immune tolerance
TRANSCRIPT
What is Immune Tolerance?
Immune tolerance refers to the state of
a biological system where there should
be an immune response, but there is
none
Tolerance refers to ‘a state of specific unresponsiveness’
to a specific antigen or failure to mount an immune response
to an antigen
it is an active response to a particular epitope and is just as
specific as an immune response
It is induced by prior exposure to that antigen
does not necessarily mean total lack of immune response
Antigens that induce tolerance are called ‘tolerogens’
Highly desirable Tolerance
Undesirable tolerance
In 19th Century, Paul Ehrlich coined the term ‘Horror
Autotoxicus’ means ‘horror of self toxicity’
it was realized that there must be a mechanism to prevent
auto antibody formation
a normal body does not mount immune response against its
own tissues
Implied the need for ‘regulating contrivance’ to stop
production of auto antibodies
Discovery of Immune tolerance•In 1938, Traub inoculated mice in Utero with lymphocytic choriomeningitis virus
•Resulted in symptomless, carrier state
•Virus was present in blood and other organs, but no antibody was produced
•If mature virus was inoculated, they produced antibody
•
Experiment contd…. Ray Owen was the first to observe the phenomenon of
immunological tolerance in vivo
He observed that non-identical dizygotic twin cattle shared
each other’s RBC through their common placenta
Each twin had its own red blood cells and a second set of
cells derived from the other twin
Neither twin made antibodies against the blood cells of the
other
Owen concluded that exposure of the immature immune
system to a foreign antigen resulted in specific tolerance to
that antigen
Burnet’s clonal selection
theory Following Owen’s observation, scientists Burnet and Fenner
postulated that age of animal at time of first encounter against
non-self antigen is a critical factor
Antigens encountered before birth result in deletion of specific
clones at some stage in early embryonic development (Clonal
deletion)
It means that if immune system encounters antigens, while it was
immature the relevant lymphocytes become tolerized
would ensure that
self-reactive antibody-forming cells are physically eliminated
before birth and
Only antibody-forming cells able to react to ‘not-self’ persist
Clonal selection
(1) A hemapoietic stem cell undergoes differentiation
and genetic rearrangement
(2) immature lymphocytes are produced with many
different antigen receptors
(3) Those that bind to antigens from the body's own
tissues are destroyed
(4) the rest mature into inactive lymphocytes
(5) those that encounter a foreign antigen are
activated
(6) Produce many clones of themselves
Medawar’s Experiment In 1953, Peter Medawar and his colleagues induced
immunological tolerance to skin allografts in mice by neonatal injection of allogenic cells
(grafts that are genetically non identical but are from same species)
The hypothesis was that “mammals and birds never develop, or develop to only a limited degree, the power to react immunologically against foreign homologous tissue cells to which they have been exposed sufficiently early in foetal life’’
Consistent with Burnet’s theory
Strain A mice normally rejects
graft from strain B
neonatal injection of spleen cells
from strain B into strain A
Newborn strain A mice show
tolerance to skin grafts from
strain B
but reject grafts from strain C
Lederberg’s modfication of
clonal theory Burnet’s hypothesis implied that all antibody-forming cells
(lymphocytes) are generated during fetal development
However, it soon became clear that lymphocytes are
generated throughout life
In 1959, Lederberg suggested modification of Burnet’s theory
States that, responsiveness is not determined by the
developmental stage of individual
Rather, It is the state of maturity of the lymphocytes at the
time of encountering antigen
According to this modification, if lymphocytes contact antigen
in its immature stage they are subjected to ‘clonal abortion’
(removal of immature lymphocytes that interact with
antigens, via cell death)
If encountered when in mature state, they become activated
The Danger Hypothesis
In 1994 Polly Matzinger suggested a new immunologic
model
states that the immune system does not distinguish between
self and nonself
discriminates between dangerous and safe by recognition of
pathogens or alarm signals from injured or stressed cells and
tissues
pathogen or cell-associated stress compounds, can induce
immune cells
Self vs non-self Immunological ‘SELF’ implies to all epitopes encoded by the
individual’s DNA
All others are considered non-self
