Download - Chapter 10 Innate Immunity
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Chapter 10
Innate Immunity
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• 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.
Introduction of innate immunity
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Characteristics:• Set up at birth
• Non–specific and early
• Heredity
• Racial or species difference
• No immune memory
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Characteristics of Innate and Adaptive ImmunityCharacteristics of Innate and Adaptive Immunity
No Immunologic
memory
Antigen independent
No time lag
No antigen specific
Antigen dependent
A lag period
Antigen specific
Development
of memory
Innate Immunity Adaptive Immunity
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Components of Innate and Adaptive ImmunityComponents of Innate and Adaptive Immunity
Innate Immunity Adaptive Immunity
skin, gut Villi, lung cilia,etc
many protein andnon-protein secretions
phagocytes, NK cell, B1, γδT, APC
physical barriers
soluble factors
cells
none
Immunoglobulins(antibody)
T , B lymphocytesAPC
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Contents
Part Components of innate Ⅰ immune systemPart Cells participating in Ⅱ innate immunityPart Recognition features of theⅢ innate immune systemPart Functions of innate immunity Ⅳ
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Part Components of innate Ⅰimmune system
Ⅰ.Barriers
Ⅱ.Humoral factors
Ⅲ. Cells
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Part Components of innate immune systemⅠ
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)
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Part Components of innate immune systemⅠ
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
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ICC
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Part Cells participating in innate immunityⅡ
Natural killer cells (NK)Mononulear phagocytesNeutrophilsDendritic cellsOther cells participating in innate immunity
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Ⅰ. Natural killer(NK)cells
1. Source: Bone marrow,exist mainly in peripheral blood(5-7%) and spleen.
Part Cells participating in innate immunityⅡ
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2. Characteristics of NK cells2. 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 (FcR )Ⅲ Activated by IL-12 and produce IFN
-γ
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 (FcR )Ⅲ Activated by IL-12 and produce IFN
-γ
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3. Recognition mechanism of NK cells
• FcγRⅢ: recognize antibody covered cell
------ADCC
• Killer activating receptor and killer inhibitory receptor
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ADCC
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Receptors associated with killer activation and killer inhibition on NK cells
• NK receptors bind with class MHC moleculesⅠ
• NK receptors bind with non class MHC moleculesⅠ
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(1) NK Receptors bind with class molecules:Ⅰ -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
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(2) NK receptors bind with non class MHC moleculesⅠ --NKG2D: Express mainly on the surface of NK and γδT
No signal transmission
Non-covalent binding with DAP-10(ITAM)
MHC class chain-related molecules A/B(MIC A/B)Ⅰ
--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
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Receptors associated with killer activation and killer inhibition on NK cells
Killer activatory receptor Killer inhibitory receptor
KIR: KIR2DS,KIR3DS
KLR: CD94/NKG2C
NKG2D
NKp46
NKp30
NKp44
NCR
KIR2DL,KIR3DL
CD94/NKG2A
Bind class I HLA
molecules
Function
Bind non-class I HLA
molecules
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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 )
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Normal condition(Class HLA molecules are Ⅰexpressed normally):
Effect of Inhibitory recepter > Activatory recepter------Killing effect of NK cell is inhibited
Abnormal condition(Class HLA molecules are Ⅰexpressed abnormally) :
NK cells lose ability of distinguishing self from non-self------NK cells kill target cells ( NKG2D and NCR)
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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。
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4. Effector of NK cells•Secretion of cytokines,e.g. IFN-γ, to a activates
macrophages
•Cytotoxicity:
-ADCC-mediated by FcγR (CD16)Ⅲ
-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- pathwayⅠ
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Target cell
NK cell
Contact tightly
TNFR-I
TNF- α
ADCC
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5. Functions of NK cells
Participate in anti-tumor and anti-virus immunity
Participate in immunological regulation
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Ⅱ. Mononuclear phagocytes
Part Cells participating in innate immunityⅡ
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monocytes and macrophages
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Phagocytes are the Most Important Cells
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…”
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macrophageTissues
Blood
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MacrophagesMacrophages
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
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
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Receptors on Macrophages:
Fcγ receptors
Complement receptors
IFN-g receptor
Chemokine receptors
Mannose receptor
Toll-like receptors(TLRs)
Scavenger receptors(SRs)
LPS receptor(CD14)
Macrophages phagocytose and degrade foreign particles, bacteria and dead (and dying) host cells.
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1. Recognizing and excluding pathogens
Recognizing
Ingestion
Digestion
Exclusion
recognizing
digestion ingestionexclusion
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(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.
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The receptor associated with antigen-recognition 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
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IgG FcR
ScavengerR
CR
Initiation of Phagocytosis
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Pathways of Intracellular KillingPathways of Intracellular Killing
m yloperoxidase-independent m yeloperoxidase-dependent
oxygen-depenedent oxygen-independent
In trace llu la r K illing
m yloperoxidase-independent m yeloperoxidase-dependent
oxygen-depenedent oxygen-independent
In trace llu la r K illing
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(2) Ingesting and digesting the pathogen
Oxygen-dependent system:
---Reactive oxygen intermediates, ROIs :
O2-, OH-, H2O2, 1O2
---Reactive nitrogen intermediates, RNIs:
NOOxygen-independent system:
---Low pH(3.5-4) , Lysozyme, Defensin
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(3) Excluding the pathogen
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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
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Ⅲ. Neutrophil
Part Cells participating in innate immunityⅡ
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NeutrophilsNeutrophils
Phagocytosis, intracellular killing, inflammation and tissue damage
Characteristic nucleus, cytoplasm
Granules and CD66 membrane marker
FcγR and CR
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Ⅳ. Other cells• Dendritic cells
• Mast cells and eosinophils
• Microfold cells
• NKT cells
• γδ T cells
• B1 cells
Part Cells participating in innate immunityⅡ
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Part Features of innate immune Ⅲrecognition
• Molecular patterns(pathogen associated molecular pattern, PAMP): dsRNA,CpG DNA,LPS.
• Pattern recognition receptors ( PRR) : the receptors that bind these conserved structures.
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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.
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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
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Part Role of innate immunityⅣ
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.
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Progression of Immunity
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)
Figure 8.5
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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
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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.
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Components Principle FunctionsBarriersPhysical barriers Prevent entryChemical barriers Microbial killingBiotic barriers Competition of microbial
Circulating and Tissue Effector CellsNeutrophils Early phagocytosis and killing of microbesMacrophages Efficient phagocytosis and killing of microbes: cytokinesNK cells Lysis of infected cells, activation of macrophagesEosinophils Nasty toxic cells designed to kill helminths (worms)Mast Cells Release of inflammatory granules
Circulating ProteinsC Killing of microbes, opsonization of microbes, activation leukocytesMannose-binding protein Opsonization of microbes and activation of CC-reactive protein Opsonization of microbes and activation of CLysozyme Bacterial cell wall lysis
CytokinesTNF, IL-1, 6, 18 InflammationIFN a, b Resistence to viral infectionIFN g Macrophage activationIL-12 IFNg production by NK cellsIL-15 Proliferation of NK cells, memory T cellsIL-10, TGF b Control of Inflammation
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