Complement membrane attack complex

Deng, J., Gold, D., LoVerde, P.T. and Fishelson, Z. (2003) Inhibition of the complement membrane attack complex by Schistosoma mansoni paramyosin. Infection and Immunity 71, 6402-641 0. 

Nangaku M, Pippin J, Couser WG. Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephrotic syndrome. J Am Soc Nephrol 1999 10 2323-2331. 

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. 

The alternative pathway may become activated by lipopolysaccharides, endotoxin (sepsis), virus, fungi, immunoglobulin A-antigen (IgA-Ag) immunocom-plexes, and foreign material. These activate C3, after which the common pathway of complement activation takes place (Fig. 4). There are also a number of inhibitors that regulate and control complement activation. The most important are the Cl-esterase inhibitor (Cl-Inh) and the membrane attack complex inhibitor factor (MACIF CD59). In sepsis a relative deficiency of Cl-Inh has been reported. Administration of Cl-Inh to patients with septic shock attenuates complement acti-... 

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

ApoJ is another protein component of HDL which is highly expressed by the RPE and neural retina, especially under oxidative stress conditions (Wong et al., 2000, 2001). It can act as a complement regulatory protein, which by binding to and inactivating the membrane-attack complex can prevent cytolysis (Bartl et al., 2001). ApoJ accumulation was identified in drusen in AMD patients (Sakaguchi et al., 2002 Wong et al., 2000). 

The late factors C5 to C9 are responsible for the development of the membrane attack complex (bottom). They create an ion-permeable pore in the bacterial membrane, which leads to lysis of the pathogen. This reaction is triggered by C5 convertase [2]. Depending on the type of complement activation, this enzyme has the structure C4b2o3b or C3bBb3b, and it cleaves C5 into C5a and C5b. The complex of C5b and C6 allows deposition of C7 in the bacterial membrane. C8 and numerous C9 molecules—which form the actual pore—then bind to this core. 

About 20 different proteins are included in the complement system Proteins C1-C9, factors B and D, and a series of regulatory proteins. All these proteins are made in the liver, and they circulate freely in the blood and extracellular fluid. Activation of the complement system involves a cascade of proteolytic reactions. In addition to forming membrane attack complexes, the proteolytic fragments released during the activation process promote dilation of blood vessels and the accumulation of phagocytes at the site of infection. 

Type II hypersensitivity results from the formation of antigen-antibody complexes between foreign antigen and IgM or IgG immunoglobulins. One example of this type of hypersensitivity is a blood transfusion reaction that can occur if blood is not cross-matched properly. Preformed antibodies bind to red blood cell membrane antigens that activate the complement cascade, generating a membrane attack complex that destroys the transfused red blood cells. In hemolytic disease of the newborn, anti-Rh IgG antibodies produced by an Rh-negative mother cross the placenta, bind to red... 

C11. Cybulsky, A. V., Rennke, H. G., Feintzeig, I. D., and Salant, D. J., Complement-induced glomerular epithelial cell injury The role of the membrane attack complex in rat membranous nephropathy. J. Clin. Invest. 11, 1096-1107 (1986). 

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. 

A complex of the complement proteins C5b, C6, Cl, C8 and multiple units of C9. The combination and activation of this range of complement proteins forms the membrane-attack complex, which is able to insert into bacterial cell walls and causes cell lysis with ensuing death. 

Over 20 different proteins constitute the complement system, many circulating in the blood as inactive zymogens they are synthesised mainly in the liver and account for about 5% of the globin fraction of blood serum. Proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages, resulting in the activation of the cell-killing membrane-attack complex. 

The membrane-attack complex (MAC) is the cytolytic end product of the complement cascade it forms a transmembrane channel, leading to osmotic lysis of the target cell (Fignre 15.1). 

Figure 15.1 Complement activation pathways. The classical, lectin and alternative pathways converge into a final common pathway when C3 convertase (C3 con) cleaves C3 into C3a and C3b. Ab = antibody, Ag = antigen, Cl-INH = Cl inhibitor, MAC = membrane attack complex, MASP = MBL-associated serine protease, MBL = mannose-binding lectin, P = properdin. Overbar indicates activation.

The first line of defense is accomplished through the generation of the membrane attack complex (MAC), which is assembled at the end of the complement cascade from the components generated by the proteolytic steps along the cascade. The MAC is directly involved in lysing the membranes of foreign microorganisms. 

Bacteriolysis. Bacteriolysis is a complement-mediated reaction. The last Five proteins in the cascade scif-asscmble to produce a membrane attack complex (hat disrupts the cell membranes of bacteria, acting like bacitracin or amphotericin B. The cell membranes lose integrity, cell contents leak... 

Lysis of the target cell membrane. This involves a collection of complement proteins associating upon the surface of a microbial membraneto form a membrane attack complex (MAC), which leads to the formation of membrane pores and, ultimately, microbial cell lysis. 

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 ... 

C3 is the functional link between the classical and alternative pathways of activation and between these pathways and the membrane-attack complex (see Figure 20-7). It is also present in the highest concentration of all the complement components in plasma and acts as a magnification factor. Structurally and genetically, C3 is related to C4, C5, and AMG, aU of which contain an internal thiol ester bond that, when activated, can form complexes with membranes and other structures. 

Activation of either pathway of complement results in the cleavage of C3 to C3b and C3a. The latter is released into the circulation and acts as an anaphylatoxin and a chemotaxin. C3b, with its activated thiol ester, binds to membranes and then activates the subsequent factors in the membrane-attack complex. C3b also acts as an opsonin, binding to receptors on phagocytic cells and resulting in the ingestion of bacteria, viruses, and other foreign particles by these cells. 

Complement activation also contributes to ischemic injury. Current evidence indicates that ischemia leads to the expression of neoantigen or ischemia antigen on cellular surfaces, and this induces binding of circulating IgM natural antibody. This immune complex causes Cl binding, complement activation and the formation of C3a and C3b. C3b activates the remainder of the complement cascade leading to the formation of the membrane attack complex, which is the principal mediator of injury. Complement inhibition results in less myocardial ischemia and reperfusion injury, reviewed by Chan.38... 

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