Difference between revisions of "Complement"

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{{review}}
 
==Introduction==
 
==Introduction==
Complement is so called because it complements the function of [[Immunoglobulins - Overview|antibody]]. It is a [[Triggered Enzyme Cascade|triggered enzyme cascade]] and there are more than 20 different proteins in the complement cascades, with most being enzymes or pro-enzymes. It can be activated by both the [[Innate Immune System|innate]] and [[Adaptive Immune System|adaptive]] immune systems and is one of the main innate protective mechanisms of invertebrates. Due to its destructive potential the complement system is heavily regulated but when activated it works largely by forming pore complexes as well as triggering [[Acute Inflammation - Introduction|acute inflammation]] and by promoting [[Phagocytosis|phagocytosis]] by [[Macrophages|macrophages]] and [[Neutrophils|neutrophils]].
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Complement is so called because it complements the function of antibody. It is a [[Triggered Enzyme Cascade - WikiBlood|triggered enzyme cascade]] and there are more than 20 different proteins in the complement cascades, with most being enzymes or pro-enzymes. It can be activated by both the innate and adaptive immune systems and is one of the main innate protective mechanisms of invertebrates. Due to its destructive potential the complement system is heavily regulated but when activated it works largely by forming pore complexes as well as triggering acute inflammation and by promoting phagocytosis by macrophages and neutrophils.
 
 
 
==Complement Fixation Pathways==
 
==Complement Fixation Pathways==
[[Image:LH Complement pathway.png|thumb|left|250px|'''Classical and alternative pathways''']]
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[[Image:LH Complement pathway.png|thumb|right|250px|'''Classical and alternative pathways''']]
 
===Classical Pathway===
 
===Classical Pathway===
[[Image:Complement Classical Pathway.png|thumb|right|250px|'''Classical pathway in detail''' - R.J.Francis, RVC 2012]]
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<p>Triggered by the binding of antibody to antigen. Only [[IgM]] and certain [[IgG]] subclasses can activate complement this way.
This pathway of the complement system is triggered by the binding of antibody to antigen. The only subclasses that can activate complement this way are the
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#Immune complexes trigger complement activation by binding C1.
[[IgM]] and certain [[IgG]]. The first step of complement activation is the binding of C1 to two Fc regions of the antibodies (IgM is such a strong activator of complement as it contains '''five''' Fc regions, while IgG contains '''one'''). C1 is actually a complex of C1q, C1r and C1s. C1q looks like a bunch of 6 tulips with each "flower" consisting of a globular protein head and a collagen "stem". C1q is required to trigger the cascade because two of its globular heads bind to the two Fc regions. C1r and C1s then become activated when the C1q heads are antibody-bound. When they are activated they form the enzyme '''C1 esterase''' (it is a serine protease).
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#*C1 cross-links two antibody molecules
<br />
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#*C1 is a complex of:
<br />
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#**C1q
It is the C1 esterase which then first digests components C4 to C4a and C4b, and C2 to C2a and C2b. It is the C4b which first binds to the antigen, and then forms a complex with C2a (some textbooks (tend to be more recent) quote this as "C2b" depending on nomenculture used) to produce the active enzyme '''C3 convertase (classical pathway)'''. The binding of one C1q molecule produces one C1 esterase molecule that can then cause the binding of many hundreds of the C4b&macr;2a molecules (or in some textbooks "C4b&macr;2b"). The role of the convertase is to digest C3 into C3a and C3b. This part of the pathway is self-propagating as the production of C3b can now be amplified by the same mechanism as the [[Complement#Alternative Pathway| alternative pathway]] (below).
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#***Looks like a bunch of 6 tulips
<br />
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#***Each "flower" consists of a globular protein head and a collagen "stem"
<br />
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#***At least two C1q globular heads must bind to antibody before the complement cascade is triggered
The main action of the C3b molecule is to form the C4b&macr;2a&macr;3b complex, or the '''C5 convertase (classical pathway)'''. The C5 convertase then activates C5 and initiates the [[#Membrane Attack Complex|membrane attack complex]] (MAC) as shown below. Other actions include the fragmentation of the C3b due to the actions of [[#Factors I and H|Factors I and H]] which forms C3bi (C3bi and iC3b are the same protein, different name), which provides an opsonin for [[Phagocytosis|phagocytosis]].
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#**C1r
<br />
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#**C1s
<br />
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#*C1r and C1s become activated when at least 2 C1q heads are antibody-bound (to FC region)
Along with the actions of the fragments mentioned above, Ca fragments C3a, C4a and C5a, and Cb fragment C2b also form a chemotactic response. This brings [[Neutrophils|neutrophils]] to the area of complement activation through the process of [[Neutrophils|extravasation]] through the increase in cell adhesion molecules on the endothelium and an increase in vascular permeability; and chemotaxis which is the direct cellular movement. The fragments can also cause [[Mast Cells|mast cell]] and [[Basophils|basophil]] degranulation. These therefore induce '''acute inflammation'''.
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#**Form the enzyme C1 esterase (serine protease)
<br />
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#C1 esterase first digests C4 to C4a and C4b and the C2 to C2a and C2b  
<br />
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#*C4b binds to the antigen
 +
#C4b then binds C2a
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#*C4b and C2a complex to form the enzyme C2a&macr;4b (C3 convertase)
 +
#C2a&macr;4b digests 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 causes the binding of many hundreds of C4b&macr;2b molecules
 +
#The C3b molecule that is produced by the action of this enzyme can also bind to it
 +
#*Forms C4b2&macr;b3b (C5 convertase)
 +
#*This activates C5 and initiates the [[#Membrane Attack Complex|membrane attack complex]] (MAC)
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*Ca fragments C3a, C4a and C5a, and Cb fragment C2b
 +
**Are chemotactic for [[Neutrophils|neutrophils]]  
 +
**Induce acute inflammation
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**Increase vascular permeability and cell adhesion molecules
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***Cause [[Mast Cells|mast cell]] and [[Basophils|basophil]] degranulation</p>
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<p>Like the alternative pathway, another major effect of classical pathway activation is to produce iC3b due to the actions of [[#Factors I and H|Factors I and H]] which promotes phagocytosis and initiates inflammation</p>
  
