Transcript presentation source

Innate Immunity in Diseases
of Lung, Heart and Blood:
The Idea behind the
UA/BWH PGA
Donata Vercelli
Respiratory Sciences Center
Department of Cell Biology and Anatomy
College of Medicine, University of Arizona
1
How Immunity Evolved
• The immune system evolved under selective
pressure imposed by infectious
microorganisms.
• Multicellular organisms have developed
various defense mechanisms that have the
capacity to be triggered by infection and to
protect the host organism by destroying the
invading microbes and neutralizing their
virulence factors.
2
How the Innate and Adaptive
Immune Systems Recognize Pathogens
• Immune responses can be innate or adaptive.
• The innate immune system uses germlineencoded receptors for the recognition of
microbial pathogens.
• The adaptive immune system (found only in
vertebrates) uses receptors generated by
somatic mechanisms (gene rearrangements)
during the ontogeny of each individual
organism.
3
The Adaptive Immune System
• Somatic mechanisms generate a diverse
repertoire of antigen receptors with random
specificities, which are clonally distributed on
immune cells (T and B lymphocytes)  plasticity
• The specificity of the receptors expressed on
each lymphocyte is not predetermined, and
neither is the response that can be induced in
lymphocytes upon ligation of their receptors by
antigen  ambiguity
4
The Cross-talk between
Innate and Adaptive Immunity
•Induction of an immune response is only appropriate if the
antigen recognized is derived from, or belongs to, a
pathogen.
•Activation of lymphocytes specific for self antigens, or
innocuous persistent environmental antigens, is deleterious.
Therefore,
•The adaptive immune response requires signals that
provide information about the origin of the antigen and the
type of response to be induced.
These signals are provided by the innate immune system.
5
Mechanisms of
Innate Immune Recognition
6
How Few Receptors
Can Recognize Many Pathogens
•Immune recognition is unique in that it occurs
between products encoded in different genomes.
•The evolution of innate immunity is driven toward
recognition of invariant molecular constituents of
the infectious agents shared by large groups of
pathogens.
Therefore
A limited number of germline-encoded receptors is
able to recognize a great variety of molecular
structures associated with pathogens.
7
Receptors and Targets
of Innate Recognition
• The targets of recognition represent molecular
patterns, called PAMPs for pathogenassociated molecular patterns, rather than
particular structures.
• Host organisms have developed a set of
receptors that can specifically recognize
PAMPs and are referred to, therefore, as
pattern recognition receptors (PRRs).
8
Innate Discrimination
between Self and Non-self is Perfect
The effect of immune recognition is destruction of the target’
The structures selected for immune recognition must have
been absolutely distinct from self antigens to avoid damage to
self cells and tissues.
Consequences:
•The ability of the innate immune system to discriminate
between self and nonself is perfect.
None of the compounds recognized by the innate immune
system are produced by the host organism, and all of them are
essential for the physiology and survival of the respective
microbes.
9
Pathogen-Associated
Molecular Patterns (PAMPs)
PAMPs represent invariant structures shared by
large groups of microorganisms, and are absolutely
essential for the microbe's survival:
•LPS: common component of gram-negative
bacteria
•teichoic acids: common component of grampositive bacteria
•double-stranded RNA: a structural signature of
several groups of RNA viruses
•bacterial DNA (unmethylated CpG sequences)
10
The Pattern Recognition
Receptor System of Innate Immunity
LPS
MD-2
LPS
LPS
LBP
LBP
mCD14
TLR2/4
LBP
sCD14
TLR2/4
RP105
(CD180)
sCD14
MD-1
CD14-positive cells
(monocyte/M, PMN)
CD14-negative cells
(e.g., endothelium, epithelium)
CD14-negative cells
(B cells)
11
TLRs:
Not that non-specific...
TLR4
LPS
(Gram-)
viruses?
TLR2
Lipo
proteins
(Gram+)
direct
anti-microbial
defense
TLR6
PGN
(w.TLR2)
apoptosis
of host
cells
TLR9
TLR5
flagellin
DNA
septic
shock
Listeria
Pseudomonas
adaptive
responses
12
Pathogen Recognition and
the Control of Adaptive Immunity
• Antigen receptors expressed on lymphocytes
have randomly generated specificities that
cannot determine the origin or biological
context of their ligands.
