Transcript PowerPoint 演示文稿 - Shandong University

Chapter 10
Innate Immunity
Introduction of innate immunity
• Innate immunity is the first line of defense against
infections.
• Innate immunity exist before encountering with
microbes and are rapidly activated by microbes
before the development of adaptive immune
responses.
• Innate immunity is present in all multicellular
organisms, including plants and insects.
Characteristics:
•
•
•
•
•
Set up at birth
Non–specific and early
Heredity
Racial or species difference
No immune memory
Characteristics of Innate and Adaptive Immunity
Innate Immunity
Adaptive Immunity
Antigen independent
Antigen dependent
No time lag
A lag period
No antigen specific
No Immunologic
memory
Antigen specific
Development
of memory
Components of Innate and Adaptive Immunity
Innate Immunity
Adaptive Immunity
physical barriers
skin, gut Villi, lung cilia,etc
none
soluble factors
many protein and
non-protein secretions
cells
phagocytes, NK cell, B1,
γδT, APC
Immunoglobulins
(antibody)
T , B lymphocytes
APC
Contents
PartⅠ Components of innate
immune system
PartⅡ Cells participating in
innate immunity
PartⅢ Recognition features of the
innate immune system
PartⅣ Functions of innate immunity
PartⅠ Components of innate
immune system
Ⅰ.Barriers
Ⅱ.Humoral factors
Ⅲ. Cells
PartⅠ Components of innate immune system
Ⅰ. Barriers:
• Mechanical defense:
skin & mucous membrane
• Anatomic barrier:
blood – brain barrier
blood – placenta barrier
blood – thymus barrier
• Biotic barrier: normal flora
• Chemical defense (lysozyme, acid)
PartⅠ Components of innate immune system
Ⅱ.Humoral factors:
Complement
Cytokine---macrophage, neutrophil, NK cell
Lysozyme
Ⅲ. Cells:
Mononuclear phagocyte, NK cell, Neutrophils,
Dendritic cells，Eosinophil, Basophil, Mast cell，
γδT cell, B1 cell, Microfold cell
ICC
PartⅡ Cells participating in innate immunity
Natural killer cells (NK)
Mononulear phagocytes
Neutrophils
Dendritic cells
Other cells participating in innate immunity
PartⅡ Cells participating in innate immunity
Ⅰ. Natural killer(NK)cells
1. Source: Bone marrow,exist mainly in peripheral
blood(5-7%) and spleen.
2. Characteristics of NK cells
 Also called large granular
lymphocytes (LGL)
 Kill various infected and malignant
cells spontaneously, without
stimulation of antigen and MHC
restriction
 Identified by the presence of
CD56,CD16 (FcRⅢ)
 Activated by IL-12 and produce IFN
-γ
3. Recognition mechanism of NK cells
• FcγRⅢ: recognize
antibody covered cell
------ADCC
• Killer activating receptor
and killer inhibitory
receptor
ADCC
Receptors associated with killer activation
and killer inhibition on NK cells
• NK receptors bind with class Ⅰ MHC molecules
• NK receptors bind with non class Ⅰ MHC molecules
(1) NK Receptors bind with class Ⅰ molecules:
-KIR(killer immunoglobin-like receptors):
•
Number of immunoglobin-like domain:KIR2D/KIR3D
•
Cytoplastic region:
longer---KIR2DL/KIR3DL(ITIM), inhibitory receptor
shorter---KIR2DS/KIR3DS, non-covalent
combination with DAP-12(ITAM), activating receptor
-KLR(killer lectin-like receptor):
•
Heterodimer of CD94 & NKG2 (C type lectin)
CD94: short cytoplastic region, no signal transmission
NKG2A: ITIM in cytoplastic region
--------CD94/NKG2A, inhibitory receptor
