Download Complement system

The complement system
immune system
2nd class
NO.2
- Complement system :is a protein cascade (like kinin and clotting factors)composed
of more than 40 proteins including regulatory factors
- Cascade is when one reaction triggers another reaction which trigger others
and so on. These types of systems can grow exponentially very fast.
-The components are made in the liver ,through some local production at sites of
inflammation may be undertaken by macrophages
-The complement system has 3 pathway ,which are all capable of igniting the another
pathway ,known as the common or membranes attack pathway.
-The majority of complement protein are soluble ,although some are membranes
bound.
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The complement system
immune system
2nd class
NO.2
-The soluble protein circulate in an inactive state ,and each must be activated
sequentially for the reaction to proceed.
-The overall serum concentration of complement protein is 3-4µg\l i.e. around 10% of
serum proteins.
- Complement proteins are often designated by an uppercase letter C and are inactive
until they are split into products.
Example: C1
- When the products are split they become active. The active products are usually
designated with a lower case a or b.
Example: C1a and C1b
-several biological activities appear as a consequence of complement activation ,the
main ones being
-1-Cell or bacterial lysis .
2-production of proinflammatery mediators ,which amplify and perpetuate the
process.
3-Solubilisation of antigen-antibody complex.
*The complement pathways.
A-The classical pathways
1-is activated by an interaction between antigen and antibody forming so –called
immune complex .
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The complement system
immune system
2nd class
NO.2
2-Antibodies can bind to, or fix complement only after reacting with their antigen .
3-The formation of the complex provokes a conformational change in the antibodies
molecules that discloses a site for binding of the first complement component C1.
4-IN addition to antigen –antibody complexes ,the activation of the classical pathway
can be initiated by aggregated immunoglobulin and by non-immunological stimuli
such as C-reactive protein.
Notes:
• The classical pathway is considered to be part of the specific immune response
because it relies on antibodies to initiate it.
• C1 becomes activated when it binds to the ends of antibodies
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Once C1 is activated, it
activates 2 other complement proteins, C2 and C4 by cutting them in half
C2 is cleaved into C2a and C2b
C4 is cleaved into C4a and C4b
Both C2b and C4b bind together on the surface of the bacteria
C2a and C4a diffuse away
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The complement system
immune system
2nd class
NO.2
C3 Activation complex
• C2b and C4b bind together on the surface to form a C3 activation complex
• The function of the C3 activation complex is to activate C3 proteins.
– This is done by cleaving C3 into C3a and C3b
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The complement system
immune system
2nd class
NO.2
-C3b
• Many C3b molecules are produced by the C3 activation complex.
• The C3b bind to and coat the surface of the bacteria.
• C3b is an opsonin
• Opsonin are molecules that bind both to bacteria and
phagocytes
• Opsonization increases phagocytosis by 1,000 fold.
-C3a
C3a increases the inflammatory response by binding to mast cells and causing them
to release histamine
The C5 activation complex
-The C5 activation complex (C2b, C4b, C3b) activates C5 proteins by cleaving them
into C5a and C5b
-Many C5b proteins are produced by the C5 activation complex. These C5b begin to
coat the surface of the bacteria
The function of C5a
• C5a disperses away from the bacteria.
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The complement system
immune system
2nd class
NO.2
– Binds to mast cells and increases inflammation.
– Most powerful chemotactic factor known for leukocytes
Building the Membrane Attack complex
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C5b on the surface of bacteria binds to C6
The binding of C6 to C5b activates C6 so that it can bind to C7
C7 binds to C8 which in turn binds to many C9’s
Together these proteins form a circular complex called the Membrane
attack complex (MAC)
Membrane Attack complex
• The MAC causes Cytolysis.
– The circular membrane attack complex acts as a channel in
which cytoplasm can rush out of and water rushes in.
• The cells inner integrity is compromised and it dies
• Animation of the classical pathway
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The complement system
immune system
2nd class
NO.2
The alternative pathway
• The alternative pathway is part of the non-specific defense because it does not
need antibodies to initiate the pathway.
• The alternative pathway is slower than the Classical pathway
• Availability of C3b is the essential requirement for activation of the alternative
pathway to proceed ,this requirement is again fulfilled by the internal
thioester bond ,which undergo continues low grade hydrolysis.
