Diagnostic ImmunologyDiagnostic Immunology

Topic: Topic: Immunological ToleranceImmunological Tolerance

Objectives:Objectives: Define Immunological toleranceDefine Immunological tolerance Discuss mechanism of tolerance inductionDiscuss mechanism of tolerance induction Know types of toleranceKnow types of tolerance

Central thymicCentral thymic Peripheral post thymicPeripheral post thymic

Explain B cell tolerance to self antigensExplain B cell tolerance to self antigens Discuss artificial induction of toleranceDiscuss artificial induction of tolerance Know therapeutic applications of toleranceKnow therapeutic applications of tolerance

Immune toleranceImmune tolerance or or immunological toleranceimmunological tolerance

is the process by which the is the process by which the immune systemimmune system does not attack an does not attack an antigenantigen. .

It can be either :It can be either :1) Natural' or 'self tolerance1) Natural' or 'self tolerance', where the ', where the

body does not mount an immune response body does not mount an immune response to self antigens.to self antigens.

2) Induced tolerance2) Induced tolerance', where tolerance to ', where tolerance to external antigens can be created by external antigens can be created by manipulating the immune system.manipulating the immune system.

It occurs in three forms: central tolerance, It occurs in three forms: central tolerance, peripheral tolerance and acquired peripheral tolerance and acquired tolerance.tolerance.

DefinitionsDefinitions::

ToleranceTolerance is a state of unresponsiveness is a state of unresponsiveness that is specific for a particular antigenthat is specific for a particular antigen

Self toleranceSelf tolerance is the mechanisms by which is the mechanisms by which the body is prevented from mounting an the body is prevented from mounting an immune response against its own tissues.immune response against its own tissues.

Self reactivitySelf reactivity is prevented by processes is prevented by processes during development rather than being during development rather than being programmed. programmed.

Factors influencing toleranceFactors influencing tolerance

Molecule structureMolecule structure Stage of differentiation when Stage of differentiation when

lymphocyte first encounter the lymphocyte first encounter the epitopesepitopes

The site of the encounterThe site of the encounter The nature of the cell presenting the The nature of the cell presenting the

epitopesepitopes Number of responding lymphocytesNumber of responding lymphocytes

Q. What is an epitope?Q. What is an epitope?

HistoryHistory TrubTrub (1938):(1938):

InuteroInutero mice against choriomeningitis virus mice against choriomeningitis virus

MedawarMedawar (1953) (1953)

Induced immunological tolerance to skin allograftInduced immunological tolerance to skin allograft

Burnet Burnet (1957)(1957)

Clonal selection theory:Clonal selection theory: Particular immunocyte is Particular immunocyte is selected by an antigen and then divides to give selected by an antigen and then divides to give rise to clone of daughter cells with the same rise to clone of daughter cells with the same specificityspecificity

LeaderburgLeaderburg (1959) (1959)

Modification of Clonal selection theory ( Stage of Modification of Clonal selection theory ( Stage of cell maturation)cell maturation)

Key discoveries ofKey discoveries of (1960) (1960)

a)a) Role of thymus in development of the immune Role of thymus in development of the immune systemsystem

a)a) Existence of two interacting subsets of Existence of two interacting subsets of lymphocyteslymphocytes

Types of ToleranceTypes of Tolerance

Central ToleranceCentral Tolerance : :

It occurs during lymphocyte It occurs during lymphocyte development. development.

[Thymus or Bone marrow][Thymus or Bone marrow] Peripheral Tolerance Peripheral Tolerance ::

Occurs after lymphocytes leave the Occurs after lymphocytes leave the primary organs. primary organs.

Central thymic Tolerance to Self Central thymic Tolerance to Self AntigensAntigens

The immune system generates a vast The immune system generates a vast array of TCRsarray of TCRs

T cells are not only effector cells but are T cells are not only effector cells but are also regulators of the immune systemalso regulators of the immune system

T cells become “educated” in the thymusT cells become “educated” in the thymus

They become dependant on self MHC for They become dependant on self MHC for survivalsurvival

III-T cell development is subjected to several III-T cell development is subjected to several checkpoints checkpoints

ββ selection checkpoint: selection checkpoint:Only cells with a rearranged Only cells with a rearranged ββ chain mature chain mature

from double negative to double positive from double negative to double positive cells. cells. Independent on MHCIndependent on MHC

