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==Introduction==

==Introduction==

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|phagocytosis]] by [[Macrophages|macrophages]] and [[Neutrophils|neutrophils]].

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]].

 

==Complement Fixation Pathways==

==Complement Fixation Pathways==

[[Image:LH Complement pathway.png|thumb|left|250px|'''Classical and alternative pathways''']]

[[Image:LH Complement pathway.png|thumb|left|250px|'''Classical and alternative pathways''']]

[[Image:Complement Classical Pathway.png|thumb|right|250px|'''Classical pathway in detail''' - R.J.Francis, RVC 2012]]

[[Image:Complement Classical Pathway.png|thumb|right|250px|'''Classical pathway in detail''' - R.J.Francis, RVC 2012]]

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

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

[[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 it is the globular heads binds 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).

[[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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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 alternative pathway (below).  

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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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.

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.

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==Functions==

==Functions==

===Opsonisation===

===Opsonisation===

<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>

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).

<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 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===

<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>

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]]

{{Learning

{{Learning

|flashcards = [[Complement Flashcards]]

|flashcards = [[Complement Flashcards]]

}}

}}

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{{Jim Bee 2007}}

{{Jim Bee 2007}}

[[Category:Innate Immune System|C]]

[[Category:Innate Immune System|C]]

[[Category:Image Review]]

[[Category:Image Review]]