Difference between revisions of "Complement Associated Diseases"
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+ | <big><center>[[General Pathology|'''BACK TO GENERAL PATHOLOGY''']]</center></big> | ||
+ | <big><center>[[General Pathology - Immunology|'''BACK TO IMMUNOLOGY''']]</center></big> | ||
+ | |||
+ | ==Complement== | ||
+ | |||
+ | * Complement is so called because it complements the function of antibody. | ||
+ | * Complement is a '''triggered enzyme cascade'''. | ||
+ | ** These are a group of plasma systems. | ||
+ | ** Other examples include: | ||
+ | *** The clotting system. | ||
+ | *** The kinin cascade. | ||
+ | ** The triggered enzyme cascades are effector mechanisms that can produce a rapid and amplified response to a trigger stimulus. | ||
+ | *** Have adaptive value if appropriately invoked. | ||
+ | *** May be harmful if triggered inappropriately. | ||
+ | ** The reaction pathways and control mechanisms involved are complex. | ||
+ | * There are more than 20 different proteins ) in the complement cascades. | ||
+ | ** Most are enzymes or pro-enzymes. | ||
+ | * The complememnt system evoluntionarily pre-dates the immune system. | ||
+ | ** Has evolved as one of the main innate protective mechanisms of invertebrates. | ||
+ | * Complement works largely by triggering acute inflammation and by promoting phagocytosis by macrophages and neutrophils. | ||
+ | |||
+ | ==Complement Fixation== | ||
+ | |||
+ | * The central event in complement activation is the hydrolysis of the major complement protein, C3. | ||
+ | ** C3 is a large 2-chain molecule. | ||
+ | ** Hydrolysis results in the removal of a small peptide, C3a (which itself is pro-inflammatory). | ||
+ | *** This leaves C3b. | ||
+ | **** C3b is highly reactive but very short-lived. | ||
+ | * The hydrolysis of C3 occurs spontaneously and slowly in plasma. | ||
+ | ** The reactive C3b formed is rapidly inactivated. | ||
+ | * Some substances can interact to alter aspects of the complement system. | ||
+ | ** '''Bacterial cell surfaces'''. | ||
+ | *** Protect the reactive C3b from rapid inactivation. | ||
+ | **** It is still inactivated, but more slowly. | ||
+ | *** This is the basis of '''alternative pathway''' of complement activation. | ||
+ | **** This is the archaic complement system. | ||
+ | ** '''Antibody-antigen complexes''' | ||
+ | *** The immune system has optimized complement activation via antibody-antigen complexes. | ||
+ | *** This is termed the '''classical pathway''' of complement activation. | ||
+ | * The difference between the alternative and classical pathways is in the mechanisms of C3 breakdown to C3b. | ||
+ | ** Once C3 is hydrolysed, the terminal pathway is the same for both mechanisms. | ||
+ | *** Often called the membrane attack complex (MAC). | ||
+ | *** Involves the binding of C5-C9. | ||
+ | |||
+ | ===Alternative Pathway Activation=== | ||
+ | |||
+ | * Control proteins in plasma are responsible for the rapid inactivation of C3b to iC3b. | ||
+ | ** These are known as Factors I and H. | ||
+ | * C3b has a binding site that anchors it to any surface. | ||
+ | ** The surfaces of certain activators therefore stabilise the usually short-lived C3b in the absence of antibody. | ||
+ | *** Gram-negative bacteria, yeasts and fungi are the most efficient activators. | ||
+ | * When active C3b is bound to particle surfaces, it is protected from inactivation by another complement component, properdin. | ||
+ | ** C3b can then bind Factor B. | ||
+ | *** This produces the complex C3bB. | ||
+ | * C3bB is the only substrate for a plasma enzyme known as Factor D. | ||
+ | ** Factor D splits a small peptide (the Ba peptide) from Factor B. | ||
+ | *** This splitting generates C3b¯Bb. | ||
+ | **** An active enzyme that splits C3. | ||
+ | **** The bar indicates an active enzyme. | ||
