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.