Diagnostic Immunology
Topic: Immunological Tolerance
Objectives:
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Define Immunological tolerance
Discuss mechanism of tolerance induction
Know types of tolerance
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Central thymic
Peripheral post thymic
Explain B cell tolerance to self antigens
Discuss artificial induction of tolerance
Know therapeutic applications of tolerance
Immune tolerance or
immunological tolerance
is the process by which the immune system does
not attack an antigen.
 It can be either :
1) Natural' or 'self tolerance', where the body
does not mount an immune response to self
antigens.
2) Induced tolerance', where tolerance to
external antigens can be created by
manipulating the immune system.
 It occurs in three forms: central tolerance,
peripheral tolerance and acquired tolerance.
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Definitions:
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Tolerance is a state of unresponsiveness that is
specific for a particular antigen
Self tolerance is the mechanisms by which the
body is prevented from mounting an immune
response against its own tissues.
Self reactivity is prevented by processes during
development rather than being programmed.
Factors influencing tolerance
Molecule structure
 Stage of differentiation when
lymphocyte first encounter the epitopes
 The site of the encounter
 The nature of the cell presenting the
epitopes
 Number of responding lymphocytes
Q. What is an epitope?
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History
Trub (1938):
Inutero mice against choriomeningitis virus
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Medawar (1953)
Induced immunological tolerance to skin allograft
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Burnet (1957)
Clonal selection theory: Particular immunocyte is
selected by an antigen and then divides to give rise to
clone of daughter cells with the same specificity
Leaderburg (1959)
Modification of Clonal selection theory ( Stage of cell
maturation)
Key discoveries of (1960)
a)
Role of thymus in development of the immune system
a)
Existence of two interacting subsets of lymphocytes
Types of Tolerance
Central Tolerance :
It occurs during lymphocyte development.
[Thymus or Bone marrow]
 Peripheral Tolerance :
Occurs after lymphocytes leave the primary
organs.
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Central thymic Tolerance to Self Antigens
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The immune system generates a vast array of
TCRs
T cells are not only effector cells but are also
regulators of the immune system
T cells become “educated” in the thymus
They become dependant on self MHC for
survival
III-T cell development is subjected to several
checkpoints
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β selection checkpoint:
Only cells with a rearranged β chain mature from
double negative to double positive cells.
Independent on MHC
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α selection checkpoint:
Cells expressing an αβ complex must interact with
MHC molecules to survive
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Lineage commitment checkpoint:
Cells are instructed to repress expression of
either CD4 or CD8 and to develop into
single positive cells
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Negative selection checkpoint:
Cells that interact strongly with MHC and
antigen in the thymus are deleted
Peripheral or Post-Thymic Tolerance to Self
Antigens
Many auto-reactive T cells escape central tolerance
due to:
a)
Antigens are absent
b)
Antigens are insufficient
However, tolerance is maintained by mechanisms
in peripheral lymphoid organs
These mechanisms include:
1-Sequestration of antigens in some tissues:
Many self antigens are hidden in tissues that are anatomically
located away from T lymphocytes
2- Privileged sites are protected by regulatory
mechanisms:
Privileged sites include brain, testes and anterior champers of
the eye
In these sites lymphocytes are controlled by apoptosis or
cytokines such as TNFβ and IL10
3- T cell death can be induced by persistent activation
or neglect:
-Cells possess Fas receptor , when it cross-links with its ligand
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FasL it promote apoptopic cell death.
Activated lymphocyte will die by passive cell death (PCD)
when deprived from its antigen
4- Regulation by suppressive cytokines
IL-2 and IL-2 receptor regulate sensitivity to Fas mediated
apoptosis
Summary of peripheral post thymic mechanisms of
tolerance:
Thymus
Deletion
Sequestration
Antigen
hidden from
immune
system
Escape
Privileged
sites
Prevention
by Fas
and
cytokines
Deletion
By
activationinduced
Cell death
Immune
regulation
By
Suppressive
cytokines
B- Cell Tolerance to Self Antigens
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High affinity IgG production is T cell dependent
Lack of T cell leads to non-self reactivity by B
cells
Self reactive B cells either:
a)
b)
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Edit their receptors to become non-reactive
Die by the process of apoptosis
In peripheral B cell tolerance, self reactive cells
are removed by negative selection in the
spleen in a process that is similar to T cell
removal in the thymus.
B cell tolerance in the BM
During B cell development in the bone marrow:
 The complete antigen receptor (IgM) is first expressed
on 'immature' B cells
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If those cells encounter their target antigen in a form
which can cross-link their IgM then such cells are
programmed to die
The requirement for cross-linking means that the antigen
has to be polyvalent
Potential clinical applications for tolerance:
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Understanding of tolerance is valuable in many
ways:
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Promote tolerance to tissue graft
Control damaging immune response in
hypersensitivity
Control damaging in autoimmune disease
Limit tumor growth