Innate immunity

Dept. Immunology, XJMU, China

Definition
o Innate Immunity
gy
which exists from birth and is not affected by
o
ol
prior contact with antigen, mediates the initial
n
mu
protection against infections (also called no-
m
_I
specific immunity or native immunity).
u
jm
o Adaptive Immunity
x
which exist from encounter antigen, mediates
the later, even more effective defense against
infection (also called specific or acquired
immunity).

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 ogy
nol
mmu
u_I
xjm

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The action phase of the non-specific anti-infection

phase time components

og y
l
Instanter response 0-4h nobarrier,macrophage,
mmu
Early response mu _I complement

xj
Inducing the
response >96h APC
of specific immunity

共 111 页 第 3 页
 The differences between the two types of immunity

Non-specific Immunity Specific Immunity

innate immunity adaptive immunity

Response is antigen-
o gy Response is antigen-
independent
no l dependent

mmu
There is immediate _
u I There is a lag time

xj
maximal responsem between exposure and
maximal response

Not antigen-specific Antigen-specific

Exposure results in no Exposure results in

immunologic memory immunologic memory
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 ogy
nol
mmu
u_I
xjm

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Characteristics
o Inbuilt immunity to resist infection
o
o
Native, natural immunity
ogy
o
Present from birth
nol
o
No antigen-specific
mmu
o u_I
Not enhanced by second exposure

o
Has no memory
xjm
Uses cellular and humoral components
o Is poorly effective without adaptive immunity
o Also involved in the triggering and amplification
of adaptive immune responses

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o Innate Immunity system
which is the first linelog y
of defense
u no
mm
against infections.It
I
works rapidly, gives
mu_
xj
rise to the acute inflammatory response,
and has some specificity of micorbes.

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Components of the innate immunity
system

o Barrier structure
o gy
o Cells
nol
mu
o Antibacterioidal substances
m of the tissue
and body fluidsu_I
xjm

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Component 1 :Barrier structure

Ø skin-mucous membranes barriers

g y
afford affective protection against non-
pathogenic organisms andlao high degree of
uno
protection against pathogens.
I m
♦ physical barrier : skin
m
mu_ and mucous
xj
♦ chemical barrier: surface secretions, eg
lactic acid in sweat
♦ microbiological barrier: normal flora in
intestinal tract

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skin-mucous membranes barriers

ogy
nol
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

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 Inflammation

ogy
nol
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

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Barrier structure

Ø blood-placenta barriers prevent the infection

o gy
in foetus from pathogens or larger molecules
n o
Ø blood-brain barriers prevent
l the infection of
mm u
_I
brain from non-pathogenic organisms and
pathogens
xj mu

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 ogy
nol
mmu
u_I
xjm

blood-placenta barriers
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 ogy
nol
mmu
u_I
xjm

blood-brain barriers
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Component 2: cells

o Phagocytes
o nature killer cells（NK cells）
y
log
o B1 cells o
o Mast cell mun
I m
o Eosinophil mu_
o Basophil xj
o B1 cells

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 Morphology and staining
characteristics of various types of
blood cells. Red blood cells and
platelets, which both lack nuclei,
are the most numerous. Most
numerous of the leukocyte
populations are the neutrophils.
Lymphocytes are the
predominant cell type responsible

ogy for immune responses.

nol
mmu
u_I
xjm

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 T&B lymphocyte（ICC） Dendritic cell (DC)

ogy
nol
NK cell
mmu
monocyte(mo)/macrophage(Mφ) neutrophil

u_I
xjm
Eosinophil basophil mast cell RBC platelet

Types of immune cells

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 ogy
nol
mmu
u_I
xjm

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CELL 1: Phagocytes

1.components
neutrophils (in blood) gy
ol o
MPS: mononuclear np hagocytosis
mu
system Im
mu _
x j
monocytes (in blood)
macrophages (in tissue)

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neutrophils
o represent 60-70% of WBCs
o Life span : 2-3 days
ogy
no
o function: phagocytosisl
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

