Complement pathway

These proteins are called acute phase proteins (or reactants) and include C-reactive protein (CRP, so-named because it reacts with the C polysaccharide of pneumococci), ai-antitrypsin, haptoglobin, aj-acid glycoprotein, and fibrinogen. The elevations of the levels of these proteins vary from as little as 50% to as much as 1000-fold in the case of CRP. Their levels are also usually elevated during chronic inflammatory states and in patients with cancer. These proteins are believed to play a role in the body s response to inflammation. For example, C-reactive protein can stimulate the classic complement pathway, and ai-antitrypsin can neutralize certain proteases released during the acute inflammatory state. CRP is used as a marker of tissue injury, infection, and inflammation, and there is considerable interest in its use as a predictor of certain types of cardiovascular conditions secondary to atherosclerosis. Interleukin-1 (IL-1), a polypeptide released from mononuclear phagocytic cells, is the principal—but not the sole—stimulator of the synthesis of the majority of acute phase reactants by hepatocytes. Additional molecules such as IL-6 are involved, and they as well as IL-1 appear to work at the level of gene transcription. 

Fujita, T., Evolution of lectin-complement pathway and its role in innate immunity, Nat. Rev. Immunol., 2, 346, 2002. 

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. 

A. Histamine release via activation of classical or alternate complement pathways... 

The reported potentiation by ozone of the membrane damage produced by the indirect pathway of complement d might also play a role if it occurs in vivo, inasmuch as this complement pathway apparent mediates the allergin-reagin-induced release of histamine. in view of... 

II antigens [133,134]. Moreover, they inhibit the secretion of the complement pathway proteins C3 and factor B [135]. 

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). 

Polymorphism of the Genes in the Complement Pathways and Clinical Data Future Directions to Improve Efficacy OF Monoclonal Therapy References... 

When given rapidly, protamine causes hypotension due to a decrease in vascular resistance, possibly linked to the release of nitric oxide from endothelium. Flypotension can be minimised by slow administration over 10-15 minutes. Protamine does not affect myocardial contractility. In some patients, systemic hypotension occurs in conjunction with pulmonary hypertension and, in severe cases, right ventricular failure. The mechanism is activation of the complement pathways by the heparin-protamine complex leading to release of thromboxane A2, which mediates pulmonary vasoconstriction. Unlike in anaphylaxis, plasma histamine concentrations are not increased. When this syndrome develops protamine administration should be stopped, and some have recommended giving heparin in an attempt to reduce the size of the heparin-protamine complex. 

IFN-y also induces the costimulatory molecules on the macrophages, which increases cell-mediated immunity. As a consequence, there is activation and increase in the tumoricidal and antimicrobial activity of mononuclear phagocytes, granulocytes and NK cells. The activation of neutrophils by IFN-y includes an increase in their respiratory burst. IFN-y stimulates the cytolytic activity of NK cells. It is an activator of vascular endothelial cells, promoting CD4+ T lymphocyte adhesion and morphological alterations, which facilitates lymphocyte extravasation. IFN-y promotes opsonization by stimulating the production of IgG subclasses that activate the complement pathway. A summary of the characteristics of selected cytokines is shown in Table 2.3. 

Pearce, E.J., Hall, B.F. and Sher, A. (1990) Host-specific evasion of the alternative complement pathway by schistosomes correlates with the presence of a phospholipase C-sensitive surface molecule resembling human decay accelerating factor. The Journal of Immunology 1 44, 2751-2756. 

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. 

The early components of the complement pathway, including Cl, are proteases that activate their substrate by limited cleavage. Activated Cl now activates several molecules of the next component by proteolysis, each of which activates several molecules of the next component by proteolysis, and so on. Therefore, the early steps in complement activation consist of a proteolytic cascade in which more and more molecules are activated at each step. Component C3 is the key component whose cleavage leads to the assembly of... 

ASP infusions associated with anaphylaxis are in parallel associated with activation of the classical complement pathway (Fig. 8). 

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. 

C3b is a dangerous protein to have floating around, since it can activate the destructive end of the complement pathway. In order to minimize random damage, two proteins (factors I and H), search out, stick to, and destroy C3b in solution. But if C3b is on the surface of a cell, then another protein (properdin), binds to and protects C3b from degradation so that it can do its job. How does C3b target foreign cells in the absence of antibodies C3b is effective only if it sticks to the surface of a cell. The chemical reaction by which it does so goes faster in the presence of the molecules typically found on the surface of many bacteria and viruses. ... 

The classical complement pathway reqnires activation by circulating antibodies, IgM or IgG (specific immnne response), while the alternative and lectin pathways can be activated in the absence of antibody (non-specific immnne response). 

Complement The binding of the first component of the complement pathway. Cl, to an... 

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