Other factors that also determines self or non-self include
The stage of differentiation when lymphocytes first
encounter the epitopes
The site of the encounter
The nature of cells presenting the epitopes
The number of lymphocytes responding to the epitopes
Ways to prevent responding to self
Ag Five possible ways-
1. Self-reactive cells may be deleted at certain stages of
development
2. Self reactive cells may be unable to respond
3. Self- reactive T cells in circulation may ignore self Ags
4. Response to self Ag may be suppressed if the Ag is in a
privileged site
5. Tolerance can be maintained by immune regulation
Which of these mechanisms would work depends on
The stage of maturity of the lymphocyte
The affinity of the receptor for the self Ag
The nature of the Ag
Concentration of the lymphocyte
Tissue distribution of lymphocyte
Pattern of expression of lymphocyte
The kinds of tolerance Tolerance is classified into
1. Central tolerance: tolerance of T or B cells induced in
during development in the primary lymphoid organs (the
bone marrow for B cells and the thymus for T cells)
2. Peripheral tolerance: induced in other tissues and lymph
nodes
The mechanisms by which these forms of tolerance are
established are distinct, but the resulting effect is similar.
Central tolerance of T cells takes place during their
development within the thymus
depends on a number of checkpoints through which cells
have to pass in order to develop
The process of generating new T cell receptors involves
gene rearrangement to generate a highly diverse T cell
receptors
Such a broad variety is necessary to provide protection
against different infectious agents
Stages of T cell
Development Double Negative (DN) stage
Double Positive (DP) Stage
Single Positive (SP) stage
Double Negative (DN)
Stage Immature T cells enter the thymus and express neither
CD4 nor CD8 co-receptors, hence called double
negative (DN) cells
The TCR b chain genes start recombination
Double Positive (DP) Stage expression of both CD4 and CD8 co-receptors occurs
T cells mature into CD4 and CD8 Double positive (DP)
cells
α chain rearrangement initiates
TCR structure is completed
These cells come into contact with cortical thymic epithelial
cells that express high levels of class I and class II MHC
molecules on their surface
These self-MHC molecules present self-peptides, which are
derived from intracellular or extracellular proteins that are
degraded in the normal course of cellular metabolism
Thymic Selection of the T cell
Repertoire Cells undergo two selection Processes-
1. Positive Selection
2. Negative Selection
Cells whose TCR fail to interact with MHC-self peptide
molecules undergo programmed cell death (Death by
neglect)
Cells that bind too strongly to MHC/self-peptide complexes,
also die
Only cells that recognize MHC molecules with moderate/low
affinity survive (positive selection) Some are able to rescue failed positive selection by receptor
editing
positive selection ensures that T cells recognize antigen only
in association with MHC
Positive selection
Negative selection
Selected cells then mature to (SP) single positive (CD4 or
CD8) T lymphocytes and migrate to the medulla
those that bind with high affinity with self-peptide-MHC
complexes are induced to undergo apoptosis (clonal
deletion)
Results in self-tolerance After negative selection, these SP cells pass from the thymus
into the circulatory system
Only 2% to 5% of DP thymocytes actually exit the thymus as
mature T cells
investigations in the late 1990s revealed that the thymus had
an extraordinary capacity to express and present proteins
from all over the body
some medullary epithelial cells of Thymus express a unique
protein, AIRE, that allows cells to express, process, and
present proteins that are ordinarily only found in other
specific organs
Aire promotes the expression of organ-specific genes in
medullary thymic epithelial cells (mTECs)
These organ-specific proteins are presented on the surface
of mTECs by MHC molecules to T cells developing in the
thymus
Thymocytes that recognize these organ-specific proteins in
the context of MHC molecules undergo negative selection
Medullary dendritic cells can acquire these antigens by
engulfing mTECs, and mediate negative selection
The role of Aire is therefore to limit the generation of self
reactive T cells
Aire Protein
Checkpoints in T cell
development b selection checkpoint- only cells with a rearranged b chain
mature from DN to DP
a selection checkpoint- cells expressing ab chains must
interact with MHC to survive
Lineage commitment checkpoint- cells must repress