 
===Alternative Pathway===
 
===Alternative Pathway===
[[Image:Complement Alternative Pathway.png|thumb|right|250px|'''Alternative pathway in detail''' - R.J.Francis, RVC 2012]]
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<p>Is found in animals that do not have antibodies i.e. animals lower than cartilaginous fish. It was discovered after the classical pathway and is thus called the 'alternative pathway'.
<p> This pathway is found in all animals, including those that do not have antibodies i.e. animals lower in order than cartilaginous fish. It was discovered after the classical pathway and was thus called the 'alternative pathway'.
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*C3b has a binding site that anchors it to any surface
 +
**The surfaces of certain activators stabilise the otherwise 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 producing 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 generates C3b&macr;Bb. (C3 convertase)
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**C3b&macr;Bb acts on C3 to generate more C3b
 +
**C3b then generates more C3b&macr;Bb
 +
***An efficient positive feedback loop
 +
*C3b&macr;Bb can also bind C3b to form C3bB&macr;b3b.
 +
**C3bB&macr;b3b is one of the two enzymes that activates the [[#Membrane Attack Complex|membrane attack complex]] (MAC)
 +
*C3bB&macr;b3b splits C5 into:
 +
**C5a, a small pro-inflammatory peptide
 +
**C5b, the initiator of the MAC</p>
 +
<p>
 +
*At the same time as C3bB&macr;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&macr;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 opsonisation when engaged. </p>
 +
<p>The main effects of alternative complement activation are therefore:
 +
#To coat bacteria with iC3b
 +
#*A major target for phagocytosis by [[Macrophages|macrophages]] and [[Neutrophils|neutrophils]] via the complement receptors
 +
#To induce an acute inflammatory response via C3a and C5a.
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#*Chemotactic for [[Neutrophils|neutrophils]]
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#*Induce the production of the cytokines (IL-1&beta; and TNF&alpha;) responsible for acute inflammation</p>
  