αα selection checkpoint: selection checkpoint:Cells expressing an Cells expressing an αβαβ complex must complex must

interact with MHC molecules to surviveinteract with MHC molecules to survive

Lineage commitment checkpoint:Lineage commitment checkpoint:Cells are instructed to repress expression Cells are instructed to repress expression

of either CD4 or CD8 and to develop of either CD4 or CD8 and to develop into single positive cellsinto single positive cells

Negative selection checkpoint:Negative selection checkpoint:Cells that interact strongly with MHC and Cells that interact strongly with MHC and

antigen in the thymus are deletedantigen in the thymus are deleted

Peripheral or Post-Thymic Tolerance to Peripheral or Post-Thymic Tolerance to Self AntigensSelf Antigens

Many auto-reactive T cells escape central Many auto-reactive T cells escape central tolerance due to:tolerance due to:

a)a) Antigens are absentAntigens are absentb)b) Antigens are insufficientAntigens are insufficient

However, tolerance is maintained by However, tolerance is maintained by mechanisms in peripheral lymphoid mechanisms in peripheral lymphoid organsorgans

1-Sequestration of antigens in some 1-Sequestration of antigens in some tissues:tissues:

Many self antigens are hidden in tissues that are Many self antigens are hidden in tissues that are anatomically located away from T lymphocytesanatomically located away from T lymphocytes

2- 2- Privileged sites are protected by regulatory Privileged sites are protected by regulatory mechanismsmechanisms::

Privileged sites include brain, testes and anterior Privileged sites include brain, testes and anterior champers of the eyechampers of the eye

In these sites lymphocytes are controlled by apoptosis or In these sites lymphocytes are controlled by apoptosis or cytokines such as TNFcytokines such as TNFββ and IL10 and IL10

These mechanisms include:These mechanisms include:

3- T cell death can be induced by persistent 3- T cell death can be induced by persistent activation or neglect:activation or neglect:

--Cells possess Fas receptor , when it cross-links with its Cells possess Fas receptor , when it cross-links with its ligand FasL it promote apoptopic cell death.ligand FasL it promote apoptopic cell death.

- Activated lymphocyte will die by passive cell death Activated lymphocyte will die by passive cell death (PCD) when deprived from its antigen(PCD) when deprived from its antigen

4- Regulation by suppressive cytokines4- Regulation by suppressive cytokinesIL-2 and IL-2 receptor regulate sensitivity to Fas IL-2 and IL-2 receptor regulate sensitivity to Fas

mediated apoptosismediated apoptosis

Summary of peripheral post thymic Summary of peripheral post thymic mechanisms of tolerancemechanisms of tolerance::

Thymus

Deletion Escape

Immune regulation

BySuppressive

cytokines

DeletionBy

activation-induced

Cell death

SequestrationAntigen

hidden from immune system

Privileged sites

Prevention by Fas

and cytokines

B- Cell Tolerance to Self AntigensB- Cell Tolerance to Self Antigens

High affinity IgG production is T cell High affinity IgG production is T cell dependentdependent

Lack of T cell leads to non-self reactivity Lack of T cell leads to non-self reactivity by B cellsby B cells

Self reactive B cells either:Self reactive B cells either:a)a) Edit their receptors to become non-reactiveEdit their receptors to become non-reactiveb)b) Die by the process of apoptosisDie by the process of apoptosis

In peripheral B cell toleranceIn peripheral B cell tolerance,, self reactive self reactive cells are removed by negative selection in cells are removed by negative selection in the spleen in a process that is similar to T the spleen in a process that is similar to T cell removal in the thymus.cell removal in the thymus.

B cell tolerance in the BMB cell tolerance in the BM

During B cell development in the bone marrow:During B cell development in the bone marrow: The complete antigen receptor (IgM) is first The complete antigen receptor (IgM) is first

expressed on 'immature' B cellsexpressed on 'immature' B cells

If those cells encounter their target antigen in a If those cells encounter their target antigen in a form which can form which can cross-linkcross-link their IgM then such their IgM then such cells are programmed to diecells are programmed to die

The requirement for cross-linking means that the The requirement for cross-linking means that the

antigen has to be antigen has to be polyvalentpolyvalent

Potential clinical applications for Potential clinical applications for

tolerancetolerance::

Understanding of tolerance is valuable in Understanding of tolerance is valuable in many waysmany ways:: Promote tolerance to tissue graftPromote tolerance to tissue graft Control damaging immune response in Control damaging immune response in

hypersensitivityhypersensitivity Control damaging in autoimmune diseaseControl damaging in autoimmune disease Limit tumor growthLimit tumor growth