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MPS

o These cells are derived from the bone

marrow and have a variety ofyfunctions in
og
the immune response: ol
mu n
phagocytosis
_I m
jm
secretion
uof cytokines
x

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monocyte

ogy
nol
mmu
u_I
xjm

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macrophages

ogy
nol
mmu
u_I
xjm

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Characteristics

o represent 5-8% of WBCs

o g y
o monocytes enter the tissues through the
ol
process of extravastion----macrophage
n
o Different names in m
m u
different tissues
– Monocyte
u_ I(blood)
j m
x cells (liver)
– Kupffer
– Mesangial cells (kidney glomerulus)
– Microglia (brain)
– Alveolar macrophages (lung)
– Histiocyte (connective tissue)
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Superficial marks
u Receptor
FcγR(IgG FcR) : Ab-mediated opsonization; ADCC
ogy
CR1 : C-mediated opsonization
nol
CKRs: MCP/MIP/IFN-γreceptor
mmu
PRR:
u_I
u MHCⅠ/Ⅱ: present the peptides of Ag to T
xjm
u AMs adhere to the vessel walls, and invade the
affected tissues and is attracted to the site of an injury
or infection.

共 111 页 第 30 页
Receptor 1: FcγR (IgG FcR)

Binding to FcR

ogy
nol
mmu
u_I
xjm Binding to FcR

ADCC Ab-mediated opsonization

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Receptor 2: CR1

ogy
nol
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

indirect recognition receptors

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Receptor 3: CKR1

o MCP-1R :monocyte chemtatic y

log protein-1
o
u no
MIP-1R:macrophage inflammatory protein-1
o IFN-γR
I mm
o M-CSFR mu_
o GM-CSFR xj

共 111 页 第 34 页
Receptor 4: Pattern recongnition receptors(PRR)

pattern recognition receptor :PRR

og y
n ol
Direct recognition receptors

m mu
u _I
macrophage expresses recognise the special

x m
polysaccharidejor other pattern molecule on
the microorganism or contabescence cell , so
called PRR,such as MBR（mannose-binding
receptor）, Scavenger receptor(SR) and TLR

共 111 页 第 35 页
 PAMP(Pathogen Associated
molecular pattern )

ogy
PRR ( Pattern-recognition
nol
mu
Receptor)
m
u _I
xjm

共 111 页 第 36 页
innate pathogen recognition

og y
no l
Pathogen-associated molecular patterns (PAMP).

mm u
o essential surface molecules
u_ I
j m
o recognised by pattern
x
recognition receptors (PRR)
on host cells

o E.g: LPS

共 111 页 第 37 页
 Receptor ligands
(Pattern Recognition Receptors) (Pathogen-Associated Molecular
Patterns)
TLR1
g y
Heterodimerizes with TLR2
o
TLR2
AraLAM o
n l
PGN, some LPS, some LTA, lipoproteins,

TLR3
m m
dsRNAu
TLR4
u_IGram(-) LPS, Taxol, some LTA
TLR5
xjm Flagellin

TLR6 Heterodimerizes with TLR2

TLR7 Imidazoquinoline

TLR9 Bacterial DNA (CpG)

TLR 8,10 Unknown

共 111 页 第 38 页
Functions

o phagocytes engulf and digest bacteria, cellular

gy
debris and other particulate matter
o
o nol
Antiviral activity
mmu
o
u
Antigen presentation_I
j m
o Secretion x

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Functions 1: phagocytosis

ogy
nol
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

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Outcome of phagocytosis:
og y
o complete engulfing
n ol
m
Phagocytes may kill ingested
m umicroorganisms, which is
_I
called complete engulfing
u
j m
o incomplete engulfing
x
Phagocytes may permit their prolonged surviral or even
their intracellular multiplication which is called
incomplete engulfing

共 111 页 第 46 页
Functions 2 : Antiviral activity

l When activated phagocytes by IFNs meet the tumor

o gy
ol
cells, it will secret cytotoxic materials
n
(such as

m mu
lysozyme, enzymes, TNF-α
u _I etc.) and kill tumor cells.