• It is thought that bacteria provide a surface for C3b and C3bBp deposition and
protection from the destruction action of circulating regulatory factors I and H.
• The alternative pathway is slower than the Classical pathway.
• The Alternative complement pathway
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The complement system
immune system
2nd class
NO.2
Initiation of The Alternative pathway
• C3 contains in unstable thioester bond.
• This unstable bond makesC3 subject to slow spontaneous
hydrolysis to C3b and C3a
• The C3b is able to bind to foreign surface antigens.
• Mammalian cells contain sialic acid which inactivates C3b.
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C3b on the surface of a foreign cells binds to another plasma
protein called factor B
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The binding of C3b to factor B allows a protein enzyme
called Factor D to cleave Factor B to Ba and Bb.
. Factor Bb remains bound to C3b while Ba and Factor D disperse
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The complement system
immune system
2nd class
NO.2
The C3 activation complex
• Properdin, also called factor P, binds to the C3bBb complex to stabilize
it.
• C3bBbP make up the C3 activation complex for the alternative
pathway
• The C3 activation complex causes the production of more C3b.
• This allows the initial steps of this pathway to be repeated and
amplified
• 2X106 molecules can be generated in 5 minutes
C5 activation complex
-When an additional C3b binds to the C3 activation complex it converts it
into a C5 activation complex.
-The C5 activation complex cleaves C5 into C5a and C5b.
-C5b begins the production of the MAC.
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The complement system
immune system
2nd class
NO.2
Overview
C-The LECTIN pathway or Mannan –binding lectin
pathways.
-Lectins are proteins which bind to carbohydrates
-Many bacteria have many mannose residues on their surface.
the lectin-based complement system begins with a “mannosebinding protein” (MBP).
-MBP reacts, in turn, with a MBP-associated serine protease
(MASP
-MASP functions, in effect, like activated C1q[r2s2], that is a C3
convertase.
D-The membranes attack pathway.
-1-This final common complement pathway ,generate one of
the more biologically active component ,C5a ,but more
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The complement system
immune system
2nd class
NO.2
importantly leads to the formation of the killer molecules of the
system .
2-This is known as the membranes attack complex (MAC)
since it provokes membranes damage.
3-MAC is composed of C5b6789 ,this complex is inserting
into and traversing the membrane bilayer .Holes are made in the
membranes ,and if a sufficient number are created death result
through osmotic lysis .
4-Control is achieved by the liability of the component ,by
dilution and by specific regulatory protein and receptors.
*Biological activities generated by complement activities .
1-Opsonisation:The concept of Opsonization is that opsonin coat
bacteria and this facilitate their removal one of the major opsonins
derives from complement the ability to bind membranes is a
feature of varies complement fragment ,but C3b account for the
most of the complement opsonic activities ,once the organism are
coated with C3b ,it is simple to see how the presence of CRs 3 and
4 on neutrophil can result in more efficient engulfment .
2-Cell recruitment and activation
-The low –molecular weight fragment C4a,C5a are known as
anaphylatoxin ,in which they activate mast cells and basophil
directly through specific receptors .
-C5a and to a lesser extent ,C3a are also chemoatactic ,a term used
to describe the ability to attract cells ,in this case neutrophil.
3-Cell lysis :Complete complement activation through either
pathway occurring on cell surfaces leads to cell lysis.
-typical target could include bacteria and enveloped viruses ,but
host erythrocytes ,platelet and lymphocyte may also become
victims in certain pathological condition .
4-Removal of immune complex :
-immune complexes of antibodies and antigen are forming in the
circulation continuously in small number ,with periodic increase
during infection or inflammatory episodes
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The complement system
immune system
2nd class
NO.2
-These are potentially harmful ,since they can become deposited in
vessel walls or tissue and initiate complement activation with all
the pro-inflammatory effect that are entail
-Larger complexes ,composed of lattice of antibodies and antigen
are more likely to become insoluble and fixed in the tissue .
-The covalent binding of C3b to antibodies in a complex inhibit
lattice formation and maintains solubility .
-C3b –coated complexes attach to erythrocyte CR1 ,which act to
remove them from circulation via the liver and spleen where they
are released and taken up by resident macrophages.
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