expression of CD4 or CD8 to develop into SP cells
Negative selection checkpoint-cells that interact with
MHC-self molecules are deleted
The decision to undergo positive or negative selection is directly related to the avidity of TCR for a particular MHC-peptide complex
This depends on
The level of expression and stability of the MHC-peptide on APC
Affinity of TCR for this complex
Low avidity interaction promotes positive selection
High avidity interaction promotes negative selection
Experiment shows that the same peptide will induce positive selection at low concentration and negative selection at high concentration
Avidity Model of Thymic
Positive and Negative Selection
Also depends on-
The architecture of thymus
The nature of APCs in the cortex vs the medulla
The type of Ag that these cells can present
Other Mechanisms of Central
Tolerance Clonal arrest: thymocytes that express autoreactive T-cell
receptors are prevented from maturation
clonal anergy: autoreactive cells are inactivated, rather than
deleted
clonal editing: autoreactive cells are given a second or third
chance to rearrange a TCR gene
clonal deletion is probably the most common mechanism
responsible for thymic negative selection.
factors that promote tolerance
fetal exposure
High doses of antigen
Long-term persistence of antigen in the host
Intravenous or oral introduction
Absence of adjuvants (compounds that enhance
the immune response to antigen)
Low levels of costimulation
Presentation of antigen by immature or
unactivated antigen-presenting cells (APCs)
Escape from central tolerance
Two factors contribute to this
(1) not all self antigens are expressed in the central lymphoid
organs where negative selection occurs, and
(2) there is a threshold requirement for affinity to self antigens
before clonal deletion is triggered
Mature self-reactive lymphocytes that recognize
self antigens in peripheral tissues are
inactivated, killed or suppressed
Sequestration
Self Ag may be sequestered in some tissues and will never
be available to T-cells
allows these antigens to avoid encounter with reactive
lymphocytes under normal circumstances;
Two ways
1. Physical barrier: location of antigen in privileged sites
2. Immunological barrier: never processed by functional APCs
Privileged sites
Cells ignore self antigens if they are expressed in
Immunologically privileged sites
The brain
the anterior chamber and lens of the eye
testes
In these sites pro-inflammatory lymphocytes are controlled
by
Apoptosis
Cytokine secretion
Apoptotic cell death
Extremely important for maintaining immune homeostasis in
healthy individuals
by two mechanisms
1. Activation induced cell death (AICD): deletion of cells
with high avidity for Ag
2. Programmed cell death (PCD): deletion of cells when
immune response is no longer required
Activation-Induced Cell Death
(AICD) External stimulus mediates apoptosis
T-cells having unusually high avidity for antigen are killed this
way
Mediated by ligation between Fas-receptor and Fas-ligand
(FasL)
Interaction between Fas and FasL activates signal that
induce apoptosis in cells
people with mutated Fas or FasL suffer from autoimmune
lymphoproliferative syndrome (ALPS)
IL-2 stimulates Fas mediated AICD by enhancing
transcription of FasL
AICD can be fratricidal or suicidal
For example, The epithelial cells lining the anterior chamber
of eye express Fas Ligand (FasL)
allows interaction with T-cells expressing Fas (CD95)
Induce apoptosis of T-cells
The fluid of the anterior chamber contains cytokines, eg.,
Transforming Growth factor b (TGF b)
Homeostasis
Balance of signals in T-cell
activation
•Signal 1: TCR-MHC-peptide interaction
•Signal 2: Ligation between co-stimulatory
molecules CD28 and B7 (CD80 & CD86)
•Expression of CTLA-4 on T-cell blocks B7
•and reduce the auto reactivity of T-cells
•T-cell activation is a competition between
stimulating and inhibiting signals
Kidney cells do not express the costimulatory ligands
required for activating a CD4 or a CD8 T cell
if a T-cell specific for a peptide made by a kidney cell
escaped from the thymus, it will not be activated unless that
peptide were presented on a professional APC
a high-affinity interaction with MHC/peptide combinations on
the surface of kidney cell, in the absence of costimulatory
ligands, could result in T-cell anergy
APC TCR
T cellCD28
ActivatedT cells
APC TCR
Functionalunresponsiveness
Normal T cellresponse
Anergy
Apoptosis(activation-inducedcell death)APC
Deletion
APC
Block inactivation
Suppression
RegulatoryT cell
Peripheral tolerance
Off signals
ActivatedT cell
APCTCR
NaïveT cell
Immunogenic antigen
(microbe, vaccine)
Tolerogenic antigen (e.g.
