Transcript Complement system - Tehran University of Medical Sciences

Complement system
references
Complement system
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C was discovered several years ago as a
heat labile of normal plasma that augment
opsonozation of bacteria by Ab.coplement
the antibacterial activity of Ab
Consist of approximately 30 serum
molecules
10% of the total serum proteins
One of the major defense system of the
body
Major function of the complement
system
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Control of inflammatory reaction and
chemotaxis
Clearance of the immune complexes
Cellular activation and antimicrobial
defense
It is a major effector in immunopathological diseases
Complement components
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C1(C1q,
C2(C2a,
C3(C3a,
C4(C4a,
C5(C5a,
C6
C7
C8
C9
C1r, C1s )
C2b)
C3b)
C4b)
C5b)
factor B
factor D
DAF, CD55
CR1,CD35
factor H
factor I
Complement activation
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1-classical pathway which is
activated by Ab bound to Ag
2-the lectin pathway activated by
carbohydrates
3-Alternative pathway activated in
the presence of various microbial
pathogen
The protein of the system act in
enzyme cascade
Complement activation
consequences of the complement
activation
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1-it generate large numbers of
activated complement proteins that
bind covalently to pathogens,
opsonizing them for engulfment by
phagocytes bearing receptors for
complement
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2-the small fragments of some
complement proteins act as chemoattractants to recruit more
phagocytes to the site of
complement activation and also to
activate these phagocytes
3-the terminal complement
components damage certain bacteria
by creating pores in the bacterial
membrane
Overview of the main components
and effector actions of complement
C1 complex
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C1q bind to Ab
complexed with Ag
C1q can also bind
directly to the surface
of some pathogenes
C1q bind to 2C1r and
2C1s zymogene
Binding of C1q heads
to the pathogene
surface cause
enzymatic acivity of
C1r, then cleave C1s
to generate serine
protease
C3 and thioester bond
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The α chain of C3 and
C4 contain a thioester
bond between cystein
and a glutamine,
fallowing cleavage to
C3a & C3b ,allowing
C3b or C4b to form
covalent bond with
protein and
carbohydrate
Classical pathway of complement
activation
proteins of the classical pathway of
complement activation
The mannan binding lectin pathway is
homologous to the classical pathway
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The MB-lectin pathway uses a protein very
similar to C1q to trigger the complement
cascade
MB-lectin binds specifically to mannose
residues on pathogens surfaces
It is present at low conc. in normal plasma
and during acute phase reaction its
production increase by liver
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MB-lectin forms a
complex with two
protease : MBL
associated serine
protease; MASP-1
and MASP-2
Closely
homologous to C1r
and C1s and
activated to cleave
C4 and C2
Hydrolysis of C3 causes initiation of
the alternative pathway
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Spontaneous hydrolysis of plasma C3
C3b is produced at a significant rate by
spontaneous cleavage (C3 tick over)
through spontaneous hydrolysis of the
thioester in the C3 to form C3(H2O),
allowing binding factor B. factor D plasma
protease cleave factor B to form
C3(H2O)Bb a fluid C3 convertase, and can
cleave C3 to C3a and C3b. Most of these
C3b inactivated by H2O
Alternative pathway of complement
activation
Relationship between the factors of
the alternative, classic and MBL
C5 convertase
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C5 convertase are
formed when a large
number of C3b on the
surface of pathogene
bind to C4b2b or
C3bBb
C5a is the most
anaphylatoxine
C5b initiate the
assembly of the
terminal complement
component
Anaphylatoxins : C4a,C3a and C5a
causes local inflammation
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C5a is more active
than C3a which is
more active than C4a
C5a is a potent mast
cell activation,
degranulate mast cell
mediators; histamin
and TNFα induce
inflammation
C5a can enhance
phagocytosis of
opsonised
microorganism
The terminal complement
components
Membrane attack complex
Regulatory components
Functional protein classes in the
complement system