Target cell lysis Opsonization Activation of the inflammatory response (e.g. degranulation, extravasation) Clearance of immune complexes

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1 Immunology Dr. John J. Haddad Chapter 13 Complement Major roles of complement (Figure 13-1): Target cell lysis Opsonization Activation of the inflammatory response (e.g. degranulation, extravasation) Clearance of immune complexes There are three major pathways of complement activation (sometimes called complement fixation ): Classical pathway involves antibodies Alternative pathway no antibody is required Lectin pathway similar to the classical pathway in most of its components, but it is initiated by mannosebinding lectin (MBL), an acute phase protein made in response to microbial infection. The MBL binds to mannose on microbial surfaces. All three pathways can generate a membrane attack complex (MAC) that inserts into membranes of cells, susceptible bacteria and enveloped viruses and makes them osmotically unstable, resulting in lysis. They all also generate small diffusible reaction products that induce local vasodilation and chemotaxis of phagocytic cells, resulting in inflammation. They all also enhance phagocytosis by binding to complement receptors on phagocytic cells. Complement proteins are synthesized and secreted by liver hepatocytes, blood monocytes, tissue macrophages, and epithelial cells of the gastrointestinal and genitourinary tracts. Many of the complement components are proenzymes that have their active sites masked. Activation occurs by proteolytic cleavage, resulting in removal of the mask and exposure of the active site. Each of the pathways involve a cascade of proteolytic steps. By convention, an activated enzyme in a complement pathway is indicated with a bar drawn over it. Note: In learning and studying the complement pathways, focus heavily on Figure 13-2 in the text, and know your way around this figure. The pictures shown in Figures 13-3 and 13-5 may help you picture what is going on, but they are cartoons. You should understand complement activation by knowing the names of the components and the roles they play in the respective pathways. Classical pathway of complement activation The classical pathway begins with antibody binding to a surface. IgM is the best activator, but the IgG1, IgG2 and IgG3 isotypes also can activate complement. IgM does it best because it is a pentamer of four-chain units and therefore contains five Fc regions in close proximity. The first component of the classical pathway, C1, crosslinks Fc fragments. For IgG to activate complement, independent IgG molecules must bind to the surface no more than nanometers apart to allow crosslinking by C1q. One IgM molecule is enough to allow complement to lyse a red blood cell, whereas about 1,000 IgG molecules are required. C1q is associated with C1r and C1s. Binding of C1q to immunoglobulin causes a conformational change in C1r to autocatalytically activate itself to C1r-bar. C1r-bar then activates C1s to C1s-bar, which then cleaves C4 (to C4a and C4b). C4b covalently binds to a cell surface near C1q by an amide linkage, and C4a diffuses away. 63

