Components and functions of the complement system

Components and functions of the equilibrize systemThe equilibrize system found in the blood of mammals is composed of heat labile substances (proteins) that compounding with antibodies or stallphone surfaces. This complex, multicomponent system is composed of about 26 proteins. The complement cascade is constitutive and non-specific but it must be pioneer in order to function. The functions of complement imply making bacteria more susceptible to phagocytosis directly lysing some bacteria and foreign cells producing chemotactic substances increasing vascular permeability causing smooth muscle condensate promoting mast cell degranulation The complement system can be activated via two distinct nerve pathways the mere pathway and the alternate pathway. Once initiated, a cascade of events (the complement cascade) ensues, providing the functions listed above. Most of the complement components are numbered (e.g. C1, C2, C3, etc.) but some are simply referred to as Factors. Som e of the components must be enzymatically cleaved to activate their function others simply combine to form complexes that are active. The following table lists these components and their functions. Components of the Classical passageway Native component combat-ready component(s) Function(s)C1(q,r,s)C1qBinds to antibody that has bound antigen, activates C1r.C1rCleaves C1s to activate protease function.C1sCleaves C2 and C4.C2C2aUnknown.C2b officious enzyme of classical pathway cleaves C3 and C5.C3C3aMediates inflammation anaphylatoxin.C3bBinds C5 for cleavage by C2b. Binds cell surfaces for opsonization and activation of alternate pathway.C4C4aMediates inflammation.C4bBinds C2 for cleavage by C1s. Binds cell surfaces for opsonization. Components of the Alternate Pathway Native component Active component(s) Function(s)C3C3aMediates inflammation anaphylatoxin.C3bBinds cell surfaces for opsonization and activation of alternate pathway.Factor BBBinds membrane bound C3b. Cleaved by Fact or D.BaUnknown.BbCleaved form stabilize by P produces C3 convertase.Factor DDCleaves Factor B when bound to C3b.ProperdinPBinds and stabilizes membrane bound C3bBb. Components of the Membrane-Attack Complex Native component Active component(s) Function(s)C5C5aMediates inflammation anaphylatoxin, chemotaxin.C5bInitiates assembly of the membrane-attack complex (MAC).C6C6Binds C5b, forms acceptor for C7.C7C7Binds C5b6, inserts into membrane, forms acceptor for C8.C8C8Binds C5b67, initiates C9 polymerization.C9C9nPolymerizes around C5b678 to form channel that causes cell lysis. ACTIVATION OF THE COMPLEMENT CASCADE Classical Pathway The classical pathway starts with C1 C1 binds to immune gamma globulin Fc (primarily IgM and IgG) C1 is recognition complex composed of 22 polypeptide chains in 3 subunits C1q, C1r, C1s. C1q is the actual recognition portion, a glycoprotein containing hydroxyproline and hydroxylysine that looks like a tulip flower. Upon binding via C1q, C1r is activated to become a protease that cleaves C1s to a form that activates (cleaves) both C2 and C4 to C2a/b and C4a/b. C2b and C4b combine to produce C3 convertase (C3 activating enzyme). C4a has anaphylactic activity (inflammatory response). C3 is central to both the classical and alternative pathways. In classical, C4b2b convertase cleaves C3 into C3a/b. C3a is a potent anaphylatoxin. C3b combines with C4b2b to form C4b2b3b complex that is a C5 convertase. C3b can also bind directly to cells making them susceptible to phagocytosis. C5 is converted by C5 convertase (i.e. C4b2b3b) to C5a/b. C5a has potent anaphylatoxic and chemotaxic activities. C5b functions as an anchor on the target cell surface to which the lytic membrane-attack complex (MAC) forms. MAC includes C5b, C6, C7, C8 and C9. Once C9 polymerizes to form a hole in the cell wall, lysis ensues. Classical Pathway Component cleavage Enzymatic activity Component assembly Alternate Pathway The alternate pathway may be initiated by immun ologic (e.g. IgA or IgE) or non-immunologic (e.g. LPS) means. The cascade begins with C3. A small amount of C3b is everlastingly found in circulation as a result of spontaneous cleavage of C3 but the concentrations are generally kept very low (see below). However, when C3b binds covalently to sugars on a cell surface, it can become protected. Then Factor B binds to C3b. In the presence of Factor D, bound Factor B is cleaved to Ba and Bb Bb contains the active site for a C3 convertase. Next. properdin binds to C3bBb to stabilize the C3bBb convertase on cell surface in the lead to cleavage of C3. Finally, a C3bBb3b complex forms and this is a C5 convertase, cleaving C5 to C5a/b. Once formed, C5b initiates formation of the membrane attack complex as described above. Generally, only Gram-negative cells can be directly lysed by antibody plus complement Gram-positive cells are mostly resistant. However, phagocytosis is greatly enhanced by C3b binding (phagocytes have C3b receptors on t heir surface) and antibody is not always required. In addition, complement can neutralize virus particles either by direct lysis or by preventing viral penetration of host cells. Alternate Pathway Component cleavage Enzymatic activity Component assembly REGULATION OF THE COMPLEMENT CASCADEBecause both the classical and alternate pathways depend upon C3b, regulation of the complement cascade is mediated via 3 proteins that affect the levels and activities of this component. C1 Inhibitor inhibits the production of C3b by combining with and inactivating C1r and C1s. This prevents formation of the C3 convertase, C4b2b. Protein H inhibits the production of C3b by inhibiting the binding of Factor B to membrane-bound C3b, thereby preventing cleavage of B to Bb and production of the C3 convertase, C3bBb. Factor I inhibits the production of C3b by cleaving C3b into C3c and C3d, which are inactive. Factor I only works on cell membrane bound C3b, mostly on red blood cells (i.e. non-activat or surfaces).