Function of Immune System

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Function of Immune System
bacteria
virus
Protection from infection
fungi
parasite
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Skin and mucous membrane constitute a barrier
against pathogens.
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Skin
Barrier
Mucous membrane
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Skin
Physical epithelial cells (keratin, impermeable).
Antibacterial peptide defensin
Chemical
Sebum fatty acid
Mucous membrane
Physical epithelia cells (more vulnerable).
Antibacterial peptide defensin
Iron-binding protein (lactoferrin)
Enzymes lysozyme (tear, saliva), protease
Chemical
Mucus / cilia (respiratory system)
Low pH (stomach)
antibodies
Competition (attachment site, nutrient)
Microbiological normal flora (gut)
Antibacterial proteins (colicin)
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The barrier can be breached by pathogens
Injury
Skin
Insect bite
Mucous membrane
Lytic enzymes
damage
Receptor-mediated entry
transcytosis
fusion, endocytosis
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When the barrier is breached by pathogens, the
immune system fights the infection.
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Immune Response
destroy
pathogen
effector
signal
sensor
(foreign)
Host cell
(self)
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Bacterial Pathogens
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Bacterial infection
exotoxin
Extracellular bacteria
toxin
endotoxin
Intracellular bacteria
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Immune Response to Extracellular Bacteria
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Complement
Complement the lytic activity of antibodies
A group of proteins in blood and tissue fluid.
Produced primarily by hepatocytes in liver.
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Complement lyses bacteria
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Alternative Pathway of Complement Activation (I)
initiaion
C3
iC3
H2O
Glu
Cys
Glu
Cys
C
1
S
OH
C
SH
O
O
Conformation change
Labile thioester
1. Slow spontaneous hydrolysis of a labile
thioester bond within C3
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Alternative pathway of complement activation (II)
Factor D
Ba
Factor B
C3b
C3
Bb
B
Bb
Bb
C3a
iC3
iC3
iC3
iC3
iC3
2
3
2. Binding of B to iC3 renders B susceptible to
cleavage by factor D (protease).
Ba
D
Bb

B
Active protease
Inactive zymogen
3. Bb cleaves C3 to C3b C3a.
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Alternative pathway of complement activation (III)
C3b
C3b
Glu
Cys
Glu
Cys
C
S
SH
C
Labile thioester
O
O
NH or O
NH2 or OH
bacteria
Cleavage of C3 exposes the labile thioester in
C3b, which reacts with bacterial surface (amino
or hydroxyl groups) to form covalent linkage.
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Alternative pathway of complement activation (IV)
D
Bb
Bb
C3a
B
C3
C3b
C3b
C3b
bacteria
bacteria
bacteria
5
4
4. C3b interacts with B, and renders B
susceptible to cleavage by D.
5. C3b,Bb (alternative C3 convertase) cleaves C3
to C3b and C3a
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Alternative pathway of complement activation (V)
Bb
C3b, B, D
Bb
C3b
bacteria
bacteria
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6. Newly generated C3b can work with B and D to
produce more C3b. This Is the major amplication
step (C3b amplication loop).
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Alternative pathway of complement activation (VI)
C5a
C3b2Bb
C5b
C5
bacteria
bacteria
bacteria
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7
7. Some C3b associates with C3b,Bb to form
C3b2,Bb.
8. C3b2,Bb (alternative C5 convertase) cleaves C5
to C5b C5a.
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Alternative pathway of complement activation (VII)
70-100A
C6
C8
C9
C7
C5b
Cell membrane
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C5b,6,7,8,9
Mambrane attack complex (MAC)
9. C5b, C6, C7, C8, C9 form membrane attach
complex (MAC) to introduce holes in bacterial
membrane. This results in lysis of bacteria.
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Lectin pathway of complement activation (I)
Mannose binding lectin (MBL)
MBL-associated serine proteases (MSAP-1, MSAP-2)
mannose
1
bacteria
1. MBL binds to mannose on bacterial cell wall,
and recruits proteases (MSAP).
(Lectins are proteins that bind to carbohydrate.)
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Lectin pathway of complement activation (II)
C2a
C4b
C4
C2
C2b
C4a
2
2. MSAP cleaves C4 and C2.
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Lectin pathway of complement activation (III)
C4b
C4b
C
S
C
SH
Labile thioester
O
O
NH or O
NH2 or OH
bacteria
Cleavage of C4 into C4b exposes a labile
thioester bond, which reacts with bacteria
surface (amino or hydroxyl groups) to form
covalent linkage.
C4b is analogous to C3b.
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Lectin pathway of complement activation (IV)
C2a
C3a
C3
C2a
C4b
C4b
C3b
3
3. C2a associates with C4b to form C4b,2a
(classical C3 convertase), which cleaves C3 into
C3b C3a.