self)
Effector and memory cells
Tolerance: functional inactivation or cell death,
or sensitive to suppression
Antigen (peptide + HLA): signal 1
Costimulation (signal 2)
Peripheral tolerance 58
Dendritic cells in peripheral
tolerance
Dendritic cells uptake antigens in their immature state, but
can’t present to T cells
Present antigen to T-cells only when they are mature
Activate T-cells
HOWEVER- if immature dendritic cell process and present
antigen to T-cell, it leads to
Anergy (unresponsiveness)
Deletion by apoptosis
Generation of regulatory T-cells
This never happens with non-self antigens, however-
because non-self antigens induce maturity of DC
Regulatory T cells (TREG cells)
Act in secondary lymphoid tissues and at sites of
inflammation
TREG cells recognize specific self antigens, and sometimes
foreign antigens
they down-regulate immune processes when engage with
these antigens in the periphery
Regulatory CD4+ T cells
Can be generated
naturally in the thymus (nTREG cells), and
after induction by antigen in the periphery (iTREG cells)
Some scientists postulate that
nTREG cells regulate responses against self antigen to
inhibit autoimmune disease
iTREG cells control reactions against benign foreign
antigens at mucosal surfaces
nTreg cells arise from a subset of T cells expressing receptors with
intermediate affinity for self antigens in the thymus
some of these cells upregulate the transcription factor FoxP3
and migrate out of thymus
Suppress reaction to self antigens
Characterized by expression of the a chain of the IL-2
Receptor (CD25)
Whether cells will die by negative selection or
develop into nTreg determined may be by
the binding of CD28 with CD80/86 or
Binding of CD40 with CD40L or the
presence of certain cytokines
FoxP3, is also imprortant for induction of
immunosuppressive function,
Mechanisms of TREG cells
both contact-dependent and contact independent processes have
been observed
1. kill APCs or effector T cells directly, by using granzyme and
perforin
2. TREG cells express high levels of CTLA-4 which interact with
CD80/86 on an APC and inhibit APC function
3. These APCs begin to express soluble factors (including
indoleamine-2,3-dioxygenase) that inhibit local immune cells
4. TREG cells also secrete immune inhibitory cytokines, such as IL-
10, TGF-a, and IL-35, suppressing the activity of other nearby T
cells and APCs
5. TREG cells express only the low-affinity IL-2R (CD25) but not the
or subunits, which are required for signal transduction
6. they can absorb this growth and survival-promoting cytokine and
discourage expansion of local immunostimulatory effector T cells.
Normlly, TREG cells inhibit
APCs presenting their cognate antigen or
effector T cells that share their same antigen specificity
Do not inhibit T cells with a different specificity
However, CD4 Treg cells inhibit T cells recognizing other
antigens, when both the TREG cell and the second T cell
recognizing another antigen interact with the same APC
Regulatory CD8+ T cells
use a range of mechanisms to inhibit other cells
from responding to antigen
three main pathways seem to exist:
APC lysis,
Inhibition of APC function, and
regulation of effector T cells that share cognate
antigen with the CD8 TREG cell.