l
x jm
ADCC (Antibody-Dependent Cell-Mediated

Cytotoxicity)

共 111 页 第 47 页
Functions 3 : Antigen presentation

o Phagocytes can present the g

o y
peptides of Ag
nol
mm
to TCR on Th cells by u
MHC protein, so the
u_ I
xjm
specific immunity begins

共 111 页 第 48 页
Functions 4 : Secretion

o Immunology regulation : Macrophages secret

gy
many CKs such as IL-1，IFN- l γo
u n o ，TNF-α et al.

o
I mm
inflammatory mediators : IL-1,IL-6,TNF-α,PAF,
complement jmu
_
x

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 ogy
nol
mmu
u_I
xjm

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CELL 2: natural killer, NK
 ogy
nol
mmu
u_I
xjm

Human NK cell

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 ogy
nol
mmu
u_I
xjm

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 Characteristics
o NK cell is one kind of lymphocyte（no express the

ogy
marker of the T and B lymphocytes）

nol
o Also known as large granular lymphocytes (LGL)
o No thymic development
mmu
u_I
o Are identified by the presence of CD56 & CD16 and
absence of CD3
xjm
o Secretion of the activated molecule （like Th cell
secreting IFNα/β/γ)
o Effective in host defense against virus infected cells
and tumor cells

共 111 页 第 54 页
NKCR
u KIR (kill inhibitory receptor )on the surface of the NK

o gy
cell can transfer the no-killing signal. There receptors

no l
mm u
recognize the MHC-I molecules. Thereby, the cells that

_I
express normally MHC-I
u
would be not killed by NK
cells
xj m
u KAR (kill active receptor )on the surface of the NK cell
can transfer the killing signal. There receptors
recognize the a wide variety of carbohydrate ligands

共 111 页 第 55 页
 （A） （B）

MHC-I+ MHC-I-
cell cell

ogy
MHC-I
n ol
Not kill
m mukill KIR

u_I
xjm KAR
NK NK

two kind of the NKCR

共 111 页 第 56 页
Ø The adaptor
molecules contain
immunoreceptor
ogy
tyrosine-based
nol
activation motifs or
mmu
ITAMs.
u_I
j m
Ø ITAMs consist x
of
short homo- or
heterodimer tails which
extend into the
cytoplasm.

共 111 页 第 57 页
Ø Unlike KARs, KIRs do not
need to associate with
adaptor molecules.

Ø KIRs consist of long

cytoplasmic domains which
ogy
contain immunoreceptor
nol
tyrosine-based inhibition
mmu
motifs (ITIMs).
u_I
Ø j m
x than
ITIMs are longer
ITAMs. These additional
regions contain the elements
used for inhibitory signaling.

共 111 页 第 58 页
Ø NK cells express inhibitory receptors
y
l og
that are specific for MHCoclass I alleles
mun
Ø In humans these_ Im
molecules are p58 and
m u
j Killer Inhibitory Receptors
p70, knownxas
(KIRs).

共 111 页 第 1 页
Ø y
The effector function of an NK cell is
l og
n o
triggered by a balance between
u
opposite signals.
If both an inhibitorymm
u _I and activating signal is
detected the NKmcell
xj
will not be stimulated to kill.

共 111 页 第 60 页
Ø However, in the absence of appropriate

ogy
interaction between KIRs and MHCI, NK cells can

nol
exert their cytolytic function
Ø
u
Upon positive stimulus an NK cell will kill. An
mm
the cell. u_I
inhibitory signal MUST be present to "turn off"

xjm

共 111 页 第 61 页
 ogy
nol
mmu
u_I
xjm
Left) ITAM alone leads to activation.
Right) ITIM blocks ITAM action, leading to inhibition.

