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The Complement (C) system refers to a
system consisting of a group of nonspecific proteins (approximately 20) present
in normal human and animal serum
Term “complement” refers to the ability of
these proteins to complement i.e. augment
the effects of other components of the
immune system
Complement is an important component of
our innate host defenses
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Term complement was coined by Paul Ehrlich
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Constitutes 5 % of normal serum proteins
Present in inactivate form, but when activated they
augment immune response
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Their level does not increase by infection or
vaccination
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They are heat-labile, inactivated at 560C for 30
minutes
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Synthesized mainly by liver, also produced by
blood monocytes, tissue macrophages, epithelial
cells of GIT and genitourinary tracts
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Species nonspecific
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Bind to Fc portion of antibody
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Does not combine with free antigen or
antibody, but only with antigen-antibody
complex
Among Igs, only IgM, IgG3, IgG1 and IgG2
in that order fix complement
This property is due to the presence of C
binding site on the Fc portion of these
immunoglobulins
Complement components
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Complement system consists of about 20
proteins which include the complement
components, the properdin system and the
regulatory protein
There are 9 complement components. Ie, C1C9. C1 has 3 subunits ie, C1q, C1r and C1s
Factors B, D, H and I, properdin (P)
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Mannose binding lectin (MBL), MBL
associated serine proteases (MASP-1 MASP2)
C1 inhibitor (C1-INH, serpin), C4-binding
protein (C4-BP), decay accelerating factor
(DAF), Complement receptor 1 (CR1),
protein-S (vitronectin)
Activation of Complement
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:
Initiated either by antigen-antibody
complexes or by a variety of nonimmunologic molecules like bacterial
endotoxin, lipopolysaccharides, zymosan
(yeast cell wall)
The action of complements act as a cascade
(one event must occur before another takes
place)
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Complement components have two unequal
fragments- ‘a’ and ‘b’
Generally b is large and a is small except C2 a
which is larger
Larger fragment join the cascade and smaller
fragment diffuse to mediate other functions
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Sequential activation of complement
components occurs via one of the 3
pathways
1) Classical pathway
2) Alternate pathway
3) Lectin pathway
◦ ACTIVATION
◦ AMPLIFICATION
◦ ATTACK
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In the classical pathway, antigen-antibody
complexes activate the pathway
In the alternative pathway (antibody
independent pathway), many cell surface
substances initiate the process - bacterial
lipopolysaccharidess (endotoxin), fungal
cell wall, viral envelopes etc
In the lectin pathway (antibody independent
pathway), mannan-binding lectin (MBL)
binds to the surface of microbes bearing
mannan ( a polymer of mannose) and this
activates the process
1.
2.
3.
4.
Initiation of pathway
Formation of C3 convertase
Formation of C5 convertase
Formation of membrane attack complex
(MAC)
all the three pathways differ each other in
their initial process till formation of C3
convertase.
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Classical Pathway Begins with Ag-Ab
Binding
Ag-Ab
C1q
C1r
C1s
Ag-Ab C1
C4
C4a
C4
C4b
Ag-Ab C14b
C2a
C2
C2
C2b
Ag-Ab C14b2a
(C3 convertase)
Ag-Ab C14b2a
C3a
C3
C3
Ag-Ab C14b2a3b
C3b
C5a
C5
C5
C5b
C6
C7
C5b67
C8
C9
C5b89
Cell damage
C5b
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ACTIVATION
◦ C1q portion of C1 attaches to the Fc portion of an
antibody
◦ Only IgG and IgM can activate complement
◦ Once activated C1s is eventually cleaved which
activates C4 and C2
◦ C4b & C2a come together to form the C4b2a
which is the C3 convertase
◦ C3 convertase activates C3 to C3a and C3b
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ACTIVATION
◦ C3a binds to receptors on basophils and mast cells
triggering them to release there vasoactive
compounds (enhances vasodilation and
vasopermeability)
◦ C3a is called an anaphylatoxin
◦ C3b serves as an opsonin which facilitates immune
complex clearance
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AMPLIFICATION
◦ Each C1s creates many C4b and C2b fragments
◦ Each C4bC2a creates many C3b (activated C3)
◦ Each C3b goes on to create many Membrane Attack
Complexes
◦ Example
 1 C1S makes 100 C4bC2b
 100 C4bC2b makes 10,000 C3b
 10,000 C3b makes 1,000,000 MAC
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ATTACK
◦ Most C3b serves an opsonin function
◦ Some C3b binds to C4bC2a to form the C5
convertase C4bC2aC3b
◦ C5 convertase cleaves C5 leading to the formation
of the Membrane attack Complex (C5-C6-C7-C8C9)
◦ The MAC “punches holes” in cell walls resulting in
lysis
C5a is a:
1. Potent
C1q anaphylatoxin
C2
C4
2. Chemoattractant
for neutrophils
4
2a
2
4
a
b
C3
C3a binds to receptors on
basophils and mast cells
triggering them to release
there vasoactive
compounds (enhances
vasodilation and
vasopermeability) ANAPHYLATOXIN
C3a
C3b
C
5
C5
C3- C5a
C5-Convertase
b
convertase
C9
Classical
Pathway
C7
C8
C6
Requires no specific
recognition of
antigen in order to
cause activation
 C1, C2 and C4 are
not involved
 Require factor B, D
and properdin
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plasma C3, with an unstable
thioester bond, can be
hydrolyzed spontaneously into
C3a and C3b.
