Complement system

• In 1895, Bordet proved that two elements have to be present in the serum in order to destroy the bacterial wall: one of these elements is an antibody that can only be found in animals that are already immunized against the bacteria, and the other element called complement, can be found in any animal.
• If fresh serum containing an antibacterial antibody was added to the bacteria at physiologic temperature (37ºC), the bacteria were lysed.
• If the serum was heated 56ºC or more, it lost its lytic capacity.
• Antibodies are heat-stable.
• Bordet concluded that the serum must contain another heat-labile component that assists, or complements, the lytic function of antibodies, and this component was later given the name complement.
• MCP, factor H, C4BP and CR1 all serve as cofactors in the reaction catalyzed by factor I.
• CD59 blocks C9 binding and prevents formation of MAC complex.
• Factor I is a plasma serine protease that degrades cell-associated C3b.
• CD59 is present on normal host cells, but it is not present on microbes.
• Factor H is a plasma protein that inhibits binding of Bb to C3b and thus is a regulator of the alternative but not the classical pathway.
• The complement system consists of serum and cell surface proteins that interact with one another and with other molecules of the immune system in a highly regulated manner.
• Complement proteins are plasma proteins that are normally inactive.
• Complement activation involves the sequential proteolysis of proteins to generate enzymes with proteolytic activity.
• There are three major pathways of complement activation: classical pathway, alternative pathway, and lectin pathway.
• Classical pathway was discovered and characterized first, but the alternative pathway is phylogenetically older.
• The pathways of complement activation differ in how they are initiated, but all of them result in the generation of enzyme complexes that are able to cleave C3.
• The alternative and lectin pathways are effector mechanisms of innate immunity, whereas the classical pathway is a mechanism of humoral immunity.
• Complement activation consists of early steps, which result in the proteolysis of C3, and late steps, which lead to the formation of a protein complex that lyses cells.
• The early steps generate two proteolytic products of C3 called C3a and C3b.
• The classical pathway of complement activation requires initiation by the interaction of IgG or IgM antibodies with an antigen and usually cell-bound antigen.
• The alternative pathway of complement activation does not require the binding of antibodies to antigens for its activation.
• The rest of the complement pathway is the same as the classical pathway.
• In neutrophils, C5a stimulates motility, firm adhesion to endothelial cells, and at high doses, stimulation of the respiratory burst and production of reactive oxygen intermediates.
• C5 convertases cleave C5 into a small C5a fragment and a C5b fragment.
• Low-level complement activation goes on spontaneously, and if such activation is allowed to proceed on normal cells, the result can be damage to normal cells and tissues.
• If C3b is deposited on the surface of normal mammalian cells, they are bound by these membrane proteins and they inhibit the binding of other components of the C3 convertase and block further progression of the complement cascade.
• These pores allow free movement of water and ions and cause cell lysis.
• Even when complement is activated on microbial cells or antigen-antibody complexes, it needs to be controlled because degradation products of complement proteins can diffuse to adjacent cells and injure them.
• C5a is the most potent mediator of mast cell degranulation.
• The proteolytic complement fragments C5a, C4a and C3a induce acute inflammation by activating mast cells and neutrophils.
• C5a is released and C5b remains bound to the complement proteins deposited on the cell surface.
• C5b binds C6 and C7.
• Macrophages and neutrophils have receptors for C3b and C4b and can bind the complement-coated cell or particle and induce phagocytosis.
• Complement-mediated lysis of foreign organisms is mediated by the membrane attack complex (MAC).
• C9 is a serum protein and polymerizes at the site of the bound C5b-8 and forms pores in plasma membranes, this complex is called Membrane Attack Complex (MAC).
• C4b deposited on cell surfaces is similarly bound by DAF, CR1 and a plasma protein called C4-binding protein (C4BP).
• The C7 component of the C5b,6,7 complex is hydrophobic, and it inserts into the lipid bilayer of cell membranes and binds C8.
• MBL triggers the complement system either by activating the C1r-C1s enzyme complex (like C1q) or associating with another serine esterase, called mannose binding protein-associated serine esterase, which cleaves C4.
• Membrane cofactor protein (MCP), type 1 complement receptor (CR1) and decay accelerating factor (DAF) are produced by mammalian cells and but not by microbes.
• C1 inhibitor (C1 INH) is a plasma protein and binds to C1r and C1s and dissociates them from C1q.