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Developmental checkpoints for
B cells
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Central Tolerance
Tolerance begins when IgM appears on B
cell
eliminate approximately 90% of the self-
reactive B cell pool
Different mechanisms
Receptor editing
Clonal deletion
Clonal anergy
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•replaces self reactive receptor with new, non-autoreactive
receptor
•When the IgM receptor on an immature B cell reacts with self
antigen further cell differentiation is blocked, but light chain
rearrangement can continue
•permits the B cell to edit its receptor and rescue potentially
auto-reactive cells from death
•if receptor editing fails they are eliminated by apoptosis (Clonal
deletion)
Receptor editing of B cells
Clonal anergy of B cells
autoreactive B cells that recognize soluble self antigens
within the bone marrow may do not die
their ability to express IgM on surface is lost
They survive to escape the bone marrow, migrate to
periphery only expressing IgD, which are unable to
respond to antigen
These B cells are called anergic B cells
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B cell self tolerance: clonal deletion
Immature
B cell recognises
MULTIVALENT
self Ag
B
Clonal deletion by
apoptosis
YYBImmature
BB
Small
pre-B
Small pre-B cell
assembles Ig
B cell self tolerance: anergy
B
B
Anergic B cell
IgD normal IgM low
Immature
B cell recognises
soluble self Ag
No cross-linking
YYB
Immature
BB
Small
pre-B
Small pre-B cell
assembles Ig
IgM
IgD
IgD
IgD
Receptor editing
A rearrangement encoding a self specific receptor can be replaced
V CD JVV V
BB!!Receptor
recognises
self antigen!!
B Apoptosis
or anergy
BBEdited receptor now recognises
a different antigen and can be
rechecked for specificity
CD JVV VV
Arrest development
And initiate
receptor editing
Peripheral tolerance
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Clonal deletion in spleen
B cells leaving the bone marrow are relatively immature
These cells migrate from the bone marrow to the outer T cell
zone of the spleen
immature B cells are classified into two subpopulations of
transitional B cells based on their cell-surface expression
of immunoglobulin receptors and membrane markers
T1: mIgMhigh, mIgDlow
T2: mIgMlow, mIgDhigh
These transitional B cells act sequentially as the precursors
to the fully mature B cell
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•In T-cell zone, T1 cells will
mature into the T2 state
•T2 B cells are then able to
enter the follicles nd develop
into mature, B cells
the most significant amount of negative selection takes
place in these cells
If T1 B cells encounter multivalent self antigen they are
eliminated by apoptosis
in healthy adults, fully 55% to 75% of immature B cells
are lost by this process
once the B cell has matured into a T2 transitional B cell,
it becomes resistant to antigen-induced apoptosis
These T2 cells also express BAFF-R, the receptor for
the B-cell survival factor
receive stimulatory survival signal survive (Positive
selection)
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Somatic hypermutation Somatic hypermutation is a cellular
mechanism by which immune systemadapts to new foreign elements thatconfronts it. (e.g. microorganism)
It diversifies B cell receptors used torecognize foreign elements. (e.g.antigen) and allows to adapt immuneresponse to new threats.
It involves mutation affecting V regionsof Ig genes.
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When B cells recognizes any antigen, theyproliferate and during this proliferation,BCR (B Cell Receptors) genes undergoextremely high rate of somatichypermutation (105-106 fold greater thannormal mutation rates).
Somatic hypermutation occurs inhypervariable region (CDR).
Via hypermutation, B cells expressreceptors possessing enhanced ability torecognize and bind specific Ag.
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Somatic hypermutation
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Process of somatic hypermutation
Antigen-activated B cells differentiate into
centroblasts that undergo clonal expansion in
the dark zone of the germinal centre.
