Download innate immunity

JPEMS– Nantes, 2014- Basic Immunology
INNATE IMMUNITY
Teacher: Pr. Régis Josien, Laboratoire d’Immunologie and
INSERM U1064, CHU Nantes
[email protected]
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Contents
1.  General features and specificity of
innate immune response
2.  Recognition of microbes by the innate
immune system
3.  Components of innate immunity
4.  Innate immune reactions
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Contents
1.  General features and specificity of
innate immune response
2.  Recognition of microbes by the innate
immune system
3.  Components of innate immunity
4.  Innate immune reactions
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The response to an initial infection
occurs in three phases
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Specificity and receptors of the innate
and adaptive immunity
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Innate immunity
ü  Constitute the first of defense againt microbes
ü  Highly conserved system during the evolution (preceding adaptive
immunity)
ü  Mediated by cells (phagocytes, DCs, NK cells, innate lymphoid
cells) and soluble molecules (complement, cytokines)
ü  Recognizes structures shared by various classes of microbes,
not present on host cells and often essential for microbes survival
(PAMPs)
ü  Recognizes also endogen molecules (DAMPs)
ü  Uses a limited number of receptors encoded in the germline
ü  Induces 2 types of reactions: inflammation (bacteria) and antiviral
defense
ü  The innate immune response instructs the adaptive immune
system
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Contents
1.  General features and specificity of
innate immune response
2.  Recognition of microbes by the
innate immune system
3.  Components of innate immunity
4.  Innate immune reactions
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Pathogens can be found in various
compartments of the body and of the cell
The innate immune system used molecular sensors to detect
extacellular and intracellular microbes
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Pathogens have different mebrane structures
Ex: structure of bacterial walls
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Pattern Recognition Receptors, PRRs
•  Recognize various pathogen associated molecular patterns
(PAMPs):
•  shared by several classes of microbes
•  not expressed by host cells (self non-self discrimination)
•  often critical for microbe survival and infectivity
•  Some PRR can also recognize molecules released by damaged or
necrotic cells: damage-associated molecular patterns (DAMPs)
•  Non clonal expression (identical receptors on different cells)
•  Immediate response
•  3 classes of PRR :
1. Secreted Molecules. Ex: mannane-binding lectin
2. Endocytic PRR. Ex: macrophage mannose receptor
3. Signalisation PRR. Toll-like receptors (TLR); NOD-like
receptors (NLR), RIG-like receptors (RLR), C-type lectin-like
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receptors (CLR)
Secreted PRR:
ex: mannane-binding lectin (MBL)
General functions of
secrecred PRR:
Others:
•  Opsonisation
•  C-reactive protein (CRP)
•  Complement activation
•  surfactants
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Endocytic PRRs
MMR: macrophage
mannose receptor
MMR
2 families:
-  Lectins
-  Scavenger receptors
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Signalisation PRR
Ø  PRR recognizing microbes and damaged cells
Ø  Binding of ligand to PRR triggers intracellular activation leading to
the activation of specific transcription factors
Ø  These transcription factors induce production of cytokines and
adhesion molecules in phagocytes and dendritic cells
Ø  Distinct PRR stimulations lead to specific transcription factor
activation and responses (inflammation vs. antiviral response)
Ø  These PRR are critical for inducing costimulation molecules
expression and therefore adaptive immune responses
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Cellular locations of receptors of the
innate immune system
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Toll-like receptors or TLR
• Toll = Drosophila gene controlling dorso-ventral polarisation
(Anderson et al., Cell 1985, 42-779)
•  Major role in immune responses in Drosophila . Induces production
of Drosomycine, a fongicidal peptide (Lemaitre et al., Cell 1996,
86:873)
• Vertebrate counter part: Toll-like receptor (TLR4)
Nature 1997, 388:394)
• 10 members in human: TLR1-TLR10
(Medzithov et al.,
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TLR structure
Domaine
Ig
Leucinrich
repeat
(LRR)
Domain TIR
(Toll-IL-1 R)
Akira et Takeda, Nat Rev Immunol 2004, 4:499
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Structure and specificities of TLR
TLR10: ligands unknown
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Signaling functions of TLR
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Adaptor molecules in TLR signaling
MyD88: myeloid
differentiation
primary-response
protein 88
TIRAP: TIRdomaincontaining
adaptor protein
(TLR 2 et 4)
TRIF: TIRdomaincontaining
inducing IFN-β
(TLR 3 et 4)
TRAM: TRIFrelated adaptor
molecule (TLR 4)
http://www.biken.osaka-u.ac.jp/act/act_akira_e.php
Cooperation and synergy between TLR
Trinchieri G. and Sher A. Nat Rev Immunol. 2007, 7:179
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NOD-like receptors (NLR) and the inflammasome
NOD= nucleotide olimerization domain
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Signalisation PRR
RIG-I: retinoic acid
inducible gene I
Contents
1.  General features and specificity of
innate immune response
2.  Recognition of microbes by the innate
immune system
3.  Components of innate immunity
4.  Innate immune reactions
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Mechanisms of protection
of epithelial barriers
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Phagocytes
•  Monocytes/macrophages
(mononucleated phagocytes)
•  Neutrophils (polymorphonuclear cells)
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Cells of the immune system
Hemogram:
Leuk: 4000-10000/mm3
Neutr: 52-75%
Lympho: 20-45%
Mono: 3-9 %
Eosino: 0-5%
HSC
Lymphoid
progenitor
Myeloid
progenitor
Baso: 0-1,5 %
DC: 0,1-0,5%
GM precursor
Gran.