<br />
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===MB-Lectin Pathway===
<br />
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<p>Lectins are proteins that bind carbohydrates e.g. collectins. They bind carbohydrates that have a terminal mannose residue and are called mannose-binding lectins.
To begin the cascade C3b binds to a surface that stabilises the C3b. C3b can bind to any surface as it has a binding site that anchors it to any surface, however it is only the surfaces of certain activators that can stabilise the otherwise short-lived C3b in the absence of antibody. These include Gram-negative bacteria, yeasts and fungi. When the active C3b is bound to particle surfaces, it is protected from inactivation by another complement component, properdin. Therefore, having the C3b bound to a surface enables the C3b to become active for longer. The C3b can then bind Factor B producing the complex C3bB. While in this complex, Factor B can become a substrate for the plasma enzyme known as Factor D. Factor D then splits a small peptide (the Ba peptide) from Factor B to generate the '''C3 convertase (alternative pathway)''' made of C3b&macr;Bb.
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*Secreted by the liver into plasma.  
<br />
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* The action of lectin binding to carbohydrate activates plasma-associated proteases called mannose-binding lectin associated proteases (MASPs)
<br />
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** These act on C4 and C2 in the same way as C1 esterase</p>
This C3 convertase (C3b&macr;Bb) then acts on C3 to generate more C3b to then generate more C3b&macr;Bb: This process enables an efficient positive feedback loop that propagates the response. The C3b&macr;Bb can also bind C3b to form C3b&macr;Bb&macr;3b which itself is a C5 convertase and is one of the two enzymes that activates the [[#Membrane Attack Complex|membrane attack complex]] (MAC). This occurs in the same way as the clasical pathway, with the C5 convertase splitting C5 into C5b, that activates the complex, and C5a, the potent chemoattractant.
 
<br />
 
<br />
 
At the same time as C3b&macr;Bb&macr;3b is being formed, Factors I and H are acting to breakdown C3b to iC3b which, as mentioned above, forms an opsonin for [[Phagocytosis|phagocytosis]].
 
 
 
[[Image:Complement Mannose Binding Lectin Pathway.png|thumb|right|250px|'''Mannose Binding Lectin pathway in detail''' - R.J.Francis, RVC 2012]]
 
<br />
 
 
 
===Mannose Binding-Lectin Pathway===
 
Lectins are proteins that bind carbohydrates e.g. collectins. They bind the carbohydrates as they have a terminal mannose residue, and are therefore called '''mannose-binding lectins'''. These are secreted by the liver into plasma.  
 
<br />
 
<br />
 
The main action of lectin binding to carbohydrate is to activate plasma-associated proteases called mannose-binding lectin associated proteases (MASPs). These act on C4 and C2 in the same way as C1 esterase, and on C3 in much the same manner as C3 convertase.
 
<br />
 
<br />
 
<br />
 
<br />
 
<br />
 
<br />
 
<br />
 
<br />
 
  
 
==Membrane Attack Complex==
 
==Membrane Attack Complex==
 
[[Image:LH Complement lysis.png|thumb|200px|right|'''Membrane Attack Complex''']]
 
[[Image:LH Complement lysis.png|thumb|200px|right|'''Membrane Attack Complex''']]
This is the lytic pathway of complement function and can be initiated via either C3b&macr;Bb&macr;3b or C4b&macr;2a&macr;3b.  
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This is the lytic pathway of complement function and can be initiated via either C3bB&macr;b3b or C4b2&macr;b3b.  
These split C5 into C5a which is pro-inflammatory, and C5b, the first molecule of the MAC (very short-lived and biologically active).
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#Split C5 into:
<br />
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#*C5a is pro-inflammatory.
<br />
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#*C5b the first molecule of the MAC (very short-lived and biologically active)
C5b rapidly attaches to cell surfaces and binds to one C6 molecule. The C5bC6 then binds to one C7 molecule and can then bind to the cell membrane via the C7. This then enables the binding of one C8 molecule. It is the C8 which inserts into the cell membrane and enables C9 to bind. These polymerize within the cell membrane (1-16 C9 molecules) resulting in a small pore being formed which causes cell lysis by osmotic shock.
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#C5b rapidly attaches to cell surfaces and binds to one C6 molecule
<br />
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#C5bC6 binds one C7 molecule
<br />
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#*C5bC6 binds to cell membrane via C7
 +
#C5b67 binds one C8 molecule
 +
#*C8 inserts into the cell membrane
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# C9 molecules bind and polymerize within the cell membrane (1-16 C9 molecules)</p>
 +
<p>The polymerization of C9 results in a small pore being formed which causes cell lysis by osmotic shock.</p>
  
 
==Complement Inhibitors==
 
==Complement Inhibitors==
To prevent inappropriate activation of the complement system there is a range of control mechanisms/compounds.
+
<p>To prevent inappropriate activation of the complement system there is a range of control mechanisms/compunds.</p>
<br />
 
 
=====Decay accelerating factor (DAF)=====
 
=====Decay accelerating factor (DAF)=====
 
Is both secreted onto and present on cell membranes and hastens the degradation of C1 esterase. Exerts control on the [[#Classical Pathway|classical pathway]].
 