During proliferation, somatic hypermutation
(SHM) induces base-pair changes into the
V(D)G region of the rearranged genes
encoding the immunoglobulin variable region
of the heavy and light chain, some of these
base-pair mutations lead to a change in the
amino-acid sequence.
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Centroblasts then differentiate into centrocytes
and move to the light zone, where the
modified antigen receptor, with help from
immune helper cells including T cells and
follicular dendritic cells (FDCs), is selected for
improved binding to the immunizing antigen.
Newly generated centrocytes that produce an
unfavorable antibody undergo apoptosis and
are removed. A subset of centrocytes
undergoes immunoglobulin class-switch
recombination (CSR).
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Cycling of centroblasts and centrocytes
between dark and light zones seems to
be mediated by a chemokine gradient,
presumbly established by stromal cells
in the respective zones. Antigen-
selected centrocytes eventually
differentiate into memory B-cells or
plasma cells.
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B-cell response to thymus-
dependent (TD) antigen
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T-cell derived soluble factors that influence clonal
expansion and maturation
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Class switching Class switching mainly occurs to produce
antibody of identical specificity (same Ag bindingregion or CDR) but different Ig isotype (differentheavy chain).
Class switching depends on three factors:
i) Switch region: DNA flanking regions withmultiple copies of short repeat (2-3 kbupstream).
ii) Switch recombinase: A protein or system ofprotein that carries out DNA recombination andrecognizes switch region.
iii) Switch factor: Cytokine signals from helper Tcells that dictates the isotype to which B cellswitches.
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Class switching
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Events of class switching
Antigenic stimulation
Cytokine release
Heavy chain DNA undergoes rearrangement
V(D)J combines to any CH segment, according
to the cytokine signal, with the help of switch
region and switch recombinase
Class switching and new heavy chain
transciption
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RNA processing to produce Ig
heavy chain
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Experimental induction of
tolerance
Protein product encoded by ‘transgene’
is treated by immune system as auto
antigen and its effects can be studied ‘in
vivo’ without trauma and inflammation
associated with grafting foreign cells or
tissues.
Parent strain and transgenic strain ideal
for control experiments because they
are congenic (differ at only one locus)
Experimental induction of
tolerance
Also, by using targeted mutagenesis ,
immunologists can ‘knock out’ specific
genes to study the role of their gene
products during immunological
tolerance.
Tolerance can be induced with soluble antigens, when rabbits are injected with bovine serum albumin (BSA) without adjuvant at birth and fail to make antibodies against this protein later in life
Medawar investigated the effects of transferring haemopoietic cells from histoincompatible mice at different times after birth.
He found that if the cells were transferred in the first few days of life (but not later) the recipient mouse acquired lifelong tolerance to the antigens of the donor
Experimental induction of
tolerance The modified theory was later proved
experimentally
Transgenic methods used to investigate self
tolerance
Introduction of specific gene into mice of defined
genetic background and to analyse its effects upon
development of immune system
If introduced gene is linked to tissue-specific
promoter, its expression is confined to specific cell
types
Factors
The stage of differentiation when
lymphocytes first confront the epitopes
The site of encounter
The nature of cells presenting epitopes
The number of cells responding to the
epitopes
Importance of induced
tolerance to protect us from unpleasant, even dangerous, allergic
reactions to such things as food (e.g. peanuts), insect
stings, grass pollen (hay fever)
to enable transplanted organs (e.g., kidney, heart, liver) to
survive in their new host (graft rejection)
to reveal the mechanisms of autoimmunity for designing
treatments for systemic lupus erythematosus (SLE) and
multiple sclerosis (MS)
Major factors affectingTolerance
Ag processing Properly
proceesedImproperly processed
Programmed Cell Death
AKA death by neglect
LACK of external stimuli induces apoptosis
Mediated by cytochrome c release from mitochondria
How do we know this? Because mice lacking components of this pathway suffer from a serious developmental disease of the CNS where brain tissues protrude out of forehead
APAF-1
Steps in PCD
A variety of apoptotic stimuli cause cytochrome c to be expelled from mitochondria into the cytoplasm
Cyt. C associates with APAF-1
APAF-1 undergoes some conformational changes, allowing dATP/ATP to attach to it
This leads to the formation of apoptosome
Apoptosome recruits and activates caspase-9
This triggers the caspase apoptotic pathway
Summary
Regulation of AICD and
PCD Independently regulated
FLIP (FLICE inhibitory protein, FLICE is something similar to FADD) binds to FADD or pro-caspase-8 to block AICD
IL-2 enhances transcription and expression of FasL and shuts down FLIP to increase AICD
BCL-2 antideath proteins bind to different proteins in PCD pathway to block PCD
Experiment for clonal deletion
H-2Kb is a foreign MHC class I molecule.
