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| | <big><center>[[General Pathology|'''BACK TO GENERAL PATHOLOGY''']]</center></big> | | <big><center>[[General Pathology|'''BACK TO GENERAL PATHOLOGY''']]</center></big> |
| − | <big><center>[[General Pathology - Immunology|'''BACK TO IMMUNOLOGY''']]</center></big> | + | <br> |
| − | | + | ==Complement System== |
| − | ==Complement== | + | For a description of the system and its functions see [[Complement - Anatomy & Physiology|here]] |
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| − | * Complement is so called because it complements the function of antibody.
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| − | * Complement is a '''triggered enzyme cascade'''.
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| − | ** These are a group of plasma systems.
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| − | ** Other examples include:
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| − | *** The clotting system.
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| − | *** The kinin cascade.
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| − | ** The triggered enzyme cascades are effector mechanisms that can produce a rapid and amplified response to a trigger stimulus.
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| − | *** Have adaptive value if appropriately invoked.
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| − | *** May be harmful if triggered inappropriately.
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| − | ** The reaction pathways and control mechanisms involved are complex.
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| − | * There are more than 20 different proteins ) in the complement cascades.
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| − | ** Most are enzymes or pro-enzymes.
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| − | * The complememnt system evoluntionarily pre-dates the immune system.
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| − | ** Has evolved as one of the main innate protective mechanisms of invertebrates.
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| − | * Complement works largely by triggering acute inflammation and by promoting phagocytosis by macrophages and neutrophils.
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| − | | |
| − | ==Complement Fixation==
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| − | * The central event in complement activation is the hydrolysis of the major complement protein, C3.
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| − | ** C3 is a large 2-chain molecule.
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| − | ** Hydrolysis results in the removal of a small peptide, C3a (which itself is pro-inflammatory).
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| − | *** This leaves C3b.
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| − | **** C3b is highly reactive but very short-lived.
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| − | * The hydrolysis of C3 occurs spontaneously and slowly in plasma.
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| − | ** The reactive C3b formed is rapidly inactivated.
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| − | * Some substances can interact to alter aspects of the complement system.
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| − | ** '''Bacterial cell surfaces'''.
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| − | *** Protect the reactive C3b from rapid inactivation.
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| − | **** It is still inactivated, but more slowly.
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| − | *** This is the basis of '''alternative pathway''' of complement activation.
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| − | **** This is the archaic complement system.
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| − | ** '''Antibody-antigen complexes'''
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| − | *** The immune system has optimized complement activation via antibody-antigen complexes.
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| − | *** This is termed the '''classical pathway''' of complement activation.
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| − | * The difference between the alternative and classical pathways is in the mechanisms of C3 breakdown to C3b.
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| − | ** Once C3 is hydrolysed, the terminal pathway is the same for both mechanisms.
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| − | *** Often called the membrane attack complex (MAC).
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| − | *** Involves the binding of C5-C9.
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| − | ===Alternative Pathway Activation===
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| − | * Control proteins in plasma are responsible for the rapid inactivation of C3b to iC3b.
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| − | ** These are known as Factors I and H.
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| − | * C3b has a binding site that anchors it to any surface.
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| − | ** The surfaces of certain activators therefore stabilise the usually short-lived C3b in the absence of antibody.
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| − | *** Gram-negative bacteria, yeasts and fungi are the most efficient activators.
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| − | * When active C3b is bound to particle surfaces, it is protected from inactivation by another complement component, properdin.
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| − | ** C3b can then bind Factor B.
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| − | *** This produces the complex C3bB.
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| − | * C3bB is the only substrate for a plasma enzyme known as Factor D.
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| − | ** Factor D splits a small peptide (the Ba peptide) from Factor B.
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| − | *** This splitting generates C3b¯Bb.
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| − | **** An active enzyme that splits C3.
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| − | **** The bar indicates an active enzyme.
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| − | * C3b¯Bb acts on C3 to generate more C3b.
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| − | ** C3b then generates more C3b¯Bb.
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| − | *** An efficient positive feedback loop.
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| − | * C3b¯Bb can also bind C3b to form C3bB¯b3b.