2 C2 binds to C4b, and then is cleaved by C2s-bar to C2a (which remains associated with C4b) and C2a which diffuses away. C4b2a-bar is called the classical C3 convertase, and its activity is to cleave C3 into C3b and C3a. The C3 convertase catalyzes the amplification step in complement activation, since one C3 convertase complex can cleave more than 200 C3 molecules. When C3 is cleaved, a thioester bond becomes labile and reactive carbonyl group on C3b reacts with hydroxyl or amino groups on the cell surface. Thus many C3b molecules become covalently bound to the cell surface. The C3a fragment diffuses away. Some C3b molecules associate with C4b2a to form C4b2a3b-(bar), the classical C5 convertase, which cleaves C5 into C5b, which attaches to the cell surface, and C5a which diffuses away. Cleavage of C5 is the last proteolytic step in the classical pathway. The C5b fragment initiates the assembly of the membrane attack complex (MAC) to be discussed a bit later. Alternative pathway of complement activation The alternative pathway can also generate the C5b protein by a pathway involving four proteins: C3, factor B, factor D and properdin. It does not involve antibody. Both gram-negative and gram-positive microorganisms, as well as some other foreign substances and organisms (Table 13-3), can activate complement by the alternative pathway. The unstable thioester bond of C3 (referred to above) can spontaneously hydrolyze at a low frequency to form C3b and C3a, and the C3b can attach covalently to the bacterial or mammalian cell surface. The sialic acid present on mammalian cell surface glycoproteins generally inactivates C3b that binds to mammalian cell surfaces. However, bacteria do not have sialic acid, and the C3b remains active long enough to bind factor B in the presence of Mg +2 ion. Factor D then cleaves factor B, and Bb remains in a complex with C3b (C3bBb-bar) while the Ba fragment diffuses away. C3bBb-bar has C3 convertase activity, and it is referred to as the alternative pathway C3 convertase. C3bBb-bar is unstable and has a half-life of only 5 minutes unless properdin binds and stabilizes it. The stabilized complex has a half-life of 30 minutes. As in the classical pathway, the C3 convertase catalyzes the amplification step, cleaving as many as 200 C3 molecules. As many as 2 x 10 6 generated in 5 minutes. Many attach covalently to the surface on which the complement was activated (see above). Some associate with C3bBb to form C3bBb3b(bar) the alternative pathway C5 convertase. Like the classical C5 convertase, C4b2a3b(bar), it cleaves C5 to generate C5b which inserts into membranes to start forming the MAC complex, and C5a that diffuses away. Lectin pathway of complement activation The mannose-binding lectin, MBL, is an acute phase protein that is produced upon microbial infection. It binds to mannose on the surface of microorganisms, and a protease associated with MBL, MASP (for MBL-associated protease) that resembles C1qr, cleaves C4 and C2 to generate C4b2a(bar), the classical C3 convertase. From there on, it is just like the classical pathway. Formation of the MAC complex C5b is very labile, and is inactivated within 2 minutes unless it is stabilized by binding of C6 (Figure 13-5, panels e and f). As C5b6 binds C7 to form C5b67, it undergoes a conformational change that exposes hybrophobic regions that enable it to insert into the phospholipid membrane if activation occurred on a cell. Subsequent binding of C8 generates C5b678 which makes a small pore, or channel, through the membrane approximately 10 angstroms in diameter. Subsequent binding and polymerization of molecules of C9 generates a much larger pore angstroms in diameter. Ions and small molecules diffuse freely, and cell undergoes osmotic lysis, 64

3 If C5b67 is generated on an immune complex that does not sit on a membrane, it is released into the medium. If it encounters a nearby cell before decaying (i.e., becoming inactive) it can insert there and cause bystander lysis by building a MAC on the nearby uninvolved cell. This can contribute to some disease processes. 65

4 Regulation of the complement system The action of complement much be confine to designated targets because once activated, complement s activity is non-specific. Many of the proteins that regulate complement are described in Table One intrinsic aspect that contributes to regulation is the inherent instability of intermediary components. For example, C3b s site for attachment to membranes becomes inactive by the time it diffuses 40 nm away from the C3 convertase that generated it. 2. Inhibitory proteins exist. For example, C1InH form as a complex with C1r2s2 and promotes its dissociation from C1q. Inhibits classical pathway. 3. There is a whole family of C3 convertase regulators. This is an important step at which to regulate complement since it prevents the major amplification step. The regulatory proteins consist of a number of structurally-related proteins containing short consensus repeats (CSRs) of amino acids. They are encoded by closely-linked genes in the regulators of complement activation (RCA) locus on human chromosome 1. The pathways of action of several of these are illustrated in Figure Several of these prevent assembly of the classical C3 convertase by binding to C4b ((C4bBP, CR1, MCP)) and preventing attachment of C2a. In the alternative pathway, regulatory components bind to C3b (CR1, MCP or factor H) and prevent attachment of B. The C4b or C3b is then inactivated by cleavage by the serum protease, factor I. Several regulatory components cause dissociation the enzymatically-active component (C2a or Bb) from the classical or alternative pathway C3 convertase, respectively. C4bBP, CR1, factor H and decay-accelerating factor (DAF) all have this activity. Once dissociated, the cell-bound component (C4b or C3b) is inactivated by cleavage by factor I. Interestingly, the mechanism of generation of C3d, the component that binds to CR2 (CD21) that makes up art of the B cell coreceptor (see Chapter 11, Figure 11-9) is described in Figure Complement activity is also regulated at the level of the MAC. Your own cells are generally resistant to lysis by your own or any human complement due to two proteins present on the membrane of many cell types homologous restriction factor (HRF) and membrane inhibitor of reactive lysis (MIRL, or CD59). These bind to C8 and prevent assembly and membrane insertion of C9. Interestingly, transplantation of an organ from a different species (a xenogeneic organ) into a human results in very fast rejection (called hyperacute rejection) of the organ, largely because of complement activation and the inability of the xenogeneic HRF and MIRL to inactivate human complement. Studies are being done in which pig HRF and MIRL are being genetically replaced by human HRF and MIRL. Studies in monkeys suggest that this approach may protect a transplanted xenogeneic organ from hyperacute rejection. Biological consequences of complement activation These are summarized in Table Antibody and complement play a major role in lysis of membrane-coated particles or cells by means of the MAC. Susceptible targets include enveloped viruses (e.g., retroviruses like HIV) and many gramnegative bacteria. Some gram-negative bacteria escape lysis by fabricating a smooth coat that is resistant to MAC insertion. Gram-positive bacteria are generally resistant to MAC insertion due to a thick peptidoglycan cell wall layer or capsule. Streptoccus pneumoniae can activate complement, but C3b cannot covalently attach to it because of its capsule. 66