C2a is the protease, which is analogous to Bb.
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Lectin pathway of complement activation (V)
C2a
C3, B, D
Bb
C4b
C3b
bacteria
bacteria
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4. Newly formed C3b generates C3b,Bb through B
and D (alternative pathway). Both C3b,Bb
(alternative C3 convertase) and C4b,2a produces
more C3b. This is the major amplification
step.
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Lectin pathway of complement activation (VI)
C5a
C4b,2a,3b
C3b,Bb
C5b
C5
C5
C5
bacteria
bacteria
bacteria
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5
5. Some C3b associates with C4b,2a to form
C4b,2a,3b (Classical C5 convertase) C3b also
associates with C3b,Bb to form C3b2Bb
(alternative C5 convertase).
6. Both C4b,2a,3b and C3b2Bb cleaves C5 into C5a
C5b.
7. C5b joins C6,7,8,9 to form the MAC.
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Alternative and Lectin pathway converge at C3b
formation
C3 convertase C3b,Bb C5 convertase C3b2,Bb
Alternative
C3
Slow spontaneous B,D
C5
C3, B, D
iC3bBb
C3b,Bb
C3b
C3
C3b2,Bb
B, D
C4b,2a
C4b,2a,3b
C6,7,8,9
C5b,6,7,8,9
C5b
MBL, MASP
MAC
lectin
C4, C2
C3 convertase C4b,C2a and C3b,Bb C5 convertase
C4b,2a,3b and C3b2,Bb
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Complement-mediated lysis is effective against
most Gram-negative bacteria.
Gram positive
outermembrane
Gram negative
peptidoglycan
Plasma membrane
cytoplasm
nucleoid
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Why doesnt complement lyse human cells?
MBL
mannose
Human cell
bacteria
Human cell surface does not have mannose
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C3b can be attached to human cells as well.
C3b
inactive
H2O or other protein
SH
C
O
OH
C3b
S
C3b
C
O
N or O
S
C
bacteria
O
C3b
S
C
O
N or O
Human cell
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Protection of human cell from lysis
Bb
Decay accelerating factor (DAF)
Bb
C3b
Human cell
Bb
Membrane cofactor protein (MCP) Complement
receptor 1 (CR1)
Factor I
Bb
C3b
Human cell
Bb
Factor I
Factor H
Bb
C3b
Sialic acid
Human cell
Regulators of complement activation (RCA) DAF,
MCP, CR1, factor H. Made of complement control
protein (CCP) modules.
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Protection of human cell from lysis
Homologous restriction factor (HRF) and CD59
C9
C5b,6,7,8
Human cell
Prevents the recruitment of C9
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Paroxymal Nocturnal Hemoglobinuria (PNH)
Symptom increased sensitivity of host cell to
complement lysis.
Cause loss of DAF and CD59 from cell surface
Genetic defect phosphatidylinositol glycan
complementation class A gene (pig-a).
Involved in the synthesis of glycosyl
phosphatidylinositol (GPI) anchor.
DAF
DAF
complement
GPI
normal
patient
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Questions
What are the players? Where do they come
from? Where are they located? When do they
act? How do they fight pathogen? What are the
sensor, signal, and effector? How do they
distinguish pathogen from host cells? How are
they linked to other immune function?
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Complement activates other immune functions.
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lysis
C3a C3b
C3
C5a C5b
C5
C4
C4a C4b
Activate other immune functions
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C5a, C3a, C4a act on mast cells, endothelial
cells, neutrophils, moncytes.
Mast cell
Endothelial cell
C5a
neutrophil
C3a
monocyte
C4a
C5a gt C3a gt C4a
Capillary blood vessel
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C5a, C3a, C4a increases local blood flow,
vascular permeability, and extravasation of
leukocytes.
Inflammation heat, pain, redness, swelling
Heat and redness (erythema, vasodilation)
skin
Swelling (edema)
leukocytes
C5a
extravasation
C4a
C3a
plasma
Plasma brings more complement and antibodies
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Anaphylaxis acute systemic inflammatory
response. C5a, C3a, C4a are called
anaphylatoxins.
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C5a, C3a induces the degranulation of mast cells.
Mast cell generated in bone marrow. resides in
skin, connective tissue, mucosal epithelial
tissue
Granules contain histamine and other vasoactive
substances.
Receptor for C5a, C3a
C5a, C3a
Histamine is a potent inducers of vasodilation
and vascular permeability
degranulation
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Bacterial infection
Lysis (MAC)
Complement activation
Mast cells
C5a, C3a, C4a
Histamine, etc
Inflammation
Other immune functions