The Innate Immune Response

1

The Innate Immune Response to Bacterial and
Fungal Infections
2

What Really Happens During the Lag Period Before
the Acquired Immune Response?
Innate immunity
Acquired immunity
3
Distinctions Between Innate and Adaptive Immunity
Innate immune system
Adaptive immune system
Receptors Germline-encoded
Somatically engineered Distribution
Non-clonal Clonal Kinetics
Rapid
Slow (requires clonal
expansion) Specificity Recognizes
non-self Recognizes altered self
through Pattern recognition
Primary structure (TCR)
Higher order
structure (Immunoglobulin
BCR) Effector Cells All
Primarily lymphocytes, Mf
4

The Innate Immune Response is Conserved
Throughout Evolution and is Triggered by
Pattern Recognition
5
Lipopolysaccharide is Composed of Lipid and
Polysaccharide
From Beutler and Rietschel, Nature Reviews
Immunology 3 169-176 (2003)
6

The Complement System is Critical for Innate
Immunity and is Triggered by Multiple Ligands
7
(No Transcript)
8

Soluble Defense Collagens Participate in Innate
Immunity
9
Domain Structure of Surfactant Protein A (SP-A),
a Lung Soluble Defense Collagen (Collectin)
Pseudomonas aeruginosa
CRD (6 X 3)
Collagen domain
Alveolar macrophage
10

Phagocytosis is Mediated by Receptors of the
Innate Immune System and the Acquired Immune
System
11
Examples of Pattern Recognition Receptors that
Participate in Innate Immunity
Receptor Expression Target
Ligand
Integrins CR3 (CD11b/CD18 aMb2) PMN,
Mo, M? Yeast
?-glucan C3bi,
fibrinogen, LPS, ICAM ?1 Integrins
Leuk Yersinia Invasin ?3
Integrin (? avb3 ) M?
Osteopontin Scavenger Receptors SR-AI/SR-AII
M? Gram-positive bacteria
Leipoteichoic acid
Gram-negative bacteria
? MARCO M? E. coli, S.
aureus ? Collectin
Receptors C1qRp PMN,
Mo, M? C1q, SPA, MBL gp-340
M? SP-D, SP-A SPR210 Mo,
M? SPA Lectins Dectin-1
M?, DC ??Yeast ? ? -1,3-/ ? -1,6
glucans CR3 (CD11b/CD18 aMb2) PMN, Mo,
M? Yeast ?-glucan CD14
Mo, M?, soluble Gram-negative
bacteria LPS
Gram-positive bacteria
Peptidoglycan Toll-like Receptors TLR2
M?, imDC Gram-positive
bacteria Peptidoglycan, Leipoteichoic acid
Mycobacteria
Lipoarabinomannan
Spirochetes Lipoproteins,
Lipopeptides Mycoplasmas
Lipopeptides TLR4 M?
Gram-negative bacteria
LPS
12
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
-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
N
C
C
E. coli S.aureus
C
N
N
E. coli S.aureus

C

C
C
C
N
N
C
N
N
N
N
N
N
N
N
N
N
N
N
N
C
SREC
LOX-1
CD 68
dSR-C I
SR-B1
CD 36
MARCO
SR-A II
SR-A I
SR-A III
SR-C
SR-B
SR-A
SR-D
SR-E
SR-F
13

Receptors Important in The Systemic Response to
Infection
14

History of Endotoxin Research
From Beutler and Rietschel, Nature Reviews
Immunology 3 169-176 (2003)
15
Core LPS Signaling Machinery c. 1990-1996
From Beutler and Rietschel, Nature Reviews
Immunology 3 169-176 (2003)
16
(No Transcript)
17
(No Transcript)
18
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
Infectious-non-self model of immunity
described by Janeway
Modified from Beutler and Rietschel, Nature
Reviews Immunology 3 169-176 (2003)
19
(No Transcript)
20
TLR Signaling Components
Vertebrates
Drosophila TLR-4
Toll

CD14
Receptor Complex
MD2
extracellular space
cytosol
TIR domain MyD88
Tube
Adaptor proteins Kinases
DD
DD
IRAK Pelle
ECSIT
dECSIT
TRAF6
dTRAF
TAK
MEKK1
Ird6
IKK-g
IKK complex
IKK-a
IKK-b
TIR Toll/IL-1 receptor DD Death domain IKK
I-kB kinase
Cactus
I-kB
NF-kB
p65
p50
Dif/Relish
21
NOD Proteins Intracellular Peptidoglycan Sensors
NOD-1 NOD-2
Ligand Recognition
Nod Protein
CARD
RICK
I-kB
NF-kB
p65
p50
22
Recruitment of TLR2 to Yeast Phagosomes
TLR2 Phase Contrast
TLR2
From Underhill et al., Nature 401811, 1999
23
From Luster, Curr. Opin. Immunol. 14129, 2002
24

The Dendritic Cell and Development of The Primary
Immune Response
25
Dendritic Cell Maturation
From Mellman Steinman, Cell 106255, 2001
26
The Innate Immune Response Orchestrates DC
Trafficking to Secondary Lymphoid Organs
From Luster, Curr. Opin. Immunol. 14129, 2002
27

Functional Differences Between Immature and
Mature DCs
Expression of CCR7 Migration towards T-cell zone
of lymph node
28
The (Primary) Acquired Immune Response is
Initiated by Innate Immune Recognition
29
Chemokines Direct Trafficking of Immune Cells
From Luster, Curr. Opin. Immunol. 14129, 2002
30

The Dual Role of Defensins in Bacterial Immunity
31
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 27628372
32
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
286420, 1999.
33

The Innate Immune Response to Viruses
34

The Early Antiviral Response Cytokines of the
Innate Immune System
35
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-CD4-Tricolor (Immunotech, Marseille,
France), anti-CD11c-PE (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),
CD4CD11c 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 2841746, 1999
36

The Antiviral Response a Cascade of
Transcriptional Events
Some targets of IRFs Gene Function p21 Cell
cycle arrest IL-15 NK cell maturation FasL Cell
death IL-12 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-? 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 pathways 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.
37
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 (M?) 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 M?. 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 (M? LPS) in vitro.
Note that NK cells cultured with unstimulated M?
did not produce IFN-g. Data represent the mean
SD of 7 experiments.
(From Cooper et al., Trends Immunol. 22633,
2001)