Transcript through “Pattern recognition”

The Innate Immune Response
to Bacterial and Fungal Infections
What Really Happens During the Lag Period
Before the Acquired Immune Response?
Innate immunity
Acquired immunity
Distinctions Between
Innate and Adaptive Immunity
Innate immune system
Receptors
Germline-encoded
Distribution
Kinetics
Specificity
Somatically engineered
Non-clonal
Clonal
Rapid
Slow
(requires clonal expansion)
Recognizes non-self
through “Pattern recognition”
Effector Cells
Adaptive immune system
All
Recognizes “altered self”
Primary structure (TCR)
Higher order structure
(Immunoglobulin; BCR)
Primarily lymphocytes, Mf
The Innate Immune Response is Conserved
Throughout Evolution and is
Triggered by Pattern Recognition
Lipopolysaccharide is Composed of
Lipid and Polysaccharide
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From: Beutler and Rietschel, Nature Reviews Immunology 3; 169-176 (2003)
The Complement System is Critical for
Innate Immunity and is Triggered
by Multiple Ligands
Soluble “Defense Collagens”
Participate in Innate Immunity
Domain Structure of Surfactant Protein A
(SP-A), a Lung Soluble Defense Collagen (Collectin)
Pseudomonas aeruginosa
CRD (6 X 3)
Collagen domain
Alveolar macrophage
Phagocytosis is Mediated by
Receptors of the Innate Immune System
and the Acquired Immune System
Examples of “Pattern Recognition Receptors”
that Participate in Innate Immunity
Receptor
Integrins
CR3 (CD11b/CD18; aMb2)
b1 Integrins
b3 Integrin (? avb3 )
Scavenger Receptors
SR-AI/SR-AII
MARCO
Collectin Receptors
C1qRp
gp-340
SPR210
Lectins
Dectin-1
CR3 (CD11b/CD18; aMb2)
CD14
Toll-like Receptors
TLR2
TLR4
Expression
PMN, Mo, Mf
Leuk
Mf
Mf
Mf
Target
Yeast
Yersinia
Gram-positive bacteria
Gram-negative bacteria
E. coli, S. aureus
PMN, Mo, Mf
Mf
Mo, Mf
Mf, DC
PMN, Mo, Mf
Mo, Mf, soluble
Mf, imDC
Mf
Ligand
b-glucan
C3bi, fibrinogen, LPS, ICAM
Invasin
Osteopontin
Leipoteichoic acid
?
?
C1q, SPA, MBL
SP-D, SP-A
SPA
Yeast
Yeast
Gram-negative bacteria
Gram-positive bacteria
b -1,3-/ b -1,6 glucans
b-glucan
LPS
Peptidoglycan
Gram-positive bacteria Peptidoglycan, Leipoteichoic acid
Mycobacteria
Lipoarabinomannan
Spirochetes
Lipoproteins, Lipopeptides
Mycoplasmas
Lipopeptides
Gram-negative bacteria
LPS
The Scavenger Receptor Superfamily
C
C
C
KEY TO DOMAINS
E. coli
S.aureus
-Complement control protein (CCP)
-Somatomedin B
LTA
LPS
Gram-positive bacteria
Gram-negative bacteria
Bacterial DNA
CL
-C-type Lectin
-Epidermal growth factor (EGF)
-Partial Epidermal growth factor (EGF)
-Potential N-linked glycosylation
C
C
C
-Potential O-linked glycosylation
C C
C C C
E. coli
S.aureus
C
N
N
N
E. coli
S.aureus
*
C
NN N
NN N
NN N
N NN
N
C
N
C
C
C
*
N
C
SR-A I
SR-A II SR-A III MARCO
SR-A
CD 36
SR-B1
SR-B
dSR-C I
CD 68
LOX-1 SREC
SR-C
SR-D
SR-E
SR-F
Receptors Important in
The Systemic Response to Infection
History of Endotoxin Research
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From: Beutler and Rietschel, Nature Reviews Immunology 3; 169-176 (2003)
Core LPS Signaling Machinery
c. 1990-1996
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From: Beutler and Rietschel, Nature Reviews Immunology 3; 169-176 (2003)
An Innate Immunity “Time Line”
Discovery of the NF-kB
signaling pathway by Toll
in Drosophila by
Hoffman and colleagues
Molecular basis of
adjuvant discovered
by Medzhitov and Janeway
Use of adjuvant
to stimulate the
immune response
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Modified from: Beutler and Rietschel, Nature Reviews Immunology 3; 169-176 (2003)
“Infectious-non-self”
model of immunity
described by Janeway
TLR Signaling Components
Vertebrates
Drosophila
TLR-4
Toll
CD14
Receptor
Complex
MD2
extracellular space
cytosol
TIR domain
MyD88
DD
IRAK
Tube
Adaptor
proteins
ECSIT
dECSIT
TRAF6
Kinases
dTRAF
TAK
MEKK1
Ird6
IKK-g
IKK-a IKK-b
TIR = Toll/IL-1 receptor
DD = Death domain
IKK = I-kB kinase
DD
Pelle
I-kB
p50 p65
IKK complex
Cactus
NF-kB
Dif/Relish
NOD Proteins:
Intracellular Peptidoglycan Sensors
NOD-1
Nod
Protein
NOD-2
Ligand
Recognition
CARD
RICK
I-kB
p50 p65
NF-kB
Recruitment of TLR2 to Yeast Phagosomes
TLR2
Phase Contrast
From: Underhill et al., Nature 401:811, 1999
TLR2
From: Luster, Curr. Opin. Immunol. 14:129, 2002
