Innate Immune Recognition

Sun Yat-sen University

Zhongshan School of Medicine

Prof. Xi Huang
huangxi6@mail.sysu.edu.cn
2014.10.17

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 Contents

1 Innate immune system

2 Innate recognition
3 Innate response
4 Innate regulation
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 What is innate immunity?
Immunity which is not intrinsically affected by
prior contact with Ag, i.e. all aspects of immunity
not directly mediated by lymphocytes.
Developed in long-term germ line evolution; also
called natural/nonspecific immunity.
Include:barriers, molecules and cells of innate
immunity system

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Host Innate Immune System
Physical
Barriers Chemical
Biological

PMN
Immune Systems Immune Cells DCs
M

Comp
Immune Lysosome
Molecules Defensins 5
 Barriers of Innate Immunity

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Anatomic and Physiologic Barriers
Figure 2-4

Intact skin/Mucus membrane

Mucosal immune system (MIS)

Secretion of anti-microbial factors

Normal flora

Blood-brain and placenta barriers 8

 Immune Cells

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Innate immune cells
Phagocytes:

neutrophil, monocyte, macrophage

Natural killer cell(NK cell)
Dentritic cell(DC)
Innate-like lymphocyte:

NKT, gdT, B
Others:

mast cell, eosinophil, basophil

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Components
Components of
of the
the Immune
Immune System
System

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Antigen presenting cells

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 Immune Molecules

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Innate Immune Molecules
1. Complment: alternative & MBL pathway
2. Lysozyme: tissue and body fluid, secre-
tion, lysosome in phagocytes
3. Antimicrobial peptides: defensin
4. Cytokines: interferon, IL-1, IL-6, IL-12,
TNF-, chemotaxin
5. Acute phase protein: CRP, MBP, SAP,
1-acid glycoprotein, FN, etc.
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Cytokines in innate immunity
Cytokines Principal functions
TNF,IL-1,chenmokines Inflammation
IFN-,- Resistance to viral infection
IFN- Macrophage activation
IL-12 IFN- production by NK cells and T cells
IL-15 Proliferation of NK cells
IL-10,TGF- Control of inflammation

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 Innate Recognition

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 The 2011 Nobel Prize

Jules A. Hoffmann Bruce Beutler

They received one-half of the 2011 Nobel Prize in Physiology or Medicine,

Medicine
for "their discoveries concerning the activation of innate immunity"
immunity
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Father of Innate Immunity Prof. Janeway C

Concept:
PRR : Pathogen recognizing receptors

PAMPs: Pathogen associated molecular

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patterns
PAMPs

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 PAMP and PRR
1 PAMP: Pathogen Associated Molecular Patterns
Lipopolysaccharide (LPS),
dsRNA, unmethylated CpG,
mannose, glucan,
Lipoteichoicacid (LTA),
Pepidoglycan (PGN)

2 PRR: receptors on professional APC and M which

enable them to recognize PAMP.
mannose receptor
Toll-like receptor
scavenger receptor
phosphatidyl serine receptor
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Pathogen Associated Molecular Pattern

PAMP are conserved, shared by a large group

of infectious agents, and clearly
distinguishable from self patterns.
Typical PAMP:
lipopolysaccharide(LPS),
mannose, glucan, dsRNA,
lipoteichoicacid(LTA),
peptidoglycan(PGN)
unmethylated CpG DNA etc
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Pathogen-Associated Molecular
Patterns (PAMPs)

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Adhesin

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non-fimbral adhesin
Bartonella fimbrial adhesins (E.
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coli )
Ligand Specificities of TLRs

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PRRs

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 Pattern-Recognition
Receptor PRR

Expressed mainly on DC and M which enable

them to recognize PAMP.
Three types of PRR:
secreted PRR: MBL,C-reactive protein
endocytic PRR:
scavenger receptor,
mannose receptor
signaling PRR:
Toll-like receptor,
NOD-like receptor,
RIG-like receptor 35
 Discovery of TLRs
Drosophila embryogenesis. (1980s)

Antifungal response in Drosophila adults.

(Hoffmann et al., Cell, 1996)

A human homologue of Toll

(Janeway et al., Nature, 1997)
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 Toll-like Receptors (TLRs)

A family of proteins, which are

structurally related to Drosophila
Toll and IL-1 receptor.
TLR1-10 in human, TLR1-13 in
mouse.
Recognize specific pathogen
associated molecular patterns
(PAMPs) such as endotoxin
(LPS).
Regulate the activation of both
innate and adaptive immunity.
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Toll-like Receptors, TLR

Inmammals, 10 members of Toll-like receptors

(TLRs) have been actually identified.
TLRs are members of the superfamily of
Interleukin-1 receptors (IL-1Rs). They share
significant homology in their cytoplasmic regions.

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Ligand Specificities of TLRs

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TLR ligands and signaling

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Akira S. et al. (2005) Int. Immunol. 17:1-14
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TLRs in innate and adaptive immunity

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TLRs control adaptive immunity

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Akira S. et al. (2001) Nature Immunology 2:675-680
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 MBL Recognition

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 NOD-like receptors, NLR
Recognize cytoplasmic PAMPs and/or
endogenous danger signals, inducing
immune responses.
Ligands: MDP and meso-DAP
Three domains:
C-terminal LRRs sense ligands
centrally located NOD domain
N-terminal effector region comprising a
protein-protein interaction domain such as the
CARD, Pyrin or BIR domain.
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NLR Domains

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 NLR subfamilies

Several subfamilies (on the basis of

their effector domains)
CARD subfamily: NODs ,IPAF, CIITA,
PYD subfamily: NALPs
BIR subfamily: NAIPs

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NLR families

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 Functions of NLR
They may then form oligomers that activate
inflammatory caspase1 causing cleavage and
activation of important inflammatory
cytokines IL-1
NLRsmay also activate the NF-B signaling
pathway to induce production of inflammatory
molecules.

