The Complement system

The complement system

The complement system

• A defensive system consisting of over 30 proteins produced by the liver and found in circulating blood serum.
• Complement kills microbes in three different ways
• 1. opsonization
• 2. inflammation
• 3. Cytolysis

A Cascade system

• The complement works as a cascade system.
• Cascade is when one reaction triggers another reaction which trigger others and so on. These types of systems can grow exponentially very fast.

Cascade activation

• 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

Two Pathways

• The complement pathway can be activated by either of two different pathways.
• Classical pathway (specific immune system)
• alternative (non-specific immune system)

The Classical Pathway

• The classical pathway is considered to be part of the specific immune response because it relies on antibodies to initiate it.

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• C1 becomes activated when it binds to the ends of antibodies

The building of a C3 activation complex

• 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

C3 Activation complex

• C2b and C4b bind together on the surface to form a C3 activation complex

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• The function of the C3 activation complex is to activate C3 proteins.
• This is done by cleaving C3 into C3a and C3b

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
• Opsonins are molecules that bind both to bacteria and phagocytes
• Opsonization increases phagocytosis by 1,000 fold.

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Bacteria

Opsonins

C3a

C3a increases the inflammatory response by binding to mast cells and causing them to release histamine

Building the C5 activation complex

• Eventially enough C3b is cleaved that the surface of the bacteria begins to become saturated with it.
• C2b and C4b which make up the C3 activation complex has a slight affinity for C3b and C3b binds to them
• When C3b binds to C2b and C4b it forms a new complex referred to as the C5 activation complex

The C5 activation complex

• The C5 activation complex (C2b, C4b, C3b) activates C5 proteins by cleaving them into C5a and C5b

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• Many C5b proteins are produced by the C5activation complex. These C5b begin to coat the surface of the bacteria.

The function of C5a

• C5a disperses away from the bacteria.
• Binds to mast cells and increases inflammation.
• Most powerful chemotactic factor known for leukocytes

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Building the Membrane Attack complex

• 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.

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• The cells inner integrity is compromised and it dies

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• Animation of the classical pathaway

Overview

The alternative pathway

• The alternative pathway is part of the non-specific defense because it does not need antibodies to initiate the pathway.

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• The alternative pathway is slower than the Classical pathway

The Alternative complement pathway

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

Factor B

• C3b on the surface of a foreign cells binds to another plasma protein called factor B

Factor D

• The binding of C3b to factor B allows a protein enzyme called Factor D to cleave Factor B to Ba and Bb.

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• Factor Bb remains bound to C3b while Ba and Factor D disperse away.

The C3 activation complex

• Properdin, also called factor P, binds to the C3bBb complex to stabilize it.

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• C3bBbP make up the C3 activation complex for the alternative pathway

The C3 activation Complex

• 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.

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• The C5 activation complex cleaves C5 into C5a and C5b.

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• C5b begins the production of the MAC.

Overview

Interferon