+ | * C3b¯Bb acts on C3 to generate more C3b. | ||
+ | ** C3b then generates more C3b¯Bb. | ||
+ | *** An efficient positive feedback loop. | ||
+ | * C3b¯Bb can also bind C3b to form C3bB¯b3b. | ||
+ | ** C3bB¯b3b is one of the two enzymes that activates the Membrane Attack Complex (MAC). | ||
+ | *** C3bB¯b3b splits C5 into: | ||
+ | **** C5a, a small pro-inflammatory peptide. | ||
+ | **** C5b, the initiator of the MAC. | ||
+ | * At the same time as C3bB¯b3b is being formed, Factors I and H are acting to breakdown C3b to iC3b. | ||
+ | ** The C3b being broken down may be: | ||
+ | *** As single C3b or in the complex C3b¯Bb. | ||
+ | *** In plasma or on bacterial surfaces. | ||
+ | ** iC3b is inactive in the complement cascade but is a major target for phagocytes. | ||
+ | *** Phagocytes have large numbers of iC3b receptors (complement receptors) which give opsonization when engaged. | ||
+ | * The main effects of alternative complement activation are therefore: | ||
+ | ** To coat bacteria with iC3b. | ||
+ | *** A major target for phagocytosis by macrophages and neutrophils via the complement receptors. | ||
+ | ** To induce an acute inflammatory response via C3a and C5a. | ||
+ | *** Chemotactic for neutrophils . | ||
+ | *** Induce the production of the cytokines (IL-1β and TNFα) responsible for acute inflammation. | ||
+ | |||
+ | ===Classical Pathway Activation=== | ||
+ | |||
+ | * There are two triggers for the classical pathway of complement activation. | ||
+ | |||
+ | ====The binding of antibody to antigen==== | ||
+ | |||
+ | * Only IgM and certain IgG subclasses can activate complement this way. | ||
+ | # Immune complexes trigger complement activation by binding C1. | ||
+ | #* C1 cross-links two antibody molecules. | ||
+ | #* C1 is a complex of: | ||
+ | #** C1q | ||
+ | #*** Looks like a bunch of 6 tulips. | ||
+ | #*** Each "flower" consists of a globular protein head and a collagen "stem". | ||
+ | #*** At least two C1q globular heads must bind to antibody before the complement cascade is triggered. | ||
+ | #** C1r | ||
+ | #** C1s. | ||
+ | #* C1r and C1s become activated when at least 2 C1q heads are antibopdy-bound. | ||
+ | #** Form the enzyme C1 esterase. | ||
+ | # C1 esterase first digests C4 to C4a and C4b. | ||
+ | #* C4b binds to the antigen. | ||
+ | # C4b then binds C2. | ||
+ | #* C2 is digested by C1 esterase to form C2a and C2b. | ||
+ | #** C4b and C2b complex to form the enzyme C2b¯4b. | ||
+ | # C2b¯4b digests of C3 into C3a and C3b. | ||
+ | #* The production of C3b can now be amplified by the same mechanism as the alternative pathway. | ||
+ | # The binding of one C1q molecule produces one C1 esterase molecule that then cause the binding of many hundreds of C4b¯2b molecules. | ||
+ | #* The C3b molecule that is produced by the action of this enzyme can also bind to it. | ||
+ | #** Forms C4b2¯b3b. | ||
+ | #*** This activates C5 and initiates the MAC. | ||
+ | * Like the alternative pathway, another major effect of classical pathway activation is to produce iC3b due to the actions of Factors I and H. | ||
+ | ** Promotes phagocytosis and initiates inflammation. | ||
+ | * All the Ca fragments (C2a, C3a, C4a, C5a) are chemotactic for neutrophils and induce of acute inflammation. | ||
+ | |||
+ | ====The binding of soluble lectins to pathogens==== | ||
+ | |||
+ | * E.g. collectins. | ||
+ | * Lectins are proteins that bind carbohydrates. | ||
+ | ** In this case, they bind carbohydrates that have a terminal mannose residue. | ||
+ | *** They are called mannose-binding lectins. | ||
+ | *** Are secreted by the liver into plasma. | ||
+ | * The action of lectin binding to carbohydrate activates plasma-associated proteases called mannose-binding lectin associated proteases (MASPs). | ||
+ | ** These act on C4 and C2 in the same way as C1 esterase. | ||
