The complement system and innate immunity - part 2.docx

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McGill University
Microbiology and Immun (Sci)
MIMM 314

The complement system and innate immunity 11:11 AM 2-18 Surface bound C3 convertase deposits large numbers of C3b fragments on pathogen surfaces and generates C5 convertase activity  The formation of C3 convedrtases is the point where all three pathways converge o C4b2a and C3bBb both cleave C3 into C3a and C3b. C3 is the most abundant complement protein in plasma and it allows upto 1000 molecules of C3b to attach onto the surface of pathogens; thus the main effect of the complement system is to deposit large amounts of C3b on the surface of the infection pathogen where it forms a covalently bonded coat that can signal the ultimate destruction of the pathogen by phagocytes  Next step in the complement cascade: generation of C5 convertase. o In the classical and lectin pathways, C5 convertase is formed by the binding of C3b to the C4b2a to form C4b2a3b. Similarly, in the alternative pathway, C5 convertase is formed by the binding of C3b to C3bBb to make C3b 2b.  C5 convertase captures C5 molecules by binding them on an acceptor site on C3b and the serine proteases, C2a or Bb cleave them into C5a, the inflammatory mediator and C5b which unlike C3b and C4b, is not attached on the cell surface; rather it initiates the assembly of the terminal complement components  C5 can only be cleaved by C3b that is in turn bound to c4b2a or C3bBb to form the active C5 convertase. 2-19 Ingestion of complement-tagged pathogens by phagocytes is mediated by receptors for the bound complement proteins  Most important functionof the complement is to facilitate the uptake and destruction of pathogens by phagocytic cells: o This occurs by the binding of COMPLMENT RECEPTORS (CRs) on phagocytes with complement components on the pathogen surfaces  CRs bind pathogens opsonized with complement components; opsonization of pathogens is a major function of C3b and its proteolytic derivatives  C4b is also acts as an opsonin but has a relatively minor role; largely because so much more C3b is produced o Best characterized is the C3b receptor, CR1 (CD35) which is expressed on both macrophages and neutrophils. But binding of C3b to CR1 cannot by itself stimulate phagocytosis, it needs the presence of other immune mediators that activate phagocytes.  For ex, C5a can activate macrophages, the C5a receptor, which has seven membrane- spanning domains. Receptors of this kind couple with G proteins and the C5a receptor signals in this way  CR2 or CD21, CR3 or CD11b:Cd18 and CR4 or CD11c:CD18 bind to inactivated forms of C3b that remain attached to the pathogen surface.  iC3b acts as an opsonin when it bound to CR3 and can induce phagocytosis on its own without other mediators (like CR1)  Another breakdown protein of C3b is C3dg which only binds to CR2, found on B cells as part of a co-receptor complex that can augment the signal received through the Ag-specific immunoglobulin receptor.  Thus an antibody whose antigen receptor is specific for a given pathogen, will receive a highly augmented signal if C3bdg is also bound on the pathogen. 2-20 Small fragments of some complement proteins can initiate a local inflammatory response  C3a, C4a and C5a produce act on specific receptors to produce local inflammatory responses o When produced in large amounts or injected systematically, they induce a generalized circulatory collapse, I.e. Anaphylactic shock. They are sometimes called anaphylatoxins. o All three induce smooth muscle contractions and increase vascular permeability but C5a, and C3a also act on the endothelial cells lining blood vessels to induce adhesion molecules.  Changes produced by C5a and C3a recruit Abs, complement and phagocytic cells to the site of an infec and the increased fluid in the tissues hastens the movement of pathogen-bearing APCs to the local lymph nodes contributing to initiation of adaptive response  C5a also acts on neutrophils and monocytes to increase their adherence to vessel walls, their migration toward sites of Ag deposition, and their ability to ingest particles. C5a also increases the expression of CR1 and CR3 on the surfaces of these cells. 2-21 The terminal complement proteins polymerize to form pores in membranes that can kill certain pathogens  Formation of membrane-attack complex: Cleavage of C5 by C5 convertase to release C5b One molecule of C5b binds one molecule of C6; then the C5b6 complex binds a molecule of C7 which inserts into the lipid bilayer. C8, which is a complex of two proteins, C8-B and C8a-gamma. C8-Beta binds to C5b and the binding of C8-beta to the membrane associated C5b67 complex allows the hydrophobic domain of C8a-gamma to insert into the lipid bilayer The C8a-gamma induces the polymerization of 10-16 molecules of C9 into a pore forming structure called the membrane-attack complex (MAC) MAC has a hydrophobic external face, allowing it to associate with the lipid bilayer but an internal hydrophilic channel allowing the free passage of water and soluble molecules The destructions of th
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