NKG2C: no signal transmission, bind with DAP-12(ITAM)
--------CD94/NKG2C, activating receptor
ITIM：immunoreceptor
tyrosine-based Inhibitory motif
ITAM：immunoreceptor
tyrosine-based activation motif
(2) NK receptors bind with non class Ⅰ MHC molecules
--NKG2D: Express mainly on the surface of NK and γδT
No signal transmission
Non-covalent binding with DAP-10(ITAM)
MHC class Ⅰ chain-related molecules A/B(MIC A/B)
--Natural cytotoxic receptor(NCR): NKp46,NKp30,NKp44
IgSF
Express on the surface of NK cells
Bind with other molecules(ITAM)
Kill target cells when KIR/KLR lose their function
Receptors associated with killer activation
and killer inhibition on NK cells
Killer activatory receptor
Killer inhibitory receptor
Function
KIR: KIR2DS,KIR3DS
KIR2DL,KIR3DL
Bind class I HLA
KLR: CD94/NKG2C
CD94/NKG2A
molecules
NKG2D
NKp46
NKp30
NKp44
NCR
Bind non-class I HLA
molecules
Figure 3-23
These are important
molecules for presentation
of peptides to CD8 T cells
These are important NK
inhibitory ligands
（ CD94/NKG2A/B/C）
 Normal condition(Class Ⅰ HLA molecules are
expressed normally):
Effect of Inhibitory recepter > Activatory recepter-----Killing effect of NK cell is inhibited
 Abnormal condition(Class Ⅰ HLA molecules are
expressed abnormally) :
NK cells lose ability of distinguishing self from nonself------NK cells kill target cells（NKG2D and
NCR)
NK cells is tolerant to self-antigen:
Only virus infected cells and tumor cells could be
killed by NK cells, not the normal tissue cells.
Virus infected cells or tumor cells  MHC-I 
inhibitory signal  Killed by NK cells。
4. Effector of NK cells
• Secretion of cytokines,e.g. IFN-γ, to a activates
macrophages
• Cytotoxicity:
-ADCC-mediated by FcγRⅢ(CD16)
-Granules like CTLs:
Perforin: creates pores in target cell membranes
Granzymes : enzymes which enter through perforin pores
and induce apoptosis of target cells.
-FasL/Fas pathway
-TNF-α/TNFR-Ⅰ pathway
Target cell
TNFR-I
TNF- α
Contact tightly
NK cell
ADCC
5. Functions of NK cells
Participate in anti-tumor and anti-virus
immunity
Participate in immunological regulation
PartⅡ Cells participating in innate immunity
Ⅱ. Mononuclear phagocytes
monocytes and macrophages
Phagocytes are the Most
Important Cells
George Bernard Shaw wrote:
“There is at bottom only one
genuine treatment for all
diseases,…to stimulate the
phagocytes. Drugs are a
delusion. …(when) the
phagocytes are stimulated; they
devour the disease…”
Tissues
Blood
macrophage
Macrophages
 Phagocytose & kill intracellularly
 Characteristic nucleus and
identified by CD14
 Act as APC
 Activated by cytokines
 Kill malignant and altered self
targets
 Adherent of plastic and glass
surfaces
Macrophages phagocytose and degrade foreign particles, bacteria
and dead (and dying) host cells.
Receptors on Macrophages:
Fcγ receptors
Complement receptors
IFN-g receptor
Chemokine receptors
Mannose receptor
Toll-like receptors(TLRs)
Scavenger receptors(SRs)
LPS receptor(CD14)
1. Recognizing and excluding pathogens
Recognizing
Ingestion
recognizing
Digestion
Exclusion
exclusion
digestion
ingestion
(1) Recognition Mechanism
Pattern recognition receptor(PRR):
The receptor on macrophage which can recognize and
bind specific molecular structure on some pathogens ,
injured or apoptotic cells.
