Beruflich Dokumente
Kultur Dokumente
Prof. Xi Huang
huangxi6@mail.sysu.edu.cn
2014.10.17
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Contents
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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
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Innate immune cells
Phagocytes:
NKT, gdT, B
Others:
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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
Concept:
PRR : Pathogen recognizing receptors
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PAMP and PRR
1 PAMP: Pathogen Associated Molecular Patterns
Lipopolysaccharide (LPS),
dsRNA, unmethylated CpG,
mannose, glucan,
Lipoteichoicacid (LTA),
Pepidoglycan (PGN)
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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
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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
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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
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RLR Domains
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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
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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
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
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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
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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
Kaposi
sarcomaassociated herpesvirus (KSHV):
ORF45
(Zhu FX. et al., Proc Natl Acad Sci USA., 2002)
RTA
(Yu Y. et al., Immunity, 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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