The complement system
- 1. The Complement System NEHA AGARWAL 155066 B.SC. HONS DEI , AGRA
- 2. A complex consisting of at least 20 serum proteins, which, once activated, acts like a part of the innate immune defense The complement components are present in serum in inactive form The complement is activated in a cascading manner (= each protein activates that following) and it has widespread physiologic and pathophysiologic effects Complement proteins are synthesized mainly in the liver, but tissue macrophages and fibroblasts can synthesize some complement proteins as well
- 3. Functions Recruit inflammatory cells (promoting inflammation). Opsonize microbial pathogens and immune complexes (facilitating antigen clearance). Kill microbial pathogens (via a lytic mechanism known as the membrane attack complex). Generate an
- 5. (1) The complement pathways are initiated by proteins that bind to pathogens, either directly or via an antibody or other pathogenspecifi c protein. After a conformational change, (2) Enzymatic mediators activate other enzymes that generate the central proteins of the complement cascade, the C3 and C5 convertases, which cleave C3 and C5, releasing active components that mediate all functions of complement, including (3) opsonization, (4) Inflammation, and (5) the generation of the membrane attack complex (MAC). Effector complement proteins can label an antibody-antigen complex for phagocytosis (opsonins), initiate inflammation (anaphylatoxins), or bind to a pathogen and nucleate the formation of the MAC. Often, these eff ectors act through (6) complement receptors on phagocytic cells, granulocytes, or erythrocytes. (7) Regulatory proteins limit the eff ects of complement by promoting their degradation or preventing their binding to host Proteins Involved in the Complement System
- 7. Pathways of complement activationAlthough the initiating event of each of the three pathways of complement activation is different, they all converge in the generation of an enzyme complex capable of cleaving the C3 molecule into two fragments, C3a and C3b. Th e enzymes that accomplish this biochemical transformation are referred to as C3 convertases. The classical and lectin pathways use the dimer C4b2a for their C3 convertase activity, while the alternative pathway uses C3bBb to achieve the same end; however, the fi nal result is the same: a dramatic increase in the concentration of C3b, a centrally located and multifunctional complement protein. C3b is an opsonin The second set of convertase enzymes of the cascade,C5 convertases, are formed by the addition of a C3b component to the C3 convertases. C5 convertases cleave C5 into the infl ammatory mediator, C5a, and C5b,
- 12. MB-LECTIN PATHWAY: Mannan binding lectin (MBL).
- 14. Alternative complement pathway activation.
- 15. C4b2a3b complex, also called C5 convertase, cleaves C5 into C5a, which is a soluble inflammatory mediator, and C5b, which is capable of complexing with additional complement components. The generation of C5b initiates the final phase of complement activation, which is the formation of the Membrane Attack Complex (MAC). The MAC is identical for all pathways of complement activation. C3a and C5a remain soluble and produce local inflammatory effects.
- 18. Up to this point in the complement cascades, all of the complement reactions take place on the hydrophilic surfaces of microbes or on immune complexes in the fl uid phase of blood, lymph, or tissues. In contrast, when C5b binds C6 and C7, the resulting complex undergoes a conformational change that exposes hydrophobic regions on the surface of the C7 component capable of inserting into the interior of the microbial membrane Released C5b67 complexes can insert into the membrane of nearby cells and mediate “innocent bystander” lysis. Under physiologic conditions, such lysis is usually minimized by regulatory proteins C8 is made up of two peptide chains: C8 alpha gamma and C8beta. Binding of C8beta to the C5b67 complex induces a conformational change in the C8 dimer such that the hydrophobic domain of C8 can insert into the interior of the phospholipid membrane. The C5b678 complex can create a small pore, 10 Å in diameter, and formation of this pore can lead to lysis of red blood cells, but not of nucleated cells. The final step in the formation of the MAC is the binding and polymerization of C9 to the C5b678 complex. As many as 10 to 19 molecules of C9 can be bound and polymerized by a single C5b678 complex. During polymerization, the C9 molecules undergo a transition, so that they, too, can insert into the membrane. The completed MAC, which has a tubular form and functional pore diameter of 70 Å to 100 Å, consists of a C5b678 complex surrounded by a poly-C9 complex (Figure 6- 10b). Loss of plasma membrane integrity leads irreversibly to cell death.
- 21. Human Complement Component Deficiencies Deficiencies of components. Deficiencies of complement components are very rare. Defects in the early components of the classical pathway do not lead to overwhelming infection, as the MBL and alternative pathways can bypass this defect