The Dendritic Cell and Development of
The Primary Immune Response
Dendritic Cell Maturation
From: Mellman & Steinman, Cell 106:255, 2001
The Innate Immune Response Orchestrates
DC Trafficking to Secondary Lymphoid Organs
From: Luster, Curr. Opin. Immunol. 14:129, 2002
Functional Differences Between
Immature and Mature DCs
Expression of CCR7
Migration towards
T-cell zone of
lymph node
The (Primary) Acquired Immune Response
is Initiated by Innate Immune Recognition
Chemokines Direct Trafficking of Immune Cells
From: Luster, Curr. Opin. Immunol. 14:129, 2002
The Dual Role of Defensins in
Bacterial Immunity
Chemokine CCL20
b-defensin BD2
b-pleated sheets are represented by green arrows;
arginine and lysine residues are shown in blue
From: Perez-Canadillas et al., J. Bio.l Chem. 2001 276:28372
The Role of Defensins in
Orchestrating the Immune Response
Inflamed defenders. A model of defensin activity in an infected epithelium. Epithelial cells synthesize
antimicrobial defensins (red) both constitutively and in response to infectious and inflammatory stimuli.
Other defensins are introduced by the influx of phagocytic cells that use them to kill ingested microbes.
Released defensins attract dendritic cells and memory T cells, setting the stage for the adaptive phase
of the immune response. From Ganz, Science 286:420, 1999.
The Innate Immune Response
to Viruses
The Early Antiviral Response:
Cytokines of the Innate Immune System
A Subset of Peripheral Blood
Dendritic Cells Produce IFN-a/b
Tracing and isolation of IPCs/pDC2s from human
peripheral blood. CD3+ T cells, CD19+ B cells, CD16+
and CD56+ NK cells, and CD14+ monocytes were
depleted from blood mononuclear cells by
immunomagnetic beads (Dynabeads M-450; Dynal,
Oslo, Norway). The cells were stained with anti-CD4Tricolor (Immunotech, Marseille, France), anti-CD11cPE (Becton Dickinson, San Jose, California), and a
mixture of fluorescein isothiocyanate-labeled antibodies
to CD3, CD15, CD16, CD20, CD57 (Becton Dickinson),
CD14 (Coulter, Miami, Florida), and CD34
(Immunotech). Within the lineage-negative population
(A), CD4+CD11c IPCs and CD11c+ immature DCs were
isolated (B). IPCs are plasmacytoid by Giemsa staining
(C) and contain rough endoplasmic reticulum and Golgi
apparatus under transmission electron microscopy (D).
The CD11c+ blood immature DCs display dendrites (E
and F)
From: Siegal et al., Science 284:1746, 1999
The Antiviral Response: a
Cascade of Transcriptional Events
Some targets of IRFs
Gene
p21
IL-15
FasL
IL-12
Function
Cell cycle arrest
NK cell maturation
Cell death
Th1 immune response
Multiphasic induction of murine type I IFN genes can be divided into three phases. (a) The immediate early phase. Virus
infection stimulates a phosphorylation cascade, leading to the activation of at least three families of transcription factors,
including NF-kB, AP-1 and IRF3. Activation of the IFN-a promoter requires all three transcription factors. (b) IRF7 induction
phase. Secretion of early IFN produces an autocrine response through stimulation of the JAK-STAT pathway. Among the
pathway’s target genes is IRF7, itself. (c) Delayed early (amplification) phase. Many members of the IFN-a gene family
possess promoter binding sites for activated IRF7 and become transcriptionally active.
NK Cells are an Important Early Source of IFN-g
CD56bright natural killer (NK) cells are the major producers of NK-derived cytokines following activation of monocytes. (a) During the
innate immune response, when macrophages (Mf) encounter pathogens they produce a variety of cytokines which can then activate the
production of IFN-g by NK cells. In turn, NK-cell-derived IFN-g is requisite for the elimination of intracellular pathogens and the further
activation of production of cyotkines by Mf. In this setting, the CD56bright NK-cell subset produces significantly more IFN-g protein
compared with the CD56dim NK-cell subset, as shown in (b). Resting CD56bright and CD56dim NK cells were co-cultured with autologous,
lipopolysaccharide (LPS)-activated macrophages (Mf + LPS) in vitro. Note that NK cells cultured with unstimulated Mf did not produce
IFN-g. Data represent the mean ± SD of 7 experiments.
(From: Cooper et al., Trends Immunol. 22:633, 2001)