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NLR signaling

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 NLR and inflammasome
inflammasome, a multiprotein complex that
contains, in addition to NLR, the adaptor
molecule ASC and the protease caspase-1.
inflammasome is responsible for the
proteolytic processing of the immature form of
the cytokines belonging to the IL-1 family (IL-
1b, IL-18, and IL-33),

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IL-1/IL-18 inflammosome

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NALP3 and IPAF inflammasome

Fabio Martinon Annu. Rev. Immunol. 2009. 27:229 58

 RIG-I like receptors RLR
Detect intracellular dsRNA of viral origin:
RIG-I (retinoic acid induced gene)
MDA-5 (melanoma differentiation associated gene)
LGP2 (laboratory of genetics and physiology)

Comprises N-terminal caspase activation and

recruitment domains (CARDs), a DECH
helicase, and a C-terminal domain (CTD).

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RLR Domains

Red box, CARD1;

blue box, CARD2;
green box, Helicase domain;
purple box, DEAD/DEAH domain

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Signaling of RLR

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e.g.,HCV protein NS3/4A eliminates antiviral
signaling by cleavage of MAVS and TRIF.

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Summary of Pattern Recognition

The Journal of Clinical Investigation, 118(2), 2008 63

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 Progression of Immunity
The epithelium surfaces of the body make up the
first lines of defense against infections.
Afterentering tissues, many pathogens are
recognized, ingested, and killed by phagocytes.
Pathogen recognition and tissue damage initiate an
inflammatory response.
Adaptive immunity are induced.

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Progression of Immunity

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(Immune Response)

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 Innate Immune
Response

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Intracellular vs. Extracellular bacteria
Figure 10-4

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 3 phases of Innate Immunity

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Action phase of immune response post virus
infection

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Innate VS Adaptive immunity

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Direct pathogenesis

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Indirect pathogenesis

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Intracellular killing mechanisms

O2-dependent: ROI, RNI (reactive nitrogen

intermediate), SOD (superoxidase dismutase)

O2independent: MPO (myeloperoxidase, )

Enzymes (lysozyme)

Defensins

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 inflammatory response

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Types of Inflammation:

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Type of Inflammation

1. Inapparent infection

2. Apparent infection.

3. Carrier state 85
 Innate immunity and diseases

Infection (sepsis, hepatitis, keratitis)

Autoimmune disorders (SLE)
Cancer (ovarian cancer)
Cardiovascular diseases (atherosclerosis)

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 Immune Regulation

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TLR ligands and signaling

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Akira S. et al. (2005) Int. Immunol. 17:1-14
TLRs in innate and adaptive immunity

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TLRs control adaptive immunity

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Akira S. et al. (2001) Nature Immunology 2:675-680
Innate immunity affects the type of adaptive immunity

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Innate immunity assists adaptive immunological effect

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 Negative regulation of TLR signaling
1st Soluble TLRs such as sTLR2 and sTLR4, act as
decoy receptors for TLR2 and TLR4 signaling.
2nd Transmembrane proteins such as SIGIRR and
ST2, sequester recruitment of adaptors and inhibit formation
of TLR signaling complex.
3rd Intracellular regulators such as MyD88s, SOCS,
IRAK-M.
4th Reduction of TLR expression or increased TLR
degradation.
5th TLR-induced apoptosis.
6th TLR tolerance.
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Negative regulation of TLR4 signaling

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 Fine-tuners of TLR Signaling

Soluble regulators

Soluble TLR2
Soluble TLR4

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(Modified from Liew, Nat Rev Immunol., 2005)
SIGIRR and ST2:
Members of immunoglobulin domain subgroup of TLR/IL-1R
super-family

Negatively regulate TLR signaling

Ligand unknown (SIGIRR)

Ligand for ST2 (IL-33)

Li et al. (2005) J. Mol. Med. 83:258-266

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 Fine-tuners of TLR Signaling

Transmembrane regulators

SIGIRR
(single immunoglobulin interleukin-1-
related receptor)

ST2
(suppression of tumorigenicity 2)

TRAILR
(TNF-related apoptosis-inducing ligand
receptor).

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(Modified from Liew, Nat Rev Immunol., 2005)
 Fine-tuners of TLR Signaling

Intracellular regulators
MyD88s
(myeloid differentiation primary response
gene 88, splice variant)

IRAK-M
(interleukin-1 receptor-associated kinase of
monomyeloic origin)

SOCS1
(suppressor of cytokine signaling 1)

TOLLIP
(Toll-interacting protein)

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(Modified from Liew, Nat Rev Immunol., 2005)
 Microbial Evasion of TLR Signaling

Hepatitis C virus: NS3-4A protease

(Li K. et al., Proc Natl Acad Sci USA., 2005)

Kaposi
sarcomaassociated herpesvirus (KSHV):
ORF45
(Zhu FX. et al., Proc Natl Acad Sci USA., 2002)

RTA
(Yu Y. et al., Immunity, 2005 )

Shigella flexneri : OspG

(Kim DW. et al., Proc Natl Acad Sci USA., 2005

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(Lemon SM, J Biol Chem., 2010)
Thank you for your time!!!

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Any questions ?

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