Activation of complement

Vascular Effects of Complement Activation. During complement activation a number of complement fragments (anaphylatoxins), which are polypeptides with inflammatory properties, are released. The anaphylatoxins C3a and C5a induce smooth muscle contraction and enhance vascular permeability (H31). The most pronounced activation of complement with the formation of anaphylatoxins and terminal C5-9 complexes has been observed in septic shock (B29, B30, P2). Studies indicate that there is a relation between high concentrations of anaphylatoxins and C5-9 complexes and the development of ARDS or MODS in patients with sepsis (H10). 

In thrombotic episodes accompanied by activation of complement, C, -esterase inhibitor is consumed by binding to the C,-esterase that is formed, leading to an increase in the C(-esterase inhibitor complex (93). 

When compared with human monoclonals (half-life 14-21 days), murine monoclonals administered to humans display a relatively short half-life (30-40 h). Chimaerization increased serum half-life by fivefold, with typical values of 230 h being recorded (Table 13.4). A prolonged half-life is desirable if the antibody is to be used therapeutically, as it decreases the required frequency of product administration. Chimaeric antibodies also allow activation of Fc-mediated functions (e.g. activation of complement, etc.), as this domain displays human sequence. 

Chan-Yeung, M., Giclas, PC., and Henson, P.M., Activation of complement by plicatic acid, the chemical compound responsible for asthma due to western red cedar (Thuja plicata), J. Allergy Clin Immunol., 65, 333, 1980. 

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. 

Cl Binds with IgG or IgM on membrane of the target cell to initiate activation of complement cascade... 

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.

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. 

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-... 

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... 

Figure 17.6 A summaiy of the three pathways for activation of complement. See text for details.

The substitution of nickel for other essential elements may also contribute to the adverse effects of nickel. Nickel can replace magnesium in certain steps in the activation of complement (McCoy and Kenney 1992). For example, nickel greatly increased the half-life and stability of the C3b, Bb enzyme which amplifies activation of the complement pathway. Nickel has also been shown to activate calcineurin, a phosphatase that binds zinc and iron, and which is usually activated by manganese (Kenney and McCoy 1992). 

It is clearly desirable to study the activation of complement in more detail, particularly to show an explicit dependence of the rate of Cl activation on the two-dimensional diffusion constant D. This would... 

Complement is a group of more than 30 proteins found in blood serum, which are activated in a cascade mechanism when antibody and antigen com-bine10/111/142 148 (Eq. 31-1). This classical pathway for activation of complement is outlined in Fig. 31-8. The proteins involved in the cascade are designated Cl to C9. Many of them undergo proteolytic cleavage, the... 

Activated Clr (often designated Clr but here and in Fig. 31-8 as Clr) is one of five different serine proteases involved in activation of complement.156 The substrate for the trypsinlike Clr is Cls, a proenzyme which is converted by the action of Clr into another trypsinlike serine protease Cls.157 160 Through a rather elaborate cascade mechanism, depicted in Fig. 31-8, the important proenzyme C2 is activated.161 Its active form C2a is a serine protease, which cleaves proteins C3 and C5 to the active forms C3b and C5b. Protein C4 is also cleaved to C4b by activated Cl. C4 and C3 are also activated, and protein C5 is cleaved... 

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-... 

IgG Immunoglobulin G is present in lymph fluid, blood, cerebrospinal fluid and peritoneal fluid. It is composed of 2 y chains of 50 kDa and 2 L chains (k or ) of 25 kDa with a total molecular weight of 150 kDa. The functions of IgG include agglutination and formation of precipitate, passage through placenta and thus conferring immunity to fetus, opsonization, antibody-dependent cell-mediated cytotoxicity (ADCC), activation of complement, neutralization of toxins, immobilization of bacteria and neutralization of virus. 

Podocyte damage in membranous nephropathy is probably caused by the local activation of complement with the formation of the membranolytic complex C5b-C9. Locally formed chemotactic fragments of complement (e.g., C5a) do not penetrate through the glomerular basement membrane, and that is why in membranous nephropathy glomeruli are not infiltrated with leukocytes. 

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. 

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. 

Although it has, to date, not been possible to identify any common structural feature among all the polysaccharide capsules of bacteria associated with the most pathogenic human disease, there is one common feature in many of them. The capsular polysaccharide of type III group B Streptococcus has terminal sialic acid residues in its structure,62,63 as do the groups B and C N. meningitidis and K1 E. coli.3 -34 The ability of terminal sialic acid residues to inhibit the activation of complement by way of the alternative pathway has been well docu-... 

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