+ | |||
+ | ==Membrane Attack Complex== | ||
+ | |||
+ | * This is the lytic pathway of complement function. | ||
+ | * Can be initiated via either C3bB¯b3b or C4b2¯b3b. | ||
+ | ** Split C5 to: | ||
+ | *** C5a - pro-inflammatory. | ||
+ | *** C5b - the first molecule of the MAC. | ||
+ | * C5b is very short-lived and biologically active. | ||
+ | ** Rapidly attaches to cell surfaces and binds to one C6 molecule. | ||
+ | * The C5bC6 complex binds one C7 and then one C8 molecule in turn. | ||
+ | * Finally, about 16 C9 molecules bind and polymerize within the cell membrane. | ||
+ | ** This polymerization of C9 results in a small pore being formed. | ||
+ | *** Causes cell lysis by osmotic shock. | ||
+ | |||
+ | ==Biological Activities of Complement Components== | ||
+ | |||
+ | ===Opsonisation=== | ||
+ | |||
+ | * Once the complement system has been triggered it deposits a shell of protein on the bacterial cell surface. | ||
+ | ** C4b, C3b, C5b and C7 molecules contain active binding sites that anchor the complex to the surface. | ||
+ | * The major protein on the cell surface is iC3b. | ||
+ | ** As well as some of the smaller C3 breakdown products (e.g. C3d), iC3b act as a target for phagocytosis. | ||
+ | *** There are very avid receptors on phagocyte membranes for these complement fragments. | ||
+ | * Complement-mediated opsonization of microorganisms is several thousand times more efficient that innate receptors. | ||
+ | * The complement fragments released after complement activation are chemotactic for phagocytes. | ||
+ | ** C2a C3a, C4a and especially C5a. | ||
+ | |||
+ | ===Inflammation=== | ||
+ | |||
+ | * The smaller complement peptides are very efficient at inducing inflammation. | ||
+ | ** C3a and C5a. | ||
+ | * They attract granulocytes to the site of complement activation. | ||
+ | ** Also stimulate their degranulation. | ||
+ | |||
+ | ===Cell Lysis=== | ||
+ | |||
+ | * Finally, the later components (C5 – C9) can kill pathogens directly by causing cell lysis. | ||
+ | * This is effective against encapsulated bacterial infection like ''Neisseria'' and ''Meningococci''. | ||
+ | |||
+ | ==Complement Inhibitors== | ||
+ | |||
+ | * Complement is a very powerful system that can be triggered by only small stimuli. | ||
+ | ** Inappropriate activation can therefore be harmful. | ||
+ | * Complement activation must therefore be tightly controlled. | ||
+ | ** There is a range of control mechanisms. | ||
+ | * ''' Decay accelerating factor''' ('''DAF''') | ||
+ | ** Is both secreted and present on cell membranes. | ||
+ | ** Hastens the degradation of C1 esterase. | ||
+ | *** Exerts control on the classical pathway. | ||
+ | * '''Factors I and H''' | ||
+ | ** Break down C3b. | ||
+ | *** Controls positive feedback by inhibiting C3b¯Bb. | ||
+ | **** Prevents the complement cascade from running to exhaustion each time it is activated. | ||
+ | * '''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. | ||
+ | * '''CD59''' | ||
+ | ** This binds the first molecule of C9 when it inserts into a cell membrane. | ||
+ | *** Prevents the polymerisation of C9 and therefore pore formation and cell lysis. | ||
+ | ** Acts as a protective mechanism for the host cells. | ||
− | |||
==Complement Associated Diseases== | ==Complement Associated Diseases== | ||
+ | |||
* 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'''. | ||
Line 23: | Line 204: | ||
***** Results in hereditary angiodaema. | ***** Results in hereditary angiodaema. | ||
− | [[ | + | <big><center>[[General Pathology|'''BACK TO GENERAL PATHOLOGY''']]</center></big> |
− | [[ | + | <big><center>[[General Pathology - Immunology|'''BACK TO IMMUNOLOGY''']]</center></big> |
− |
Revision as of 14:49, 21 November 2007
Complement
- Complement is so called because it complements the function of antibody.