• Signaling through an antigen receptor is
insufficient on its own to induce the activation
of lymphocytes or their differentiation into
appropriate effector cells.
13
Costimulation, the Link between
Innate and Adaptive Immunity
•Activation of T lymphocytes requires a costimulatory second
signal in the form of B7 molecules expressed on antigen
presenting cells (APC).
•The function of costimulatory activity is to signal the
presence of pathogens.
•The expression of costimulation must be controlled by
pathogen recognition.
14
Innate Immunity Provides
Cues for the Adaptive Response
IL-4
IL-13
pathogen
CD3
Signal 1
TCR
MHC II
PRR
CD4
IL-4, IL-13
APC
Th2 cell
CD28
B7
Signal 2
cytokines
15
Innate and Adaptive Immunity
Innate
Adaptive
Encoding of Receptors
germline
somatically
Distribution of receptors
non-clonal
clonal
Repertoire of receptors
limited
very large
Target
invariant
variable
Recognition
perfect
imperfect
Speed
fast
slow
Long-lasting memory
no
yes
16
The UA/BWH PGA
inflammation
MI
DVT
COPD
asthma
infection
genetics
17
Immunity at the
Host/Environment Interface
1st interface
environment
2nd interface
innate immunity
pattern
recognition
receptors
surface receptors
effector molecules
adaptive
immunity
counterreceptors
18
Innate Immunity in
Diseases of Heart, Lung and Blood
lipopolysaccharide
(gram-negative bacteria)
lipoteichoic acid
(gram-positive bacteria)
lipoarabinomannan
(mycobacteria)
DNA, RNA
•monocyte/MØ
•neutrophils
•T cells
•epithelium
•endothelium
•eosinophils
•basophils
•fibroblasts
(viruses)
1
pattern
recognition
receptors
2
3
surface receptors counterreceptors
effector molecules
19
Macrophages
Neutrophils
PAMP
(CD14-positive)
MD-2
LBP
mCD14
Myd88
Costimulation:
CD80
CD86
Cell adhesion:
LFA-1 (CD11a/CD18)
Mac-1 (CD11b/CD18)
VLA-4
TLR
COX-2
activation
PGs
Cytokines:
TNF-a
IL-1
IL-6
IL-10
IL-12
IL-23
IL-18
TGF-b
Chemokines:
RANTES
MIP-1a
MIP-1b
MCP-1
IL-8
20
Endothelium
(CD14-negative)
PAMP
MD-2
LBP
TLR
sCD14
Cell adhesion:
ICAM-1
ICAM-2
ICAM-2
V-CAM1
E-selectin
OX40L
Cytokines:
GM-CSF
IL-1
IL-6
IL-18
TGF
Chemokines:
RANTES
MCP-1
IL-8
21
Epithelium
PAMP
LBP
(CD14-negative)
EGFR
MD-2
sCD14
TLR
Mucus secretion
MUC2
MUC5AC
activation
Cell adhesion
ICAM-1
ICAM-2
ICAM-2
V-CAM1
Cytokines
GM-CSF
IL-1
Anti-microbial peptides
IL-6
b-defensins
IL-18
SP-A
TGF-b
SP-D
NOS-2
activation
NO
Chemokines
Eotaxin
RANTES
IL-8
22
Receptor/Ligand Pairs on Effector Cells
EGF
PAF
EGFR
PAFR
Cytokines
Costimulation
Cell adhesion
Chemokines
IL-1R
IL-6R
IL-10R
IL-12R
IL-18R
TGF-bR
TNFR
CCR2
CCR3
CCR5
CCR6
CXCR1
CXCR2
CD80/CD28
CD86/CD28
CD80/CTLA-4
CD86/CTLA-4
LFA-1/ICAM
Mac-1/ICAM
OX40/OX40L
VLA-4/V-CAM
23
Where Should We Start?
MD1, 2
LBP
TLR2, 4, 5, 6, 9
RP105
CD14
Nod1
Cytokines
IL-10
Myd88
Anti-microbial peptides
b-defensin 1, 2
SP-A, SP-D
… with prototypic
innate immunity genes
arranged along the
PAMP/TLR signaling
pathway in different cell
types (including VERY
recent additions) …
Mucus
Muc2
Muc5Ac
24