Complement system alternative pathway

Proteins of the Complement System Alternative, Classical, Lectin, and Membrane Attack Pathways and Complement Regulating Proteins... 

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-... 

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... 

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. 

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). 

Factors Cl to C4 (for complement ) belong to the classic pathway, while factors B and D form the reactive components of the alternative pathway. Factors C5 to C9 are responsible for membrane attack. Other components not shown here regulate the system. 

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 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. 

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. 

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. 

Capsular polysaccharides are actively involved in the mediation of complement, in that they are able to suppress the activation of the immediate, alternative-pathway mechanism, thus forcing the immune system to use the classical pathway this is an important factor in the virulence of bacteria (see Section VI,1). 

Complement components Host defence against infectious and inflammatory processes Complement C3, C5a, B, D, I and P levels are all reduced in hepatitis and cirrhosis There are 16 components of the complement system, which is divided into the classic and alternative pathways... 

Jatrorrhizine was found to possess anti-inflammatory activity as measured in the cobra venom factor-induced (CVF) rat paw edema. CVF edema was used to examine jatrorrhizine and other substances in order to detect novel compounds, since it has been shown that joint cyclooxygenase and lipoxygenase inhibitors, as well as immunoreactive drugs, exhibit more pronounced inhibitory effects on CVF in comparison to carrageenin-induced edema. CVF edema is dependent on activation of the complement system which plays an important role in acute and chronic inflammatory reactions, mediating the activity of immune complexes. This test system represents a functionally new type of acute inflammation via activation of the alternative complement pathway [290]. 

The sequential activation of either the classical or the alternative pathway, with or without complete activation of the membrane-attack complex, produces biological effector molecules that initiate inflammation and facilitate the elimination of the antigens either by lysis (e.g., bacteria) or phagocytosis (e.g., immune complexes). A few of the specific functions of the complement system follow ... 

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