Prec.
MonocytesDC precursor
M-CSF
Monocyte
B
T
NK
ILCs
Lymphocytes Innate lymphoid
cells
Eosinophil
Basophil
PreDC
Neutrophil
Polymorphonuclear cells
plasmocytes
antibodies
Blood
FLT3L
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Mastocyte Macrophage
Dendritic
cell
Tissues
Blood and
lymph nodes
G-CSF
Maturation of mononucleated
phagocytes
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Monocytes/macrophages
•  Monocytes:
–  Circulating cells (500-1000/ml)
–  ½ life: 2-3 days
–  Specific surface marker: CD14
•  Macrophages (MØ):
–  Tissular
–  ½ life: long (until several months)
–  Differentiation varies with microenvironnement
–  Recent data indicate that most tissue MØ derive
actually from embryonic cells and self renew locally
–  Activity: proinflammatory ou favoring tissue repair
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Activation and functions of macrophages
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Infection stimulates macrophages to release
cytokines chemokines and lipid mediators
that initiate an inflammatory response
médiateurs
lipidiques
Roles of inflammation:
Inflammatory cytokines : TNF-α, IL-1, IL-6
1. 
Recrutement of cellular and soluble
effectors
2. 
Limit pathogen dissemination
3. 
Initiate tissue repair
Lipid mediators of inflammation: prostaglandins,
leucotriens and platelet activating factor (PAF)
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Classical and alternative
macrophage activation
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Neutrophils
•  Circulating cells (> 50% of leucocytes), not found in healthy
tissus but recruted in large numbers if inflammation
•  Polynucleated + granules which stain for acidic and basic
colorants (May Grünwald Giemsa)
•  Role: phagocytosis +++ and bactericidal
•  Production in bone marrow increase ++ in response to infection
•  Infectious risk +++ if neutropenia (+++ if < 500/mm3)
•  ½ life: short (6-10 h in blood)
•  Die rapidly after phagocytosis: elimination by MØ and pus
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formation
Eosinophils and basophils
•  Are not phagocytes
•  Mostly secretory functions
•  Eosinophils:
–  Granulation stained with acidic colorants (eosin –
orange in MGG)
–  Bone marrow production induced by IL-5
–  Circulating cells; also found in large number in gut
mucosa (role?)
–  Proinflammatory functions: secretion of basic
proteins (cationics): MBP, ECP
–  Role in responses to parasites ++ and allergies34
Eosinophils et basophils
•  Basophils:
–  Granulations stained with basic colorants (violet in
MGG)
–  Found in pathological tissues (parasites, allergies)
–  Differentiation and activation induced by IL-3
–  Role in allergic response (immediate) +++
–  Maybe a role in antigen presentation?
–  Secretory functions: cytokines, chemokines
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Mast cells
•  Cells constitutively present in skin and mucosal
epithelium (not in the blood)
•  Can be activated by TLR and antibody (IgE)-dependent
mechanisms
•  Secretory functions: vasoactives amines (histamin),
enzymes, cytokines chemokines, lipid mediators
•  Promote strong inflammation
•  Role in responses to helminths and allergies +++
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Dendritic cells
•  Phagocytic cells
•  Main function: antigen presentation to
naive T cells
•  Lesson#4
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•  NK cells
•  Complement
èLesson#3
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Contents
1.  General features and specificity of
innate immune response
2.  Recognition of microbes by the innate
immune system
3.  Components of innate immunity
4.  Innate immune reactions
39
Innate responses to
bacteria: inflammation
Ø  Inflammatory cytokines
Ø  Recrutement of phagocytes to
inflammatory tissues
Ø  Phagocytosis and killing of microbes
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Acute inflammatory response
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Activated macrophages secrete cytokines with
local and systemic effects
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Cytokines produced by macrophages induce
production of acute phase proteins in liver
Acute phase proteins have
anti-bacterial functions:
(
•  Opsonisation
•  Complement activation
= CRP
)
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Neutrophil extravasation. Step 1= rolling
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Leukocyte rolling
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Steps of neutrophil extravasation
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Leukocyte extravasation
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Phagocytosis and intracellular killing
of microbes
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Mechanisms of respiratory burst
H2O2
O2-
SOD
NOX
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Bactericidal agents produced or released by
phagocytes on the ingestion of microorganisms
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Chemotaxis of neutrophils
Bacteria produce the tripeptide formyl-Met-LeuPhe (fMLP) that is chemoattractant for neutrophils
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Innate responses to virus
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PRR involved in virus recognition
Viral PAMPs
PRR
Transcription
factor
Cellular sources of type I IFN
1.  Plasmacytoid dendritic cells: a subset of
leukocytes specialized in the recognition of
virus and the production of massive
amounts or type I IFN
2.  All virus infected cells
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Anti-viral action of type I interferons
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Interferons are antiviral proteins produced
by cells in response to viral infection
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Role of innate immunity in stimulating
adaptive immune responses
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Role of TLR in induction of adaptive immunity
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Medzhitov, Nat Rev Immunol 2001, 1:135