Immune response to extracellular bacteria

1
Immune response to extracellular bacteria
Immune response
neutralize
destroy
Toxin
Bacteria
Exotoxin (secreted) diphtheria toxin, cholera
toxin, etc
Endotoxin (component of bacteria) Lipopolysacchari
de (LPS)
2
Primary Immune Response infected by a
pathogen for the first time.
skin
Immediate response
Internal tissue
Bacteria invasion
complement
3
Complement
A group of proteins (about 35) produced primarily
by hepatocytes in the liver. Also produced by
other cells such as macrophages.
Present in blood and tissue fluids as inactive
precursors.
Activated by bacterial infection. Activated
complements attack bacteria.
4
Classical pathway of complement activation
Bacteria are bound by antibodies.
bacteria
Antigen
Antigen
L
L
Primary immune response Natural antibodies bind
to carbohydrates and lipids on bacterial surface.
H
H
Antibody
H heavy chain
L light chain
B cell
5
C1 binds to antibody.
Antibody
C1r
C1s
C1 C1q C1r C1s
C1q
Free antibodies do not bind C1. Binding to
antigen induces conformation change in antibody
and reveals the C1 binding site.
6
Binding of C1q to antibody activates C1r, C1s
protease.
Antigen-antibody


C1s
C1r
C1q
C1q
C1q (conformation change)
C1r
C1r
zymogen
Active serine protease
C1s
C1s
zymogen
Active serine protease
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C1s activates C4.
C4b
C4b
glu
cys
glu
C4b
cys
C1s
C
S
unstable
C4
C
HS
O
O
O
OH
Covalent linkage
C4a
bacteria
C1s activates C2.
zymogen
C2
C2b

C1s
C1s
Active serine protease
C2a
C2
C4b2a
C4b
bacteria
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C4b2a activates C3.
C3b
C3b
Similar to C4
glu
cys
glu
C3b
cys
C4b2a
C
S
unstable
C3
C
HS
O
O
O
OH
Covalent linkage
C3a
bacteria
C4b,2a is classical C3 convertase.
C3b activates Factor B.
Similar to C2
zymogen
B
Ba
Factor D (protease)

Active serine protease
B
Bb
B
C3bBb
C3b
C3b
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C3b is the major amplification point.
C3
C3bBb cleavages additional C3 into C3b.
C3bBb is alternative C3 convertase.

B
Bb
C3b
C3b
C3b
C3b
C3b
C3b
More C3bBb
Amplification
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antibody
C4
C1
bacteria
C2
C3
more C3, B
B
D
D
Bacteria coated with C3b
Targeted for destruction
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C4b2a3b and C3b2B activates C5.
C5 associates with C3b
C5a
C5
C2a cleaves C5
C2a
C5b
C2a
C4b
C4b
C3b
C3b
C4b2a3b is the classical C5 convertase.
C5 associates with C3b
C5a
C5
Bb cleaves C5
Bb
C5b
Bb
C3b
C3b
C3b
C3b
C3b2Bb is the alternative C5 convertase.
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C5 associates with C6,7,8,9 to form Membrane
attack complex (MAC).
70-100A
C6
C8
C9
C7
C5b
cell membrane
C5b initiates the formation of MAC
C5b,6,7,8,9
Membrane attack complex (MAC)
MAC disrupts cell membrane.
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Lectin pathway of complement activation
Mannose binding lectin (MBL)
C-type lectin domain (Ca2-dependent carbohydrate
binding)
Mannose N-acetylmannoseamine N-acetylglucoseamine
Oligomers (2-6 subunits)
polypeptide
subunit
(6-18 carbohydrate binding sites)
(3 x polypeptide)
Specificity
MBL bind to surface that display repetitive
carbohydrate patterns (bacteria, fungi, virus,
parasite).
MBL does not bind to human cell.
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Binding of MBL to bacterial surface
activates associated proteases.


MASP
MBL-associated serine protease
C4
MASP
C4bC2a
C2
MASP activates C4 and C2 by proteolytic cleavage.
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Classical pathway and lectin pathway are similar.
Classical
Lectin
Ab C1q
MBL
Ab
MASP
C1s
C1r
C1r,s
MASP
C4
MBL
C1q
C4
C4b2a
C2
C2
C3
C5
MAC
common
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Alternative pathway of complement activation
Factor B binding site exposed
C3b
B
Classical Lectin
B
C3b
Glu
Cys
HS
C
Glu
Cys
O
C4b2a
O
S
C
C3
thioester exposed
O
Glu
Cys
thioester hidden
S
C
Factor B binding site exposed
O
B
iC3
iC3B
iC3
B
Slow spontaneous hydrolysis
Glu
Cys
Glu
Cys
C
HS
O
C
HS
O
OH
Alternative
OH
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Ba
iC3
B
Bb
iC3
B
Factor D
Glu
Cyc
Glu
Cyc
C
HS
C
O
HS
O
OH
OH
iC3B
iC3Bb (C3 convertase)
C3bB
C3b
B
C3b
C3
Converge with classical and lectin pathway
Glu
Cyc
HS
C
O
O
Covalent attachment to bacterial surface
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All three pathways converge at C3.
C3
classical
alternative
C4
C1
B,D
C4b2a
iC3
C3
iC3Bb
MBL
C2
lectin
C3b
B, D
C3bBb
C3 is the most abundant complement component
C3
amplification
C3b2Bb
C4b2a3b
C5b
C5
C6,7,8,9
MAC
common
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C3 structure
186kDa
9kDa
177kDa
C3a
thioester
TED (thioester domain)
C3a
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Structural change during C3 to C3b conversion
MG8
TED
C3a stabilizes MG8 structure. MG8 interacts with
TED. The thioester is hidden between TED and MG8
domains.
Cleavage of C3 releases C3a. MG8 structure is
changed. MG8 no longer interacts with TED. TED
is released and exposes the thioester.
C3a
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C3 to C3b conversion reveals binding site for
Factor B.
B
TED
TED
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skin
Internal tissue
complement
Bacteria tagged with C3b
Destruction by other immune functions
Lysis by MAC
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Questions
What is the main site of complement production?
Where are complements located?
How are complement activation initiated by
the three pathways?
How is the complement activation cascade
amplified?
How do activated complements destroy bacteria?
Relevant part in textbook
p168-176