Chapter 10 Innate Immunity

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Chapter 10Innate Immunity
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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.

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• Characteristics
• Set up at birth
• Nonspecific and early
• Heredity
• Racial or species difference
• No immune memory

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Characteristics of Innate and Adaptive Immunity
Innate Immunity
Adaptive Immunity

• Antigen independent

• Antigen dependent

• No time lag

• A lag period

• No antigen specific

• Antigen specific

• No Immunologic
• memory

• Development
• of memory

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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
Immunoglobulins (antibody)
cells
phagocytes, NK cell, B1, ?dT, APC
T , B lymphocytes APC
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Contents

• Part? Components of innate
• immune system
• Part? Cells participating in
• innate immunity
• Part? Recognition features of the
• innate immune system
• Part? Functions of innate immunity

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Part? Components of innate immune
system

• ?.Barriers
• ?.Humoral factors
• ?. Cells

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Part? Components of innate immune system

• ?. 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 system

• ?.Humoral factors
• Complement
• Cytokine---macrophage, neutrophil, NK cell
• Lysozyme
• ?. Cells
• Mononuclear phagocyte, NK cell,
  Neutrophils,
• Dendritic cells,Eosinophil, Basophil, Mast
  cell,
• ?dT cell, B1 cell, Microfold cell

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ICC
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Part? Cells participating in innate immunity

• Natural killer cells (NK)
• Mononulear phagocytes
• Neutrophils
• Dendritic cells
• Other cells participating in innate immunity

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?. Natural killer(NK)cells
Part? Cells participating in innate immunity

• 1. Source Bone marrow,exist mainly in peripheral
  blood(5-7) and spleen.

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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?R?)
• Activated by IL-12 and produce IFN -?

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3. Recognition mechanism of NK cells

• Fc?R? 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 molecules
• NK receptors bind with non class ? MHC molecules

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• (1) NK Receptors bind with class ? molecules
• -KIR(killer immunoglobin-like receptors)
• Number of immunoglobin-like
  domainKIR2D/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

ITIMimmunoreceptor tyrosine-based Inhibitory
motif ITAMimmunoreceptor tyrosine-based
activation motif
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• (2) NK receptors bind with non class ? MHC
  molecules
• --NKG2D Express mainly on the surface of NK
  and ?dT
• No signal transmission
• Non-covalent binding with
  DAP-10(ITAM)
• MHC class ? 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

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Receptors associated with killer activation and
killer inhibition on NK cells
Killer activatory receptor
Killer inhibitory receptor
Function
KIR KIR2DS,KIR3DS KLR CD94/NKG2C
NKG2D NKp46
NKp30 NKp44
KIR2DL,KIR3DL CD94/NKG2A
Bind class I HLA molecules
Bind non-class I HLA molecules
NCR

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Figure 3-23
These are important NK inhibitory ligands(
CD94/NKG2A/B/C)
These are important molecules for presentation of
peptides to CD8 T cells
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• Normal condition(Class ? HLA molecules are
  expressed normally)
• Effect of Inhibitory recepter gt Activatory
  recepter------Killing effect of NK cell is
  inhibited
• Abnormal condition(Class ? HLA molecules are
  expressed 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-?, to a
  activates macrophages
• Cytotoxicity
• -ADCC-mediated by Fc?R?(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-a/TNFR-? pathway

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TNFR-I TNF- a
Target cell
Contact tightly
NK cell
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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?. Mononuclear phagocytes
Part? Cells participating in innate immunity
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monocytes and macrophages
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Phagocytes are the Most Important Cells
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Tissues
macrophage
Blood
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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

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Macrophages phagocytose and degrade foreign
particles, bacteria and dead (and dying) host
cells.
Receptors on Macrophages Fc? receptors Complement
receptors IFN-g receptor Chemokine
receptors Mannose receptor Toll-like
receptors(TLRs) Scavenger receptors(SRs) LPS
receptor(CD14)
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1. Recognizing and excluding pathogens

• Recognizing
• Ingestion
• Digestion
• Exclusion

recognizing
ingestion
digestion
exclusion
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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
• ------Fc?R and C3bR/C4bR

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Initiation of Phagocytosis
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Pathways of Intracellular Killing
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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
• NO
• Oxygen-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
• Recognizing and excluding pathogens and died
  cells Killing target cells(tumor cells and
  virus-infected cells)
• Participating in and stimulating inflammation
• Participating in immunological regulation
• Processing and presenting antigen, initiating
  adaptive immune response

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?. Neutrophil
Part? Cells participating in innate immunity
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Neutrophils

• Phagocytosis, intracellular killing, inflammation
  and tissue damage
• Characteristic nucleus, cytoplasm
• Granules and CD66 membrane marker
• Fc?R and CR

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?. Other cells
Part? Cells participating in innate immunity

• Dendritic cells
• Mast cells and eosinophils
• Microfold cells
• NKT cells
• ?d T cells
• B1 cells

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Part? 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.

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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 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.

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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 Langerhans cells (a
skin dendritic cell)
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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 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

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