Complement system activation pathways

Cascade systems also provide for response to more than one allosteric stimulus in a single pathway. Thus, as shown in Fig. 11-4, glycogen catabolism can be initiated in more than one way. Two pathways are known for initiation of both blood clotting and activation of the complement system. Many pathways activate the MAP kinase pathway shown in Fig. 11-13. 

Figure 31-8 Pathways for activation of the complement system. Active proteases are designated by abbreviations in boldface.

Recently, a potential cytosolic component of the MEP precursor pathway, xylulose kinase, has been cloned and tested for function in an Escherichia coli complementation system. " The kinase activates exogenous xylulose in the cytoplasm. DXP is the precursor for DXS, which resides in the plastid, suggesting the activated substrate must be transported into the plastid. Another xylulose kinase homologue in Arabidopsis that contains a plastid targeting sequence was not active in the E. coli system, suggesting that it may have some other function in the plastid. Perhaps plant and bacterial tissue cultures may be fed xylulose to condition accumulation of isoprenoid metabolites. 

Kl. Kalter, E. S., Daha, M. R Ten Cate, J. W Verhoef, J., and Bouma, B. N., Activation and inhibition of Hageman factor-dependent pathways and the complement system in uncomplicated bacteremia or bacterial shock. J. Infect. Dis. 151,1019-1027 (1985). 

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-... 

Herceptin attaches to the HER2/neu receptor and activates the complement system (a series of serum and cell-associated proteins involved in immune response) to destroy those cells expressing such receptors. Through this action, Herceptin disrupts the signaling pathway for breast cancer cell proliferation (refer to diagram below). 

Activation of the Complement System by Antibody-Antigen Complexes The Classical Pathway R. R. Porter and K. B. M. Reid... 

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. 

MBP is present in various mammalian sera and activates the complement system through the classical pathway. It also specifically binds to murine monoclonal IgM and, hence, can be used to purify IgM MAb from mouse ascitic fluids. The binding reaction is calcium-dependent, so that IgM can be specifically eluted with a buffer containing a calcium chelator (e.g., EDTA). 

The principal stages in complement activation. Complement activation occurs exclusively on the microbial cell membrane, where it is triggered 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. Activation of each complement system involves a cascade of proteolytic reactions. Each component of the complement system is a proenzyme that is activated by the preceding component of the chain by a limited proteolytic cleavage. The ultimate result of this chain reaction is the development of a complex that attacks the cell membrane. 

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). 

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. 

The complement system consists of about 20 interacting soluble proteins that circulate in the blood and extracellular fluid. Immunoglobulin molecules bound to the surface of the microorganisms activate Cl, the first component of the complement pathway. The activation occurs through the Fc portion (see Topic D2) of the bound antibody. Only bound antibody can activate complement, soluble antibody not bound to an antigen has no such effect. 

In addition to these immediate changes within the complement system, which occur within minutes, there are "Chronic" changes probably arising from hypo-synthesis of the components as it has been discussed for the dotting factors. IgG antibodies predominantly belong to subclasses IgGl and IgG3 [141], which coincides wdl with these subclasses ability to activate the classical complement pathway. 

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. 

The complement system has been reviewed151,152 it is composed of a series of proteins, C1-C9, present in normal human serum, that serve as important mediators in the host defense. The terminal components, C3-C9, are involved in the destruction of invading microorganisms, but, in order to achieve this, they have to be activated. This activation process can be divided into two pathways, the alternative pathway and the classical pathway, although both pathways can occur simultaneously in the host defense-mechanism. 

The MBlectin pathway is initiated by the interaction of the MBlectin with a bacterial cell surface polysaccharide. The activation of complement component C3 is common to all three pathways. It is noted that there are similarities to the blood coagulation cascade. See Sim, R.B., Ed., Activators and Inhibitors of Complement, Kluwer Academic, Dordrecht, Netherlands, 1993 Whaley, K., Loos, M., and Weiler, J., Eds., Complement in Health and Disease, 2nd ed., Kluwer Academic, Dordrecht, Netherlands, 1993 Rother, K., Till, G.O., and Hansch, G.M., Eds., The Complement System, 2nd ed.. Springer, Berlin, 1998 Volanakis, J.E. and Erank, M.M., Eds., The Human Complement System in Health and Disease, Marcel Dekker, New York, 1998 Prodinger, W.M., Wurznen, R., Erdei, A., and Dierich, M.P., Complement, in Fundamental Immunology, Paul, W.E., Ed., Lippincott-Raven, Philadelphia, 1999, pp. 967-995 Lambis, J.D. and Holer, K.M., Eds., Therapeutic Interventions in the Complement System, Humana Press, Totowa, NJ, 2000 Szebeni, J., The Complement System Novel Roles in Health and Disease, Kluwer Academic, Boston, 2004. 

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