共 111 页 第 62 页
Function 1:NK cells can kill virus-infected cells
(hypothesis: balance between activating and stimulating receptors)

ogy
nol
mmu
u_I
xjm stress-induced
protein

healthy cell stressed cell

共 111 页 第 63 页
Virus-infected and tumor cells are able to
alter MHC-I expression. gyl o
Ø
un o
Infected cells can inhibit the synthesis of all
Im m
proteins. This decreases the amount of MHC-I
produced.
mu _
Ø xjalso selectively prevent the export
Viruses can
of MHC-I molecules.
Ø In each case, the number of MHC class I
molecules on the cell surface is decreased.

共 111 页 第 64 页
Ø Decreased MHC-I expression results in a
decrease in the number of KIR/MHC-I
interactions.
o g y
n o l
Ø What interactions mare
m u still present are
_I
insufficient to inhibit
u
NK cell triggering

x j m
Ø Thus, lack of expression completely, or
the
expression of MHC-I in inadequate amounts,
reduces inhibition signaling.

共 111 页 第 65 页
A B

n o l
mmu
u _I
jm to
Activating receptorxbound
KAR. Without enough MHC,
KIR can’t bind. NK cell only
receives activating stimulus,
which results in target cell
death.
o g y
Activating receptor bound to
KAR. When MHC is present
in adequate amounts, NK cell
receives BOTH activating
and inhibiting stimuli. Thus,
target cell death is averted.

共 111 页 第 66 页
 What’s
that? I
I know can’t
you – I’ll bind!
bind.

og y
n ol
mmu
u_I
“normal” MHC:protein m “altered” MHC:protein
xj
Infected cells can also change the proteins bound in
the MHC. One way is by glycosylation. If this occurs, the
MHC-I:protein complex the cell expresses will be altered.
KIRs can't bind to these "foreign" complexes, so no
inhibitory signal will be sent to the cell.

共 111 页 第 67 页
 ogy
nol
mmu
u_I
xjm

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Function 2: Cytotoxicity

o Antibody-Dependent Cell-Mediated Cytotoxicity

o g y
o
o l
Direct NK Cell-Mediated Cytotoxicity
n
mm
n Lack of cell surfaceIMHC
u Class I
u_
n Recognize x jm
cell-surface protein

o Influenza hemagglutinin

共 111 页 第 69 页
 o gy
nol Target cell
CD69 CD16
FcγRIIImmu
u_ I
CD2 m
xj
ADCC (antibody-dependent cell-mediated cytotoxicity)

共 111 页 第 70 页
 ogy
nol
mmu
u_I
xjm

共 111 页 第 71 页
 Antibody-Dependent
Cell-Mediated Cytotoxicity

ogy
nol
mmu
u_I
xjm

共 111 页 第 72 页
Direct NK Cell-Mediated Cytotoxicity

ogy
nol
mmu
u_I
xjm

共 111 页 第 72 页
 NK Cell

ogy
nol
mmu
u_I
xjm

Virus-infected Cell

共 111 页 第 74 页
Features of NK Cell-Mediated Cytotoxicity
o gy
o l
No priming, memory, specificity
n
No MHC Restriction mu
_
Response amplifiedI m
by certain cytokines
mu
IFN
IL-12
xj
IL-15

共 111 页 第 75 页
Induction of NK Cells During a Viral Infection

ogy
nol
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

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 ogy
nol
mmu
u_I
xjm

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CELL 3: eosinophil

ogy
nol
mmu
u_I
xjm

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EOSINOPHIL

ogy
nol
mmu
u_I
xjm

共 111 页 第 80 页
EOSINOPHIL

o (represent 1-3% of circulating WBCs)

o gy
Possess a bi-lobed nucleus and a heavily granulated
cytoplasm. n o l
m m u
u_ I
Granules stain orange/red with the acidic dye Eosin Y.

jm
Somewhat phagocytic but DO NOT act as APCs.
x of the eosinophil is believed to be
o The major role
against parasites, particularly parasitic worms.

共 111 页 第 81 页
EOSINOPHIL
o Eosinophils kill by ADCC [antibody dependent cell-
mediated cytotoxicity] by binding to parasite - specific
IgE via cell surface
ogy
FcεRs.
nol
mmu
o When eosinophils bind to IgE on the surface of a worm,

u_I
the cell is triggered to degranulate. The contents of the

xjm
granules cause damage to the worm's tegument. There
are many hydrolytic enzymes present in the granules
responsible for the anti-helminthic activity. One
component which is unique to the eosinophils - and
highly toxic to worms - is a substance known as Major
Basic Protein (MBP).

