THE COMPLEMENT

SYSTEM
IMMUNOLOGY
BMS 101
Mellah Katongi
 THE COMPLEMENT SYSTEM

Complement is a system of more than 30 proteins produced by the

liver and found in circulating blood plasma.
Complement Proteins:
Found in serum and cell surfaces
Are in inactive forms(zymogens)
Some are acute phase ie they increase in conc.x2 to x3
Have shared gene sequences meaning they can evolve by gene
duplication and recombination
The Immune System is the Third Line
of Defense Against Infection
Complement kills microbes in 3 different ways
I. Opsonization
II. Inflammation
III. Cytolysis
In conjunction with specific antibodies, complement components act
as the primary humoral defense system against bacterial and viral
infections.
 complement cascade
The complement works as a cascade system-one reaction triggers
another reaction and so on. Making it a very fast system
At each step, the number of protein molecules activated increases,
amplifying the reaction.
Complement activation involves the sequential activation of
complement proteins, either by protein-protein interactions,
conformational changes or by proteolytic cleavage by other
complement proteins.
 complement cascade
Activation of these zymogens results in specific serine protease
activity capable of cleaving other complement proteins, producing the
complement cascade.
Complement proteins are designated by an upper case letter C eg C1
and are inactive until they are split. Active products are designated
with a lower case a or b
 Complement Pathways
1. Classical pathway -initiated by presence of Ag-Ab complexes
2. Alternative pathway-recognises foreign cell surfaces
3. Lectin or mannose binding pathway-recognises mannose on cell
surfaces
The classical
pathway
THE CLASSICAL
PATHWAY
The classical pathway
The classical pathway is considered
to be part of the specific immune
response because it relies on
antibodies to initiate it.
Antigens on the surface of the
pathogen attracts antibodies to form
antigen-antibody complex
C1(composed of C1q, C1r, and C1s)
becomes activated when it binds to
the Fc of 2 antibodies. Alternatively,
one pentameric IgM molecule may
serve as the catalyst
Once C1 is activated, it activates
2 other complement proteins, C2
and C4 by cutting them in half,
yielding C4b2b, which is known
as the C3 convertase/C3
activation complex
Both C2b and C4b bind together
on the surface of the bacteria
C2a and C4a diffuse away
C3 Activation complex
The function of the C3
activation complex /C3
convertase is to activate
C3 proteins.
This is done by cleaving C3
into C3a and C3b.many
C3bs are produced.
 C3b and C3a

C3a is a powerful chemotactic factor

C3b is an opsonin that can increase vascular permeability
Opsonins are molecules that bind both to
C3a increases the inflammatory
bacteria and phagocytes response by binding to mast cells and
Opsonization increases phagocytosis by
causing them to release histamine
1,000 fold
Building the C5 activation complex
C2b and C4b which make up the C3 activation complex, C2bC4b has a
slight affinity for C3b. and When C3b binds to C2b and
C4b(C3bC2bC4b) it forms a new complex referred to as the C5
activation complex/C5 convertase.
The C5 activation complex (C2b, C4b, C3b) activates C5 proteins by
cleaving them into C5a and C5b. 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
• Macrophage activator
Building the Membrane Attack
complex(MAC)
• 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
ALTERNATIVE
PATHWAY
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
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.

• 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.

• 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.

• The C5 activation complex cleaves C5

into C5a and C5b.

• C5b begins the production of the MAC.

Overview
Mannose-binding
Lectin Pathway
This pathway is activated by the binding of mannose-
binding lectin (MBL) to mannose residues on the
pathogen surface.
This in turn activates the MBL-associated serine
proteases, MASP-1 and MASP-2, which activate C4
and C2, to form the C3 convertase, C4b2a.