5 Other organisms produce proteins that mimic the effect of normal complement regulatory components such as C4bBP, CR1 and DAF, thereby protecting themselves from lysis. Many nucleated cells, including most cancer cells, can endocytose the MAC, thereby preventing osmotic disruption and death by osmotic lysis. 2. Complement opsonizes immune complexes, or makes them highly susceptible to phagocytosis. The C3b or C4b bound to the immune complexes or particle surfaces binds to complement receptors C1, C3 and C4. They are then phagocytosed. Some degradation products also bind (e.g., ic3b). The C5a product of C5 cleavage increases the number of CR1 molecules on the neutrophil surface ten-fold from 5,000 to 50,000, thereby facilitating phagocytosis. 3. Complement participates in virus neutralization by coating the virus and preventing attachment and subsequent infection of cells. Coated viruses also can be bound by complement receptors on inflammatory cells including neutrophils and macrophages, and this leads to their destruction by phagocytosis or by release of toxic mediators. 4. Complement facilitates clearance of immune complexes from the body. Deficiency in complement components that comprise C1, C2 or C4 can predispose a person to the autoimmune disease, lupus erythematosis. This is because when autoimmune complexes are formed, the classical pathway cannot generate C3b to opsonize the complexes. Deficiency in complement receptor 1 (CR1) which binds C3b also predisposes to lupus. This is because the CR1 on the surface of red blood cells (RBCs) participated in clearing immune complexes from the body. There are only about 100 CR1 molecules on each RBC surface, but there are so many RBCs, they can carry a lot of immune complexes. These complexes are stripped from the RBCs in the liver and spleen, and the complexes are phagosytosed and destroyed (Figure 13-14). 5. Complement plays a major role in the inflammatory response. When we described the steps in complement activation, we referred to C3a, C4a and C5ab as fragments that diffused away and did not participate in the complexes that were forming. These components are potent mediators called anaphylatoxins that bind to receptors on mast cells and basophils and stimulate release of histamine. C5a is the most powerful of the anaphylatoxins and is active at concentrations as low as M. Histamine has potent effects, increasing vascular permeability and stimulating smooth muscle contraction. C3a, C5a and C5b67 all contribute to inflammation by inducing extravasation of monocytes and neutrophils. Deficiencies in complement components or in regulators of complement can cause a number of serious diseases or susceptibilities C3 deficiencies are the most severe. Without C3, the MAC cannot be activated. Other deficiencies make a person susceptible to specific problems. For example, factor D or properdin deficiencies are associated with recurrent Neisseria infections. Deficiency of C1Inh, which occurs in 1 of 1000 people as an autosomal dominant, gives rise to hereditary angioedema. Deficiency of DAF or HRF due to a defective glycosyl phosphatidylinositol membrane anchor can lead to inability to inactivate MACs that may insert into a patient s own cells. RBCs can be lysed, resulting in paroxysmal nocturnal hemoglobinurea (hemoglobin in the patient s urine) due to chronic hemolytic anemia. 67

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