- Complement is a triggered enzyme cascade.
- These are a group of plasma systems.
- Other examples include:
- The clotting system.
- The kinin cascade.
- The triggered enzyme cascades are effector mechanisms that can produce a rapid and amplified response to a trigger stimulus.
- Have adaptive value if appropriately invoked.
- May be harmful if triggered inappropriately.
- The reaction pathways and control mechanisms involved are complex.
- There are more than 20 different proteins ) in the complement cascades.
- Most are enzymes or pro-enzymes.
- The complememnt system evoluntionarily pre-dates the immune system.
- Has evolved as one of the main innate protective mechanisms of invertebrates.
- Complement works largely by triggering acute inflammation and by promoting phagocytosis by macrophages and neutrophils.
Complement Fixation
- The central event in complement activation is the hydrolysis of the major complement protein, C3.
- C3 is a large 2-chain molecule.
- Hydrolysis results in the removal of a small peptide, C3a (which itself is pro-inflammatory).
- This leaves C3b.
- C3b is highly reactive but very short-lived.
- This leaves C3b.
- The hydrolysis of C3 occurs spontaneously and slowly in plasma.
- The reactive C3b formed is rapidly inactivated.
- Some substances can interact to alter aspects of the complement system.
- Bacterial cell surfaces.
- Protect the reactive C3b from rapid inactivation.
- It is still inactivated, but more slowly.
- This is the basis of alternative pathway of complement activation.
- This is the archaic complement system.
- Protect the reactive C3b from rapid inactivation.
- Antibody-antigen complexes
- The immune system has optimized complement activation via antibody-antigen complexes.
- This is termed the classical pathway of complement activation.
- Bacterial cell surfaces.
- The difference between the alternative and classical pathways is in the mechanisms of C3 breakdown to C3b.
- Once C3 is hydrolysed, the terminal pathway is the same for both mechanisms.
- Often called the membrane attack complex (MAC).
- Involves the binding of C5-C9.
- Once C3 is hydrolysed, the terminal pathway is the same for both mechanisms.
Alternative Pathway Activation
- Control proteins in plasma are responsible for the rapid inactivation of C3b to iC3b.
- These are known as Factors I and H.
- C3b has a binding site that anchors it to any surface.
- The surfaces of certain activators therefore stabilise the usually short-lived C3b in the absence of antibody.
- Gram-negative bacteria, yeasts and fungi are the most efficient activators.
- The surfaces of certain activators therefore stabilise the usually short-lived C3b in the absence of antibody.
- When active C3b is bound to particle surfaces, it is protected from inactivation by another complement component, properdin.
- C3b can then bind Factor B.
- This produces the complex C3bB.
- C3b can then bind Factor B.
- C3bB is the only substrate for a plasma enzyme known as Factor D.
- Factor D splits a small peptide (the Ba peptide) from Factor B.
- This splitting generates C3b¯Bb.
- An active enzyme that splits C3.
- The bar indicates an active enzyme.
- This splitting generates C3b¯Bb.
- Factor D splits a small peptide (the Ba peptide) from Factor B.
- C3b¯Bb acts on C3 to generate more C3b.
- C3b then generates more C3b¯Bb.
- An efficient positive feedback loop.
- C3b then generates more C3b¯Bb.
