade, activation of the Cl component eventually leading to activation of the other components. The classical pathway can be initiated by a number of substances, the most important probably being the antibody molecule. The alternative pathway can be activated by other substances. It bypasses the Cl, C2 and C4 components. 

Evidence for complement consumption in acute PEM has also been presented. Chandra (1975) has demonstrated significant immunocon-glutinin titers, an antibody to activated complement components, in acute PEM. Consistent with this observation, Chandra also found electrophoretically altered C3 in serum of such patients, and in some subjects anticomplementary activity capable of reducing the hemolytic complement titer through activation of the complement cascade. Haller et al. (1978) have also reported increased levels of C3D and reduced factor B, suggesting vivo activation of the alternative pathway. We have demonstrated diminished serum opsonic activity in acute PEM for IE. coli (Keusch et al., 1977a, b) particularly for a strain opsonized via the alternative pathway. 

Complement Activation Complement proteins are so-named because they complement antibody activity to eliminate pathogens. The alternate pathway of the complement cascade is normally activated by bacterial surface molecules. Complement activation during dialysis was first identified by the rapid drop in white blood cell counts (neutropenia) during the first 30 min of dialysis. Regenerated cellulose membranes activate complement through the alternate pathway (Chenoweth et al., 1983). Modified cellulose membranes approach the biocompatibility profile of synthetic materials in terms of neutropenia and complement activation. 

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