MET-Kb transgenic: Non-b haplotype mice
that were given the gene for H2-Kb. As the
gene was controlled by the metallothionein
promoter (specific for such sites as the
liver), they were called MET-Kb transgenic.
Anti-Kb Ig transgenic: Non-b mice, which
had been given the genes for anti- H2-Kb
antibodies (anti-Kb in short).
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Double transgenic: contains genes for both H-2Kb antigen and Anti-Kb antibody. The result wasto be the production of self reactive B cells foranti-Kb Ig.
Double transgenic offspring expressed H-2Kb inthe liver and exported B cells specific for H-2Kbfrom the bone marrow.
However, these self-reactive B cells werepartially deleted in the spleen and entirelydeleted in the lymph nodes and thus noautoantibody was produced – no idiotypecorresponding to the anti-Kb Ig was detectable.
Conclusion: In peripheral B cells, tolerancewas induced by clonal deletion.
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Experiment for clonal anergy
HEL (Hen Egg Lysozyme) transgenic: Amouse was given the HEL gene linked to atissue specific promoter. The HEL (largelysoluble) induced B cell and T cell tolerance.
Anti-HEL Ig transgenic: A second transgenic line (anti-HEL Ig) carried rearranged heavy and light chain genes encoding a high-affinity HEL antibody.
An allotypic marker (IgHa) distinguished this from endogenous immunoglobulin (IgHb).
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The majority of B cells in these transgenics
carried IgM and IgD of the ‘a’ allotype.Double
transgenic offspring were highly HEL
tolerant, producing neither anti-HEL antibody
nor antibody-secreting B cells.
Conclusion: HEL-binding (self reactive) B
cells were not, however, deleted, but had
downregulated surface IgM, but not IgD,
receptors. They behaved as anergic cells.
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TH1 and TH2 suppress each
other Cytokines secreted by TH1: IFNgamma, TNFalpha
etc.
Cytokines secreted by TH2: IL-4, IL-5, IL-6, IL-10
etc.
IFNgamma prevents production of TH2 cells
IL-10 downergulates macrophage effector
functions e.g. Ag presentation to TH1
Case in point: DTH
Delayed-type hypersensitivity involves local
accumulation of a LOT of non-specific immune
cells like macrophages
“Delayed” because it takes a while (2-3 days) for
the reaction to develop
“Hypersensitivity” because it causes tissue
damage
AKA type IV hypersensitivity
Simplified mechanism of
DTH Involves a lot of cytokines
TH1-secreted cytokines cause extravasation,
drawing in macrophages
Activated macrophages present Ag more
efficiently, activating more TH1
TH1 in turn secretes more cytokines to activate
and draw in macrophages
This positive feedback is very powerful, like a
chain reaction
Luckily…
Cytokines secreted by TH2 turns off macrophage
effector functions, one of which being Ag
presentation to T-cells
This is an excellent example of how immune
regulation is crucial to induce desirable tolerance.