共 111 页 第 82 页
CELL 4 : BASOPHIL

ogy
nol
mmu
u_I
xjm

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BASOPHIL/MAST CELL
EM MORPHOLOGY

ogy
nol
mmu
u_I
xjm

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BASOPHIL

o Only present in the bloodstream, and represent <1%

of circulating WBC
o g y
no l
o
mu
Lobed nucleus--more variable,
m
large coarse granules

u _ I
stain blue with basic dye methylene blue.

o j m
x role in the allergic response when
They play a major
they release their granules (containing histamine,
serotonin, heparin, prostaglandin, etc into the
bloodstream following exposure to specific allergens).

共 111 页 第 3 页
 BASOPHIL
o Basophils bear Fc receptors for IgE (FcεRs)

o g y
o When an individual is exposed to an
no l allergen, allergen

m mu
specific IgE is produced. This IgE binds to the surface of

response]. u _ I
basophils [in the sensitization phase of the allergic

Upon re-exposure m
xjto the allergen, the allergen binds to IgE
on the surface of basophils resulting in degranulation
effector phase].

共 111 页 第 86 页
CELL 5 : MAST CELLS

o Mast cells are released from the bone marrow as

g
undifferentiated precursor cells and do not
o y
n o l
differentiate until they enter the tissues
(skin, connective tissue, mucosal epithelium, etc.)
m m u
o
u _
Morphology and function I similar to circulating
j m
basophils - but clearly
x
derived from a distinct cell
lineage.

共 111 页 第 87 页
CELL 5 : MAST CELLS
o Mast cells bear Fc receptors for IgE (FcεRs)
and contain large numbers of cytoplasmic
o
granules which also play a very g y
important role in
the allergic response.
u ol
n
I m m
o u_
They produce a variety
m of cytokines
x j
o TNF is produced and stored within the
cytoplasm of the mast cell, and it can be
released quickly following mast cell activation.

共 111 页 第 88 页
 ogy
nol
mmu
u_I
xjm

共 111 页 第 89 页
Component 3: Antibacterioidal substances of
the tissue and body fluids

Ø Complement is activated by either the classic

various peptides which havelo

y
pathway or alternative pathway and generates
g following
the
effects: un o
I m m
Cytolysis _Opsonization
Chemotaxis jmu
x

共 111 页 第 90 页
Component 3: Antibacterioidal substances of
the tissue and body fluids

Ø Lysozyme is a low molecular weight protein

found in relatively high concentration
o g y in
polymorphonuclear leukocytes
n l as well in most
oa mucolutic
tissue fluid. Its functionsuas
enzyme, splitting the I mm
cell wall (glyco-peptides)
+
mu_
j
of many G (Gram-positive bacteria), resulting
in their lysis.x It mainly act on G-(gram-negative
bacteria)

共 111 页 第 91 页
Component 3: Antibacterioidal substances of
the tissue and body fluids

ogy
Ø Interferon (IFN) has antiviral, anti-tumor and
immunomodulating functions
un ol
Imm
mu_
xj

共 111 页 第 92 页
Innate Immunity

g y
o A set of disease-resistance mechanisms that are
o
o l
present before the onset of infection and not specific
n
to a particular pathogen
m m u
u_I
o j m
x period just after the host’s exposure
- Respond immediately. It is the 1st line of defense
during the critical
to a pathogen.