- C3b¯Bb can also bind C3b to form C3bB¯b3b.
- C3bB¯b3b is one of the two enzymes that activates the Membrane Attack Complex (MAC).
- C3bB¯b3b splits C5 into:
- C5a, a small pro-inflammatory peptide.
- C5b, the initiator of the MAC.
- C3bB¯b3b splits C5 into:
- C3bB¯b3b is one of the two enzymes that activates the Membrane Attack Complex (MAC).
- At the same time as C3bB¯b3b is being formed, Factors I and H are acting to breakdown C3b to iC3b.
- The C3b being broken down may be:
- As single C3b or in the complex C3b¯Bb.
- In plasma or on bacterial surfaces.
- iC3b is inactive in the complement cascade but is a major target for phagocytes.
- Phagocytes have large numbers of iC3b receptors (complement receptors) which give opsonization when engaged.
- The C3b being broken down may be:
- The main effects of alternative complement activation are therefore:
- To coat bacteria with iC3b.
- A major target for phagocytosis by macrophages and neutrophils via the complement receptors.
- To induce an acute inflammatory response via C3a and C5a.
- Chemotactic for neutrophils .
- Induce the production of the cytokines (IL-1β and TNFα) responsible for acute inflammation.
- To coat bacteria with iC3b.
Classical Pathway Activation
- There are two triggers for the classical pathway of complement activation.
The binding of antibody to antigen
- Only IgM and certain IgG subclasses can activate complement this way.
- Immune complexes trigger complement activation by binding C1.
- C1 cross-links two antibody molecules.
- C1 is a complex of:
- C1q
- Looks like a bunch of 6 tulips.
- Each "flower" consists of a globular protein head and a collagen "stem".
- At least two C1q globular heads must bind to antibody before the complement cascade is triggered.
- C1r
- C1s.
- C1q
- C1r and C1s become activated when at least 2 C1q heads are antibopdy-bound.
- Form the enzyme C1 esterase.
- C1 esterase first digests C4 to C4a and C4b.
- C4b binds to the antigen.
- C4b then binds C2.
- C2 is digested by C1 esterase to form C2a and C2b.
- C4b and C2b complex to form the enzyme C2b¯4b.
- C2 is digested by C1 esterase to form C2a and C2b.
- C2b¯4b digests of C3 into C3a and C3b.
- The production of C3b can now be amplified by the same mechanism as the alternative pathway.
- The binding of one C1q molecule produces one C1 esterase molecule that then cause the binding of many hundreds of C4b¯2b molecules.
- The C3b molecule that is produced by the action of this enzyme can also bind to it.
- Forms C4b2¯b3b.
- This activates C5 and initiates the MAC.
- Forms C4b2¯b3b.
- The C3b molecule that is produced by the action of this enzyme can also bind to it.
- Like the alternative pathway, another major effect of classical pathway activation is to produce iC3b due to the actions of Factors I and H.
- Promotes phagocytosis and initiates inflammation.
- All the Ca fragments (C2a, C3a, C4a, C5a) are chemotactic for neutrophils and induce of acute inflammation.
The binding of soluble lectins to pathogens
- E.g. collectins.
- Lectins are proteins that bind carbohydrates.
- In this case, they bind carbohydrates that have a terminal mannose residue.
- They are called mannose-binding lectins.
- Are secreted by the liver into plasma.
- In this case, they bind carbohydrates that have a terminal mannose residue.
- The action of lectin binding to carbohydrate activates plasma-associated proteases called mannose-binding lectin associated proteases (MASPs).
- These act on C4 and C2 in the same way as C1 esterase.
Membrane Attack Complex
- This is the lytic pathway of complement function.
- Can be initiated via either C3bB¯b3b or C4b2¯b3b.
- Split C5 to:
- C5a - pro-inflammatory.
- C5b - the first molecule of the MAC.
- Split C5 to:
- C5b is very short-lived and biologically active.