Is both secreted onto and present on cell membranes and hastens the degradation of C1 esterase. Exerts control on the [[#Classical Pathway|classical pathway]].
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=====CD59=====
 
=====CD59=====
 
This binds the first molecule of C9 when it inserts into a cell membrane and prevents the polymerisation of C9 and therefore pore formation and cell lysis. It acts as a protective mechanism for the host cells.
 
This binds the first molecule of C9 when it inserts into a cell membrane and prevents the polymerisation of C9 and therefore pore formation and cell lysis. It acts as a protective mechanism for the host cells.
 
 
==Functions==
 
==Functions==
 
===Opsonisation===
 
===Opsonisation===
Once activated the complement system 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 and the major protein on the cell surface is iC3b (also known as C3bi) (some of the smaller C3 breakdown products (e.g. C3d) are also present).
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<p>Once activated the complement system 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 and the major protein on the cell surface is iC3b (some of the smaller C3 breakdown products (e.g. C3d) are also present).</p>
 
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<p>Complement fragments (C2a C3a, C4a and especially C5a) released after complement activation are chemotactic for phagocytes and iC3b acts as a target for phagocytosis. Phagocytes have receptors that bind avidly with the complement fragments. Complement-mediated opsonisation of microorganisms is several thousand times more efficient that innate receptors.</p>
Complement fragments (C2b, C3a, C4a and especially C5a) released after complement activation are chemotactic for phagocytes and iC3b acts as a target for [[Phagocytosis|phagocytosis]]. Phagocytes have receptors that bind avidly with the complement fragments. Complement-mediated opsonisation of microorganisms is several thousand times more efficient than innate receptors.
 
  
 
===Inflammation===
 
===Inflammation===
The smaller complement peptides are very efficient at inducing inflammation i.e. C3a and C5a. They attract [[Blood Cells - Overview|granulocytes]] to the site of complement activation as well as stimulating their degranulation.</p>
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<p>The smaller complement peptides are very efficient at inducing inflammation i.e. C3a and C5a. They attract [[Blood Cells - Overview|granulocytes]] to the site of complement activation as well as stimulating their degranulation.</p>
  
 
===Cell Lysis===
 
===Cell Lysis===
 
<p>The components (C5 – C9) can kill pathogens directly by causing cell lysis. This is effective against encapsulated bacterial infection like Neisseria and Meningococci.</p>
 
<p>The components (C5 – C9) can kill pathogens directly by causing cell lysis. This is effective against encapsulated bacterial infection like Neisseria and Meningococci.</p>
 
 
==Links==
 
==Links==
 
*[[Complement Associated Diseases|Pathology of complement associated diseases]]
 
*[[Complement Associated Diseases|Pathology of complement associated diseases]]
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{{Learning
 
{{Learning
 
|flashcards = [[Complement Flashcards]]
 
|flashcards = [[Complement Flashcards]]
}}
 
 
{{Chapter}}
 
{{Mansonchapter
 
|chapterlink = http://www.mansonpublishing.co.uk/book-images/9781840761436_sample.pdf
 
|chaptername = The Complement System
 
|book = Veterinary Immunology
 
|author = Michael J Day
 
|isbn = 9781840761436
 
 
}}
 
}}
 
<br><br>
 
<br><br>
{{Robert J Francis
 
|date = May 1, 2012}}
 
 
 
{{Jim Bee 2007}}
 
{{Jim Bee 2007}}
 
[[Category:Innate Immune System|C]]
 
[[Category:Innate Immune System|C]]
 
[[Category:Image Review]]
 
[[Category:Image Review]]
[[Category:Robert J Francis reviewed]]
 

Revision as of 14:52, 24 April 2012


Introduction

Complement is so called because it complements the function of antibody. It is a triggered enzyme cascade and there are more than 20 different proteins in the complement cascades, with most being enzymes or pro-enzymes. It can be activated by both the innate and adaptive immune systems and is one of the main innate protective mechanisms of invertebrates. Due to its destructive potential the complement system is heavily regulated but when activated it works largely by forming pore complexes as well as triggering acute inflammation and by promoting phagocytosis by macrophages and neutrophils.