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| − | ** C3bB¯b3b is one of the two enzymes that activates the Membrane Attack Complex (MAC).
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| − | *** C3bB¯b3b splits C5 into:
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| − | **** C5a, a small pro-inflammatory peptide.
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| − | **** C5b, the initiator of the MAC.
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| − | * At the same time as C3bB¯b3b is being formed, Factors I and H are acting to breakdown C3b to iC3b.
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| − | ** The C3b being broken down may be:
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| − | *** As single C3b or in the complex C3b¯Bb.
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| − | *** In plasma or on bacterial surfaces.
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| − | ** iC3b is inactive in the complement cascade but is a major target for phagocytes.
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| − | *** Phagocytes have large numbers of iC3b receptors (complement receptors) which give opsonization when engaged.
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| − | * The main effects of alternative complement activation are therefore:
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| − | ** To coat bacteria with iC3b.
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| − | *** A major target for phagocytosis by macrophages and neutrophils via the complement receptors.
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| − | ** To induce an acute inflammatory response via C3a and C5a.
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| − | *** Chemotactic for neutrophils .
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| − | *** Induce the production of the cytokines (IL-1β and TNFα) responsible for acute inflammation.
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| − | ===Classical Pathway Activation===
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| − | * There are two triggers for the classical pathway of complement activation.
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| − | ====The binding of antibody to antigen====
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| − | * Only IgM and certain IgG subclasses can activate complement this way.
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| − | # Immune complexes trigger complement activation by binding C1.
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| − | #* C1 cross-links two antibody molecules.
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| − | #* C1 is a complex of:
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| − | #** C1q
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| − | #*** Looks like a bunch of 6 tulips.
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| − | #*** Each "flower" consists of a globular protein head and a collagen "stem".
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| − | #*** At least two C1q globular heads must bind to antibody before the complement cascade is triggered.
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| − | #** C1r
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| − | #** C1s.
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| − | #* C1r and C1s become activated when at least 2 C1q heads are antibopdy-bound.
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| − | #** Form the enzyme C1 esterase.
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| − | # C1 esterase first digests C4 to C4a and C4b.
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| − | #* C4b binds to the antigen.
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| − | # C4b then binds C2.
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| − | #* C2 is digested by C1 esterase to form C2a and C2b.
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| − | #** C4b and C2b complex to form the enzyme C2b¯4b.
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| − | # C2b¯4b digests of C3 into C3a and C3b.
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| − | #* The production of C3b can now be amplified by the same mechanism as the alternative pathway.
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| − | # The binding of one C1q molecule produces one C1 esterase molecule that then cause the binding of many hundreds of C4b¯2b molecules.
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| − | #* The C3b molecule that is produced by the action of this enzyme can also bind to it.
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| − | #** Forms C4b2¯b3b.
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| − | #*** This activates C5 and initiates the MAC.
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| − | * Like the alternative pathway, another major effect of classical pathway activation is to produce iC3b due to the actions of Factors I and H.
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| − | ** Promotes phagocytosis and initiates inflammation.
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| − | * All the Ca fragments (C2a, C3a, C4a, C5a) are chemotactic for neutrophils and induce of acute inflammation.
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| − | ====The binding of soluble lectins to pathogens====
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| − | * E.g. collectins.
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| − | * Lectins are proteins that bind carbohydrates.
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| − | ** In this case, they bind carbohydrates that have a terminal mannose residue.
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| − | *** They are called mannose-binding lectins.
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| − | *** Are secreted by the liver into plasma.
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| − | * The action of lectin binding to carbohydrate activates plasma-associated proteases called mannose-binding lectin associated proteases (MASPs).
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| − | ** These act on C4 and C2 in the same way as C1 esterase.
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| − | ==Membrane Attack Complex==
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| − | * This is the lytic pathway of complement function.
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| − | * Can be initiated via either C3bB¯b3b or C4b2¯b3b.
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| − | ** Split C5 to:
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| − | *** C5a - pro-inflammatory.
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| − | *** C5b - the first molecule of the MAC.
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| − | * C5b is very short-lived and biologically active.
