The Complement system
SONU
SC 112
THE COMPLEMENT SYTEM
• The complement system is the series of heat-
labile serum proteins that function in both
adaptive and innate host defense system
• It is named “complement system” because it was
first identified as a heat-labile component of
serum that “complemented” antibodies in the
killing of microbes
• These components are proteins which are highly
regulated and interacted via series of proteolytic
cascades
The complement system
• This defensive system consisting of over 30
proteins produced by the liver and found in
circulating blood serum
• Main functions of complement system
1) Opsonization (its components bind to microbes-easy to
be recognized by phagocytes)
2) Inflammation (complements produce mediators)
3) Cytolysis (cell lysis----cell death)
A Cascade system
• The complement works as a cascade
system.
– Cascade occurred when one reaction triggers
another reaction then 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 system can be activated via two main
pathways
– Classical pathway (specific immune system)
– Alternative (non-specific immune system)
– ***Lectin Pathways (microbes with surface contains mannose
Complement pathways
Component sequences
•For alternative pathway start from C3 to C5, C6,
C7, C8, C9
•For classic pathway are numbered from C1 to C9
that is C1-C4-C2-C3-C5-C6-C7-C8-C9
•Up to C5, activation involves proteolytic cleavage,
liberating smaller fragments from C2 upto C5
Complement system
The Classical Pathway
• The classical pathway is
considered to be part of
the specific immune
response because it
relies on antibodies to
initiate its cascade
• C1 becomes activated
when it binds to the ends
of antibodies
Classical pathway…
• 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 to form C3 convertase
(C4bC2b formerly C4b2a)
• C2a and C4a diffuse away
Classical pathway…
• C2b and C4b bind
together on the surface
of the microbes
• C3 activation complex is
an enzyme
• The function of the C3
activation complex
(convertase)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 (opsonization)
• C3b is an opsonin
– Opsonins are molecules that bind both to
eria
bacteria and phagocytes Bact
– Opsonization increases phagocytosis by
1,000 fold.
Opsonins
C3a
• C3a binds to mast cells which release histamine,
a mediator for inflammation
• Histamine increase capillaries permeability
C5 activation complex
(convertase)
• As more C3b are available in the blood,
– C2b and C4b which make up the C3
activation complex has a affinity for C3b
activation complex thus C3b binds to them
• When C3b binds to C2b and C4b it forms
a new complex referred to as the C5
activation complex (C4bC2bC3b)
C5 activation complex
(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 C5
activation complex
• These C5b begin to coat the surface of the
bacteria.
C5a
• C5a
– Binds to mast cells and increases inflammation
– Most powerful chemotactic factor known for
leukocytes
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 has piercing agents
which destruct cell membrane
• The cells inner integrity is
compromised and it dies
The alternative pathway
• The alternative pathway is part of the non-
specific defense (innate) 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 makes
C3 subject to slow
spontaneous hydrolysis to
C3b and C3a
• The C3b is able to bind to
foreign surface antigens
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
dissolve away.
The C3 activation complex
(convertase)
• Properdin, also called factor P, binds to the
C3bBb complex to stabilize it.
• C3bBb make up the C3 activation complex for
the alternative pathway
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
C5 activation complex
• When an additional C3b
binds to the C3 activation
complex (C3bBb) it
converts it into a C5
activation complex
(3CbBb3Cb)
• The C5 activation
complex cleaves C5 into
C5a and C5b.
• C5b begins the production
of the MAC.
Summary
Opsonization
Inflammation
Cytolysis
Major Biologic Effects Of Complement
A. OPSONIZATION (giving a mark)
• Cells or antigen-antibody complexes and other
particles are phagocytosed much more easily in
the presence of C3b
– Because of the presence of C3b receptors on
the surface of many phagocytic cells.
B. CHEMOTAXIS
• C5a stimulates movement of neutrophils and
monocytes toward sites of antigen deposition
MAJOR BIOLOGIC EFFECTS…
C. ANAPHYLATOXINS
• C3a, C4a, C5a can produce increased vascular
permeability and smooth muscle contraction.
C3a and C5a also stimulate mast cells to
release histamine.
D. CTOLYSIS
• Insertion of the C5b6789 complex into the cell
surface leads to the killing or lysis of many types
of cells including erythrocytes, bacteria, and
tumor cells.
Classic And Alternative pathways
Classic Pathway Alternative pathway
* Specific acquired immunity * Non-specific innate immunity
* Initiated by antibody * Bacterial endotoxin, capsule
* Interaction of all components * C1, C4, C2 are by-passed
* Properdin system not involved * Properdin system is involved
The end!