C3b attaches to the surface of
bacteria, yeasts, viruses (or
even host’s own cells ®).
Mg+
+
Ba
(stabilizatio
n
of C3bBb)
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analogous to the C4b2a
complex in the classical
pathway
©
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ACTIVATION
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AMPLIFICATION
◦ Spontaneous conversion from C3 to C3b occurs
in body
◦ Normally, C3b is very short lived and quickly
inactivated
◦ Binding with bacteria or other foreign material
allow C3b to bind and stay active
◦ Factor B binds to C3b
◦ Factor B is then cleaved by factor D into Ba and
Bb
◦ C3bBb remains which acts as a C3 convertase (C3
 C3a and C3b)
◦ C3bBbC3b is formed which acts as a C5
convertase
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ATTACK
◦ C5 is cleaved to C5a and C5b
◦ C5b then starts the assembly of the Membrane
Attack Complex
C3a
C3
C3b
C3
C
5
Anaphylatoxin
Alternative
Pathway
C3-Convertase
C5-Convertase
C7
C8
C9
C6
C3b
C3a
C5 C5aD
b
BbB Ba
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Action of membrane attack complex (MAC):
Insertion of MAC to the target cells leads to
disruption of the membrane and entry of
water and loss of electrolytes from the cell,
thus resulting in cytolysis
Regulation of complement system:
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Destruction of tissues by excessive activity
of complement is prevented by regulation
Control of the complement cascade in
normal serum is exerted by:
Inhibitors – halt the complement cascade
Inactivators – destroy the complement
proteins
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Regulation of the complement system:
1) the complement binding site on the H
chain of IgM and IgG is available to the C1
component only if antigen is bound to the
antibody
2) C1 inhibitor inactivates the protease
activity of C1, thus to activate the classical
pathway the process should proceed past
this point by generating sufficient C1 to
overwhelm the inhibitor
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3. Regulation of the alternative pathway is
mediated by the binding of factor H to C3b
and cleavage of this complex by factor I, a
protease.
The pathway can proceed beyond this
regulatory point only if sufficient C3b
attaches to cell membranes which protects
it from degradation by factor H and I
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4. Properdin protects the C3b and enhances
activation of alternate pathway
5. Decay accelerating factor ( DAF, CD55) –
a glycoprotein located on the surface of
human cells provides protection of cells
from lysis
It acts by binding to C3b and C4b and
limits the formation of C3 convertase and
C5 convertase, this prevents the formation
of membrane attack complex
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Biological effects of complement :
1) Bacteriolysis and cytolysis:
insertion of membrane attack complex to
cells lysis of bacteria, erythrocytes, tumor
cells etc
2) Amplification of inflammatory response:
C3a, C4a, C5a are anaphylatoxic by
degranulation of mast cells to release
histamine and other mediators
They cause increased vascular permeability,
smooth muscle contraction
C567 is chemotactic
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3) Hypersensitivity reactions:
Complement participates in type II
(cytotoxic) and type III (immune complex)
hypersensitivity reactions
4) Opsonization:
Facilitates the destruction of pathogens by
phagocytic cells by binding of C3b to the
receptors on phagocytes
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5) Immune adherence:
C3 and C4 bound antigen-antibody
complexes adhere to RBCs, platelets and
are thus rapidly recognised by phagocytes
6) Endotoxic shock:
Endotoxin activated complement cascade
leads to excessive C3 activation and platelet
adherence
Platelet lysis releases large amount of
platelet factors leading to disseminated
intravascular coagulation (DIC)
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7)Autoimmune diseases:
Serum complement levels are decreased in
diseases like systemic lupus erythematosus
and rheumatoid arthritis thus may be
involved in pathogenesis of them
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Clinical aspects:
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Deficiencies of complement:
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Leads to poor host resistance against
infections and results in recurrent bacterial
and fungal infections and collagen
disorders
Deficiency
C1 inhibitor
Disease
Hereditary
angioneurotic oedema
C1, C2, C4 components Systemic lupus
erythematosus, other
collagen vascular
diseases
C3 and its regulatory
Recurrent pyogenic
protein C3b inactivator infections
C5, C6, C7, C8, C9
components
Bacteremia, mainly by
Gram negative
diplococci,
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Quantitation of complement:
Complement activity in serum is measured
by estimating the highest dilution of the
serum that lyses sheep RBCs sensitized by
anti-erythrocytic antibody
Complement components can be measured
by radial immunodiffusion method ( does
not differentiate active and inactive
fractions)