Chapter 3
Cellular Mechanisms of
Innate Immunity
Copyright © 2022 W. W. Norton & Company, Inc.
Comparison of the receptor characteristics of
the innate and adaptive immune systems
2
3
Phagocytic or dinner receptors
dectin-1 recognizes β-glucans and carbohydrates
Scavenger receptors participate in the removal of foreign
substances and waste materials
4
Activation of G-coupled receptors
C5A
Binds peptide motifs such as N-formylmethionine-Leu-Phe
5
In 1880érne Ilya Ilyich Mechnikov identified
microbe eating cells in star fish
Nobel Prize in 1908 6
Oxidative burst
C5a
Chronic Granulomatous Diseases (CGD) extreme susceptibility
The first disease which to be identified via positional cloning (x-linked 1986)
7
NETs
Trap microbes but also prevent spreading of damaging proteases etc.
8
Milk RNAse
9
Infection stimulates cytokine and chemokine production
C3a, C5a and fMLP
10
”Pathogen“ detection receptors
SIGNAL
RESPONSE
11
MICROBIAL ASSOCIATED MOLECULAR PATTERNS
“MAMPS”
Something the bugs just cant live without!
Conserved structures among microbes
Include oligosaccharides, lipids, polypeptides, glycoproteins, etc
flagel
12
Mammalian TLRs
13
14
Direct recognition
15
Indirect recognition
The Nobel Prize in Physiology or Medicine 2011
Bruce A. Beutler Jules A. Hoffmann Ralph M. Steinman
17
Hypothesis for the discovery of Toll
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Toll receptors needed for resistance
immunity disease
19
A mouse mutant that are unaffected by LPS
but very susceptible to certain bacterial infections
C57BL/10ScCr mouse
C3H/HeJ mouse (mutant)
20
The amazing figures
21
Receptors of conserved microbial signatures
22
TLR signaling activate the expression of pro-inflammatory cytokines
MyD88/MAL/TRIF/TRAM
23
TLR in antiviral defence
24
25
RIG-I and MDA-5 are cytoplasmic sensors of viral RNA
MDA-5 sense dsRNA
26
cGAS is a cytosolic sensor of DNA that signals through STING
l
to activate type I interferon production
cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP–AMP)
27
Surveillance receptors
28
Human NOD-like receptors - NLRs
NOD1/2 – peptidoglycans
NLRP3 – cellular damage (loss of intracellular potassium)
NAIP/NLRC4 - flagellin 29
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32
Kobayashi et al (2005) Science 307, 731-4 - (red hot paper 2005)
PAMPs stimulate Langerhans cells to migrate
33
Outcome of P/MAMP receptor stimulation: Cytokines
stimulation
inhibition
differentiation
cell death
chemoattract
34
Key Cytokines Produced by Innate Immune
Responses
1) IL-1 - macrophages, epithelial cells
2) IL-6 - macrophages, endothelial cells (also T cells)
3) IL-12 - macrophages, dendritic cells
1) TNF-a - macrophages, NK cells (also T cells)
2) IFN-a - dendritic cells, virally infected cells
3) IFN-b - virally infected cells
35
Production of monocytes granulocytes
(Granulocyte-macrophage
colony-stimulating factor)
Adaptive immunity
Production of IL-6/8 and other chemokines
Activation of viral defence
Activation of CasP 8 or NFkB
36
JAK-STAT pathway
37
38
TNF and receptors
Juxtacrine signalling
39
A few of some 50 chemokines
Recept
Class Chemokine Produced by Cells attracted Major effects
ors
Monocytes, Mobilizes,
Macrophages, CXC activates, and
C X C L 8 (I L - Neutrophils, Naive
Fibroblasts, R 1, C degranulates
8) T cells
Epithelial cells, XCR2 neutrophils
Endothelial cells Angiogenesis
Activates
CXCL7
CXC CXC neutrophils, Clot
(P B P, beta -T G, Platelets Neutrophils
R2 resorption,
N A P - 2)
Angiogenesis
C X C L 1 (G R O
Activates
alpha), C X C L 2 Monocytes,
CXC Neutrophils, Naive neutrophils
(G R O beta), C X Fibroblasts,
R2 T cells, Fibroblasts Fibroplasia
C L 3 (G R O Endothelium
Angiogenesis
gamma)
Monocytes, N K Competes with H I
Monocytes, T
C C L 3 (M I P - 1 CCR and T cells, V - 1 Antiviral
cells, Mast cells,
alpha) 1, 3, 5 Basophils, defense promotes T
Fibroblasts
Dendritic cells H 1 immunity
Monocytes,
Monocytes, N K
CCL4 Macrophages, CCR Competes with H I
and T cells,
(M I P - 1 beta) Neutrophils, 1, 3, 5 V-1
Dendritic cells
Endothelium
Activates
CC
Monocytes, Monocytes, N K macrophages
CCL2 Macrophages, CCR2 and T cells, Basophil histamine
(M C P - 1) Fibroblasts, B Basophils, release
Keratinocytes Dendritic cells Promotes T H 2
immunity
Monocytes, N K Degranulates
T cells, and T cells, basophils
CCL5 CCR
Endothelium, Basophils, Activates T cells
(RANTES) 1, 3, 5
Platelets Eosinophils, Chronic
Dendritic cells inflammation
Leukocyte –
CXX Monocytes,
CX3CL1 CX3C endothelial
X C (C Endothelium,Micr Monocytes, T cells
(Fractalkine) R1 adhesion Brain
X 3 C) oglial cells
inflammation
Adhesion molecules involved in leukocyte interactions
42
Inflammation or injury induces changes in endothelial cells
Weibel-Palade
bodies with
pre-formed adhesion
Molecules (P-selectin)
TNF & IL-1 released
due to inflammation Adhesion molecule expression
in tissue (P-selectin interacts with sialyl lewis
on neutrophils) 44
Leukocyte recruitment to sites of inflammation
CXCL8
histamine/C5a
(slow blood flow) (chemokine CXCL8 binds IL-8R promote LFA-1 change – also stored in wiebel palade bodies )
46
The release of TNF-a by macrophages
induces local protective effects, but TNF-a
can have damaging effects when released
systemically (septic shock).
Vasodilation > low blood pressure
Loos of plasma volume
Blood clotting in small vessels >
Obstruction of blood flow
47
Beyond local activity
Endogenous pyrogens 48
CRP – binds phophocoline
49
Fever
Oligoadenylate synthetase
P-eIF2a
50
IFIT proteins – antiviral effector molecules
P-eIF2a - PKR
51
Group 1 ILCs (Th)
Group 2 ILCs (Th2 cells)
Group 3 ILCs (Th17 cells)
NK cells (Cytotoxic T cells)
52
Stimuli that can up-regulate NKG2D and DNAM-1 ligands
MHC
KIR
ITIM ITAM
55
B1 cells and natural antibodies
LPS
56
