Complement System PDF

Complement system Complement system is one of the major effector mechanisms of innate immunity. It also plays an important role in acquired immunity. Complement system is composed of more than 30 different plasma proteins. These proteins are produced mainly by the liver. They are also produced loca...

Complement system Complement system is one of the major effector mechanisms of innate immunity. It also plays an important role in acquired immunity. Complement system is composed of more than 30 different plasma proteins. These proteins are produced mainly by the liver. They are also produced locally by macrophages. Some complement proteins are produced by epithelial cells (e.g. GIT). In the absence of infection, these proteins circulate in an inactive form but in the presence of pathogens they become activated. Complement proteins are found in plasma and tissue fluids. Complement protein are designated by the letter C followed by a number for example Cl, C2, C3, C4, etc. Some complement proteins bind to components of the microbial membrane or to antibodies bound to antigens. Others are zymogens (pro-enzymes) with latent protease activity that when activated cleave one or more of other complement proteins. When enzymatically cleaved, the larger fragment binds to microbial membrane and the smaller fragment is released. The letter “b” is usually added to the name of the larger fragment and the letter “a” to the smaller fragment (e.g. C4b and C4a). The only exception is for C2 in which the larger fragment can also be given the letter “a” and the small fragment the letter “b”. Complement activation pathways: There are three major pathways of complement activation: classical, lectin and alternative pathway. Each pathway requires different proteins to initiate its activation but the late steps are similar. The classical pathway is activated by certain types of antibodies bound to antigens. The alternative pathway is activated on microbial cell surfaces in the absence of antibody. The lectin pathway is activated by binding to the mannose residues on microbes. All of the three pathways result ultimately in the activation of the C3 and the formation of the C5 convertase which leads to the activation of the lytic pathway. 1- Classical pathway: The classical pathway is initiated by binding of the C1 to the constant region (Fc) of IgG or IgM antibodies. C1 is a multi-subunit protein containing three different proteins (C1q, C1r2 and C1s2). The enzymatic activity of C1 resides in C1r and C1s. The function of C1q is the binding to the antibody. C1q binds to IgG or IgM antibodies that have bound to antigenic surfaces. It does not bind to free antibodies. Each C1q molecule must bind to at least two constant regions to be activated. The binding requires presence of calcium and magnesium. The binding of C1q to the antigen-antibody complex results in activation of C1r which in turn cleaves and activates C1s. The active C1s cleaves C4 into C4a and C4b. The C4b fragment binds to the membrane and C4a is released. The active C1s also cleaves C2 into C2a and C2b. C2a binds to membrane in association with C4b and C2b is released. The resulting C4b2a complex is the C3 convertase which cleaves C3 into C3a and C3b. C3b binds to the membrane in association with C4b2a and C3a is released. The resulting C4b2a3b is the C5 convertase which cleaves C5 into C5b and C5a and initiates lytic pathway. Lytic pathway (Formation of Membrane attack complex; MAC) This stage begins when the C5 is cleaved by C5 convertase into C5a and C5b. C5b combines with the C6 to form C5b6 which, in turn, binds to C7 forming C5b67 complex. C5b67 complex is strongly hydrophobic and as a result interacts with the membrane lipids. One C5b67 molecule can combine with one molecule of C8 and multiple molecules of C9 (up to 15 molecules) to form membrane attack complex (MAC). MAC creates pores in the microbial membrane resulting in microbe lysis. 2- Alternative pathway: It does not require antibodies. Alternative pathway is in continuous state of low-level activation. Activation of the alternative pathway occurs in two cascades: 1- Fluid phase C3 convertase (Tickover activation): The fluid cascade is initiated when the internal thioester bond of C3 is spontaneously hydrolyzed to form C3i [or C3(H2O)]. C3i then binds to the alternative pathway protein called factor B to form C3iB. C3iB is cleaved by another alternative protein called factor D (serine protease) to form C3iBb and release Ba. C3iBb complex is instable and rapidly decays. C3iBb complex is called the fluid-phase alternative C3 convertase which cleaves C3 into C3b and C3a. 2- Membrane-bound alternative cascade:When C3b generated by tickover activation binds to a microbial surface, it will bind factor B to form solid phase C3bB which is cleaved by factor D to form instable C3bBb.C3bBb is stabilized by properdin to form stable C3bBbP. C3bBbP is the solid-phase alternative C3 convertase. C3bBbP cleaves C3 into C3a and C3b. C3b remains with the C3bBbP to form C3bBbP3b, the alternative pathway C5 convertase which cleaves C5 and initiates lytic pathway.