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The ComplementThe Complement
SystemSystem
DefinitionDefinition
The Classical Complement PathwayThe Classical Complement Pathway
The Lectin PathwayThe Lectin Pathway
The Alternative Complement PathwayThe Alternative Complement Pathway
Ways in which Microorganisms can Resist Body Defenses byWays in which Microorganisms can Resist Body Defenses by
Circumventing the Complement PathwaysCircumventing the Complement Pathways
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Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
Introduction..Introduction..
•^
The complement system refers to a series of proteinscirculating
in
the
blood
and
bathing
the
fluids
surrounding tissues.
-^
The
proteins
circulate
in
an
inactive
form,
but
when
activated
they
act
in
concert
in
an
orderly
sequence
to
activated
they
act
in
concert
in
an
orderly
sequence
to
exert their biological effects.
-^
The term “Complement” refers to the ability of theseproteins to complement i.e. augment the effects of othercomponents of immune system eg. Antibody 12/23/201312/23/
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
HistoryHistory
-^
Jules Jean BaptisteVincent Bordet
-^
(Belgium
)^
13 June
6 April
-^
Won noble prize in
-^
Won noble prize in 1919 for discovery inimmunity
12/23/201312/23/
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
Outcome of complement activationOutcome of complement activation •^
Three main effects 1.^
Lysis of cells
such as bacteria, allografts
and tumor cells
Generation of mediators
that participate in
Generation of mediators
that participate in
inflammation and attract neutrophils
Opsonization
ie. Enhancement of
phagocytosis
12/23/201312/23/
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
Components of the complement systemComponents of the complement system^ There are more than 20 components of which
followings are important.^ –
C1,C2,C3,C4,C5,C6,C7,C8,C
C1,C2,C3,C4,C5,C6,C7,C8,C
- Factor B, Factor D, Factor H, Factor I,– Properdin, C1 inhibitor, C4 binding protein, S
protein
12/23/201312/23/
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
Activation of complementsActivation of complements
Why it needs to be activated?
Several complement components are proenzymes,which must be cleaved to form active enzymes.
Activation of the complement can be initiated either by
antigen
–antibody
complexes
or
by
variety
of
nonimmunologic molecules eg. Endotoxin.
12/23/201312/23/
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
ComplementComplement
CascadeCascade ActivationActivationActivationActivation
12/23/201312/23/
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
Fig. 2: Assembly of C1 during theFig. 2: Assembly of C1 during theClassical Complement PathwayClassical Complement Pathway
The Fab of IgG or IgM
bind to epitopes onan
antigen.
C1q,
C1r,
and
C1s
then
assembles on the Fcportion
of
the
antibodies
to
form
antibodies
to
form
C1, the first enzymeof
the
classical
complementpathway.
The
enzyme
C
is
able
to
cleave
C
into
C4a
and
C4b,
as
well as C2 into C2aand C2b
.
12/23/201312/23/
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
Fig. 3: Cleavage of C4 by C1 during theFig. 3: Cleavage of C4 by C1 during the
Classical Complement PathwayClassical Complement Pathway
The
enzyme
C
is
able to cleave C4into C4a and C4b.The
C4b
then
binds
to
adjacent
binds
to
adjacent
proteins
and
carbohydrates
on
the surface of theantigen. 12/23/201312/23/
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
Fig. 4: Cleavage of C2 and Formation of C3Fig. 4: Cleavage of C2 and Formation of C
Convertase during the Classical ComplementConvertase during the Classical Complement
PathwayPathway
C2 binds to the C4b and
the
enzyme
C
subsequently cleavesC2 into C2a and C2b. The
classical
The
classical
complement pathwayis now activated. TheC4b2a functions as aC
convertase
that
can
enzymatically
cleave
hundreds
of
molecules of C3 intoC3a and C3b. 12/23/201312/23/
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
Fig. 6: Formation of C5 Convertase during theFig. 6: Formation of C5 Convertase during the
Classical Complement PathwayClassical Complement Pathway
Some
molecules
of C3b bind toC4b2a, the C3 convertase,
to
convertase,
to
form C4b2a3b,a^
C
convertase thatcleaves C5 intoC5a and C5b. 12/23/201312/23/
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
Fig. 7: Formation of C5 Convertase during theFig. 7: Formation of C5 Convertase during the
Classical Complement PathwayClassical Complement Pathway
C4b2a3b functions as a C5 convertase
that cleaves C5 into C5a and C5b.C5a is the most potent complementprotein
triggering
inflammation.
It
causes
mast
cells
to^
release
vasodilators such as histamine so thatblood
vessels
become
more
permeable;
it^
increases
the
expression
of
adhesion
molecules
on
expression
of
adhesion
molecules
on
leukocytes
and
the
vascular
endothelium
so
that
leukocytes
can
squeeze out of the blood vessels andenter
the
tissue
(diapedesis);
it
causes
neutrophils
to
release
toxic
oxygen
radicals
for
extracellular
killing; and it induces fever. C5a alsofunctions
as
a
chemoattractant
for
phagocytes.
Leukocytes
will
move
towards increasing concentrations ofC5a.
C5b
becomes
part
of^
the
Membrane Attack Complex (MAC).^ 12/23/201312/23/
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
The Alternative Complement PathwayThe Alternative Complement Pathway
-^
Activation of the alternative complement pathway begins when C3b
(or
C3i)
binds
to
the
cell
wall
and
other
surface
components of microbes
. C3b can also bind to IgG antibodies.
Factor
B
then
combines
with
the
cell
C
3 b
to
form
C
3 bB
Factor
B
then
combines
with
the
cell
C
3 b
to
form
C
3 bB
Factor D
then splits the bound Factor B into Bb and Ba,
forming
C3bBb
•^
properdin
then binds to the Bb to form
C3bBbP that functions
as a C3 convertase
(see Fig. 1)
capable of enzymatically
splitting hundreds of molecules of C3 into C3a and C3b. 12/23/201312/23/
1919
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
Alternative PathwayAlternative Pathway
-^
C
is
an
unstable
molecule
continually
undergoing
hydrolysis
in
the
blood
and
lymph
.^
This
rate
of
hydrolysis
can
be
lymph
.^
This
rate
of
hydrolysis
can
be
accelerated
in
the
presence
of
some
pathogens. C3b then binds to Factor Bmaking
it
susceptible
to
cleavage
by
Factor D. This creates the
C3 convertase
of the Alternative Pathway, C3bBb. 12/23/201312/23/
Prof. Muhammad Akram Hossain,Prof. Muhammad Akram Hossain,
AutoimmunityAutoimmunity