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| − | ** Rapidly attaches to cell surfaces and binds to one C6 molecule.
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| − | * The C5bC6 complex binds one C7 and then one C8 molecule in turn.
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| − | * Finally, about 16 C9 molecules bind and polymerize within the cell membrane.
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| − | ** This polymerization of C9 results in a small pore being formed.
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| − | *** Causes cell lysis by osmotic shock.
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| − | ==Biological Activities of Complement Components==
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| − | ===Opsonisation===
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| − | * Once the complement system has been triggered it deposits a shell of protein on the bacterial cell surface.
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| − | ** C4b, C3b, C5b and C7 molecules contain active binding sites that anchor the complex to the surface.
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| − | * The major protein on the cell surface is iC3b.
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| − | ** As well as some of the smaller C3 breakdown products (e.g. C3d), iC3b act as a target for phagocytosis.
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| − | *** There are very avid receptors on phagocyte membranes for these complement fragments.
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| − | * Complement-mediated opsonization of microorganisms is several thousand times more efficient that innate receptors.
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| − | * The complement fragments released after complement activation are chemotactic for phagocytes.
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| − | ** C2a C3a, C4a and especially C5a.
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| − | ===Inflammation===
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| − | * The smaller complement peptides are very efficient at inducing inflammation.
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| − | ** C3a and C5a.
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| − | * They attract granulocytes to the site of complement activation.
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| − | ** Also stimulate their degranulation.
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| − | ===Cell Lysis===
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| − | * Finally, the later components (C5 – C9) can kill pathogens directly by causing cell lysis.
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| − | * This is effective against encapsulated bacterial infection like ''Neisseria'' and ''Meningococci''.
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| − | ==Complement Inhibitors==
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| − | * Complement is a very powerful system that can be triggered by only small stimuli.
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| − | ** Inappropriate activation can therefore be harmful.
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| − | * Complement activation must therefore be tightly controlled.
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| − | ** There is a range of control mechanisms.
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| − | * ''' Decay accelerating factor''' ('''DAF''')
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| − | ** Is both secreted and present on cell membranes.
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| − | ** Hastens the degradation of C1 esterase.
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| − | *** Exerts control on the classical pathway.
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| − | * '''Factors I and H'''
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| − | ** Break down C3b.
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| − | *** Controls positive feedback by inhibiting C3b¯Bb.
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| − | **** Prevents the complement cascade from running to exhaustion each time it is activated.
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| − | * '''Complement receptor 1''' ('''CR1''') is present on many cell types especially RBCs; it functions to bind C3d - the breakdown product of C3b – resulting from the action of Factors I and H. On it binds potentially inflammatory immune complexes in plasma; these are then transported to the liver where they are phagocytosed by the hepatic macrophages and removed. A common inflammatory disease resulting from poorly eliminated immune complexes is globerulonephritis.
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| − | * '''CD59'''
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| − | ** This binds the first molecule of C9 when it inserts into a cell membrane.
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| − | *** Prevents the polymerisation of C9 and therefore pore formation and cell lysis.
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| − | ** Acts as a protective mechanism for the host cells.
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| | ==Complement Associated Diseases== | | ==Complement Associated Diseases== |
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| | * Most diseases associated with complement are linked to deficiencies of certain components. | | * Most diseases associated with complement are linked to deficiencies of certain components. |
| | * Some deficiencies give inefficient removal of immune complexes, resulting in '''autoimmune disease'''. | | * Some deficiencies give inefficient removal of immune complexes, resulting in '''autoimmune disease'''. |
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| | **** C2 kinin is a potent inducer of inflammation and of vasodilatation. | | **** C2 kinin is a potent inducer of inflammation and of vasodilatation. |
| | ***** Results in hereditary angiodaema. | | ***** Results in hereditary angiodaema. |
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| | <big><center>[[General Pathology|'''BACK TO GENERAL PATHOLOGY''']]</center></big> | | <big><center>[[General Pathology|'''BACK TO GENERAL PATHOLOGY''']]</center></big> |
| − | <big><center>[[General Pathology - Immunology|'''BACK TO IMMUNOLOGY''']]</center></big>
| |