共 111 页 第 93 页
Innate Immune Response

o A universal and evolutionarily conserved mechanism

ogy
of host defense against infection
nol
o A set of disease-resistance mechanisms that are
mmu
present before the onset of infection and not specific
u_I
to a particular pathogen
xjm
o First line of Defense
Respond immediately. It is the 1st line of
defense during the critical period just after the host’s
exposure to a pathogen

共 111 页 第 94 页
Innate Immune Response
o Predates the adaptive immune response
n Found in all multicellular organisms
ogy
nol
o Adaptive only in vertebrates

mmu
n Uses receptors and effectors that are ancient in
their lineage
u_I
pathogens xjm
n Must provide protection against a wide variety of

o Distinguishes self from non-self perfectly

o Defects in innate immunity are very rare and almost
always lethal

共 111 页 第 95 页
 ogy
nol
mmu
u_I
xjm

共 111 页 第 96 页
The Innate Immune Response:
Common Misconceptions

o
o g y
The innate immune system is an evolutionary
rudiment whose only function is to contain the
ol
infection until the “real” immune response can kick in.
n
mm u
o Adaptive immunity _
u I
developed because of the
j m
inflexibility of the nonclonal receptors used by the
x response. The innate system cannot
innate immune
cope with the high mutational rate and heterogeneity
of pathogenic organisms.

共 111 页 第 97 页
 og y
o The Innate immune system instructs the adaptive

n o
immune response to respond to l
microbial infection

m mu
u _I
o m
xj to respond or not respond to a
The major decision
particular ligand is decided by the genome-encoded
receptors of the innate immune system

共 111 页 第 98 页
Adaptive Immunity

o Occurs within 5 or 6 days after the initial exposure to an

Ag.
ogy
nol
o Displays a high degree of specificity.

m
in a memory response:mu
o Exposure to the same Ag some time in the future results

u_I
respond more quickly, stronger, and often more
jm
effective in neutralizing and clearing the pathogen.
x
o Lymphocytes & antibodies (Ab)

共 111 页 第 1 页
 ogy
nol
mmu
u_I
xjm

共 111 页 第 100 页
 Adapted from Medzhitov and Janeway
PAMP Cur. Opin. Immunol. 1997 9:4-9

Phagocytosis
Y PRR

APC
Complement Endosome

ogy Direct Bactericidal Activity

Pathogen-specific
Antibody
MHC

Y no
B7
l Phagocytosis
Oxygen burst

mmu Anti-microbial peptides

I
Naive Inflammatory

_
T Cell

u
and effector

xjm cytokines

Activated
CD40L, FasL, CD30L, CD27L
T Cell

B Cell

共 111 页 第 101 页
 ogy
nol
mmu
u_I
xjm

共 111 页 第 102 页
 ogy
Adaptive and innate immunity do not operate
ol
independently of each other; they function as a highly
n
mu
interactive and cooperative system, producing a total
m
u_I
response more effective than either could alone.

xjm

共 111 页 第 103 页
Innate Acquired
immediate specificity
amnesic memory

Inflammation
og y
nol
IL-18
mmu IFNγ
IL-15
u _I IL-17
x jm
IL-12, IL-23, IL-27

TNFα
IL-1

minutes hours days

共 111 页 第 104 页
 ogy
The major difference between the
ol
innate and adaptive immune
n systems
mmu
u_I
xjm

共 111 页 第 105 页
 Components

Innate Immunity Adaptive Immunity

o g y
n ol
physical barriers
skin, mucous membrane, mu
lung cilia,etc _ Im none

jm u soluble factors
x
complement, cytokines,etc Immunoglobulins
(antibody)
cells
phagocytes, NK cells, T and B lymphocytes,
etc APC

共 111 页 第 106 页
 ogy
nol
mmu
u_I
xjm

共 111 页 第 107 页
 ogy
nol
mmu
u_I
xjm

共 111 页 第 108 页
Recognition receptors in innate immunity

ogy
nol
mmu
u_I
xjm

共 111 页 第 109 页
Reviewing Question

1. What’s definition of immune immunity?

g y
2.illustrate the superficial marks on the membrane surface
o
of phagocytes.
nol
m m u
u _ I
3. what’s the biological activity of phagocytes?

x jm
4. Illustrate the Mechanisms of NK cell killing virus-infected
cells.
5. illustrate The major elements of the innate and adaptive
immune systems by using a table.

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