The receptor associated with antigenrecognition of macrophage
 Pattern recognition receptor (PRR) or non-opsonic
receptor
------Mannose receptor(MR)
Scavenger receptor(SR)
Toll like receptor(TLR)
 Opsonic receptor
------FcγR and C3bR/C4bR
Initiation of Phagocytosis
ScavengerR
IgG FcR
CR
Pathways of Intracellular Killing
Intracellular Killing
oxygen-depenedent
myloperoxidase-independent
oxygen-independent
myeloperoxidase-dependent
(2) Ingesting and digesting the pathogen
Oxygen-dependent system:
---Reactive oxygen intermediates, ROIs :
O2-, OH-, H2O2, 1O2
---Reactive nitrogen intermediates, RNIs:
NO
Oxygen-independent system:
---Low pH(3.5-4) , Lysozyme, Defensin
(3) Excluding the pathogen
2. Functions of macrophage
① Recognizing and excluding pathogens and died cells;
Killing target cells(tumor cells and virus-infected cells)
② Participating in and stimulating inflammation
③ Participating in immunological regulation
④ Processing and presenting antigen, initiating adaptive
immune response
PartⅡ Cells participating in innate immunity
Ⅲ. Neutrophil
Neutrophils
 Phagocytosis,
intracellular killing,
inflammation and tissue
damage
 Characteristic nucleus,
cytoplasm
 Granules and CD66
membrane marker
 FcγR and CR
PartⅡ Cells participating in innate immunity
Ⅳ. Other cells
• Dendritic cells
•
•
•
•
•
Mast cells
and eosinophils
Microfold cells
NKT cells
γδ T cells
B1 cells
PartⅢ Features of innate immune
recognition
• Molecular patterns(pathogen associated molecular
pattern, PAMP): dsRNA,CpG DNA,LPS.
• Pattern recognition receptors（PRR） : the receptors
that bind these conserved structures.
PAMP :
1.Structures that are characteristic of microbial
pathogens and are not present on mammalian cells.
2.Microbial products that are often essential for survival
of the microbes.
The receptors of the innate immune system( PRRs) are
encoded in the germline.
• Very conserved
• Limited diversity
PRRs including:
Scavenger receptor, SR
Mannose receptor，MR
Toll-like receptor, TLR
Part Ⅳ Role of innate immunity
1. Defense against microbes
• The early local reaction of innate immunity is the
inflammatory response, in which leukocytes are
recruited to the site of infection and activated to
eradicate the infection.
• Inflammation produces a variety of systemic changes
in the host that enhance the ability of the innate
immune system to eradicate infection and, in sever
infections, can contribute to systemic tissue injury or
death.
Progression of Immunity
Figure 8.5
At least three cell types reside within or beneath the epithelium
and induce inflammation in response to trauma or microbial
products: Macrophages, Mast Cells, and Langerhan’s cells (a skin
dendritic cell)
2. Stimulating adaptive immune responses
• Provides signals that function in concert with antigen
to stimulate the proliferation and differentiation of
antigen-specific T and B lymphocytes.
• Works as effector cells or molecules
Important functions of innate immunity:
• Innate immunity is the initial response to microbes
• The effector mechanisms of innate immunity are often
used to eliminate microbes even in adaptive immune
responses
• Innate immunity to microbes stimulates adaptive immune
responses and can influence the nature of the adaptive
responses to make them optimally effective against
different types of microbes.
Components
Principle Functions
Barriers
Physical barriers
Prevent entry
Chemical barriers
Microbial killing
Biotic barriers
Competition of microbial
Circulating and Tissue Effector Cells
Neutrophils
Early phagocytosis and killing of microbes
Macrophages
Efficient phagocytosis and killing of microbes: cytokines
NK cells
Lysis of infected cells, activation of macrophages
Eosinophils
Nasty toxic cells designed to kill helminths (worms)
Mast Cells
Release of inflammatory granules
Circulating Proteins
C
Killing of microbes, opsonization of microbes, activation leukocytes
Mannose-binding protein
Opsonization of microbes and activation of C
C-reactive protein
Opsonization of microbes and activation of C
Lysozyme
Bacterial cell wall lysis
Cytokines
TNF, IL-1, 6, 18
Inflammation
IFN a, b
Resistence to viral infection
IFN g
Macrophage activation
IL-12
IFNg production by NK cells
IL-15
Proliferation of NK cells, memory T cells
IL-10, TGF b
Control of Inflammation