- Rapidly attaches to cell surfaces and binds to one C6 molecule.
- The C5bC6 complex binds one C7 and then one C8 molecule in turn.
- Finally, about 16 C9 molecules bind and polymerize within the cell membrane.
- This polymerization of C9 results in a small pore being formed.
- Causes cell lysis by osmotic shock.
- This polymerization of C9 results in a small pore being formed.
Biological Activities of Complement Components
Opsonisation
- Once the complement system has been triggered it deposits a shell of protein on the bacterial cell surface.
- C4b, C3b, C5b and C7 molecules contain active binding sites that anchor the complex to the surface.
- The major protein on the cell surface is iC3b.
- As well as some of the smaller C3 breakdown products (e.g. C3d), iC3b act as a target for phagocytosis.
- There are very avid receptors on phagocyte membranes for these complement fragments.
- As well as some of the smaller C3 breakdown products (e.g. C3d), iC3b act as a target for phagocytosis.
- Complement-mediated opsonization of microorganisms is several thousand times more efficient that innate receptors.
- The complement fragments released after complement activation are chemotactic for phagocytes.
- C2a C3a, C4a and especially C5a.
Inflammation
- The smaller complement peptides are very efficient at inducing inflammation.
- C3a and C5a.
- They attract granulocytes to the site of complement activation.
- Also stimulate their degranulation.
Cell Lysis
- Finally, the later components (C5 – C9) can kill pathogens directly by causing cell lysis.
- This is effective against encapsulated bacterial infection like Neisseria and Meningococci.
Complement Inhibitors
- Complement is a very powerful system that can be triggered by only small stimuli.
- Inappropriate activation can therefore be harmful.
- Complement activation must therefore be tightly controlled.
- There is a range of control mechanisms.
- Decay accelerating factor (DAF)
- Is both secreted and present on cell membranes.
- Hastens the degradation of C1 esterase.
- Exerts control on the classical pathway.
- Factors I and H
- Break down C3b.
- Controls positive feedback by inhibiting C3b¯Bb.
- Prevents the complement cascade from running to exhaustion each time it is activated.
- Controls positive feedback by inhibiting C3b¯Bb.
- Break down C3b.
- 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.
- CD59
- This binds the first molecule of C9 when it inserts into a cell membrane.
- Prevents the polymerisation of C9 and therefore pore formation and cell lysis.
- Acts as a protective mechanism for the host cells.
- This binds the first molecule of C9 when it inserts into a cell membrane.
Complement Associated Diseases
- Most diseases associated with complement are linked to deficiencies of certain components.
- Some deficiencies give inefficient removal of immune complexes, resulting in autoimmune disease.
- E.g. deficiencies in C1, C2, C4 and DAF.
- Immune complexes lodge ing the small capillary beds and induce inflammation.
- Results in, for example, glomerulonephritis, vasculitis, rheumatoid arthritis and inflammation/ irritation of the skin.
- E.g. Systemic Lupus Erythematosis.
- Deficiencies may also result in chronic infection.
- E.g. deficiences in C3, Factor B and Factors H and I.
- Factors H and I are inhibitors.
- Lack of thrse results in exhaustion of the C3 supply, causing a functional C3 deficiency.
- Factors H and I are inhibitors.
- Opsonisation and the lytic pathway do not function optimally without C3.
- E.g. deficiences in C3, Factor B and Factors H and I.
- Other deficiencies.
- C6
- Results in very few effects other that the inability to eliminate encapsulated bacterial infections.
- C1 esterase inhibitor.
- A rare genetic deficiency.
- C1 esterase inhibitor is an enzyme which controls the functioning of C1 esterase.
- Lack of this enzyme causes inappropriate activation of C2 and production of large quantities of C2a (also known as C2 kinin).
- C2 kinin is a potent inducer of inflammation and of vasodilatation.
- Results in hereditary angiodaema.
- C2 kinin is a potent inducer of inflammation and of vasodilatation.
- C6