Complement Fixation Pathways

Classical and alternative pathways

Classical Pathway

Triggered by the binding of antibody to antigen. Only IgM and certain IgG subclasses can activate complement this way.

  1. 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 antibody-bound (to FC region)
      • Form the enzyme C1 esterase (serine protease)
  2. C1 esterase first digests C4 to C4a and C4b and the C2 to C2a and C2b
    • C4b binds to the antigen
  3. C4b then binds C2a
    • C4b and C2a complex to form the enzyme C2a¯4b (C3 convertase)
  4. C2a¯4b digests 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 causes the binding of many hundreds of C4b¯2b molecules
  5. The C3b molecule that is produced by the action of this enzyme can also bind to it
  • Ca fragments C3a, C4a and C5a, and Cb fragment C2b
    • Are chemotactic for neutrophils
    • Induce acute inflammation
    • Increase vascular permeability and cell adhesion molecules

Like the alternative pathway, another major effect of classical pathway activation is to produce iC3b due to the actions of Factors I and H which promotes phagocytosis and initiates inflammation

Alternative Pathway

Is found in animals that do not have antibodies i.e. animals lower than cartilaginous fish. It was discovered after the classical pathway and is thus called the 'alternative pathway'.

  • C3b has a binding site that anchors it to any surface
    • The surfaces of certain activators stabilise the otherwise 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 producing 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 generates C3b¯Bb. (C3 convertase)
    • 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 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 opsonisation when engaged.

The main effects of alternative complement activation are therefore:

  1. To coat bacteria with iC3b
  2. 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

MB-Lectin Pathway

Lectins are proteins that bind carbohydrates e.g. collectins. They bind carbohydrates that have a terminal mannose residue and are called mannose-binding lectins.

  • 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

Membrane Attack Complex

This is the lytic pathway of complement function and can be initiated via either C3bB¯b3b or C4b2¯b3b.

  1. Split C5 into:
    • C5a is pro-inflammatory.
    • C5b the first molecule of the MAC (very short-lived and biologically active)
  2. C5b rapidly attaches to cell surfaces and binds to one C6 molecule
  3. C5bC6 binds one C7 molecule
    • C5bC6 binds to cell membrane via C7
  4. C5b67 binds one C8 molecule
    • C8 inserts into the cell membrane
  5. C9 molecules bind and polymerize within the cell membrane (1-16 C9 molecules)

The polymerization of C9 results in a small pore being formed which causes cell lysis by osmotic shock.

Complement Inhibitors

To prevent inappropriate activation of the complement system there is a range of control mechanisms/compunds.

Decay accelerating factor (DAF)

Is both secreted onto and present on cell membranes and hastens the degradation of C1 esterase. Exerts control on the classical pathway.

Factors I and H

Break down C3b and controls positive feedback by inhibiting C3b¯Bb thus preventing the complement cascade from running to exhaustion each time it is activated.

Complement receptor 1 (CR1)

Is present on many cell types especially erythrocytes and functions to bind C3d (the breakdown product of C3b) resulting from the action of Factors I and H. It binds potentially inflammatory immune complexes in plasma and these are then transported to the liver where they are phagocytosed by the hepatic macrophages and removed.

CD59

This binds the first molecule of C9 when it inserts into a cell membrane and prevents the polymerisation of C9 and therefore pore formation and cell lysis. It acts as a protective mechanism for the host cells.

Functions

Opsonisation

Once activated the complement system 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 and the major protein on the cell surface is iC3b (some of the smaller C3 breakdown products (e.g. C3d) are also present).

Complement fragments (C2a C3a, C4a and especially C5a) released after complement activation are chemotactic for phagocytes and iC3b acts as a target for phagocytosis. Phagocytes have receptors that bind avidly with the complement fragments. Complement-mediated opsonisation of microorganisms is several thousand times more efficient that innate receptors.

Inflammation

The smaller complement peptides are very efficient at inducing inflammation i.e. C3a and C5a. They attract granulocytes to the site of complement activation as well as stimulating their degranulation.

Cell Lysis

The components (C5 – C9) can kill pathogens directly by causing cell lysis. This is effective against encapsulated bacterial infection like Neisseria and Meningococci.

Links


Complement Learning Resources
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