Dr. Fadwah Al-Ghalib
Diagnostic Immunology
3rd Year
3rd Yr Diagnostic Immunology
Dr. Fadwah Alghalib
IMMUNOLOGICAL TOLERANCE
Read Chapter 12 in Roitt's Book of immunology
OBJECTIVES:
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What is immunological tolerance?
Historical background,
Mechanism of tolerance induction
Types of Tolerance : Central and peripheral tolerance
B cell tolerance to self antigens
Artificial induction of tolerance
Therapeutic applications of tolerance
-----------------------------------------Immunological tolerance is the failure to mount an immune response to an antigen. It
can be:
o Natural or "self" tolerance. This is the failure (a good thing) to attack the
body's own proteins and other antigens. If the immune system should respond
to "self", an autoimmune disease may result.
o Induced tolerance. This is tolerance to external antigens that has been created
by deliberately manipulating the immune system. Its importance: (allergic
reactions, to avoid graft rejection, To stop the mechanism of autoimmunity).
Tolerance prevents harmful reactivity against the body's own tissue.
Definitions:
Tolerance: is a state of unresponsivness that is specific for a particular antigen.
Self tolerance: it is an aspect of tolerance that prevents the body from mounting an
immune attack against its own tissue.
Self reactivity:
is prevented during development rather than being genetically
programmed.
Factors that influence Tolerance:
1- Molecular structure
2- The stage of differentiation when lymphocytes first confront their epitopes
3- The site of the encounter
4- The nature of the cells presenting epitopes
5- The number of lymphocytes responding to the epitopes.
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Dr. Fadwah Al-Ghalib
Diagnostic Immunology
3rd Year
Historical Background:
1- Traub (1938): induced specific tolerance by inoculating mice in utero with
lymphocytic choriomeningitis
virus producing an infection that was
maintained throughout life, they did not produce neutralizing antibodies when
challenged with the virus in adult life.
2- Medawar (1953): induced immunological tolerance to skin allografts in mice
by neonatal injection of allogenic cells. (See fig 1.1 )
(Fig -1.1)
3- Burnet (1957): Clonal selection:
A particulate immunocyte (a particular B or T cell) is selected by antigen and
then divides to give rise to a clone of daughter cells, all with the same
specificity.
According to this theory, antigens encounter after birth activate specific
clones of lymphocytes, whereas when antigens are encountered before birth,
results in the deletion of the clones specific for them.
4- Leaderburg (1959):
modification of the clonal selection theory. [ immature
lymphocyte
contacting antigen would be subjects to clonal abortion whereas mature cells
would be activated.
5- Key discoveries in 1960s:
a. Crucial role of the thymus in the development of the immune
system.
b. The existing of the two interacting subsets of lymphocytes (T
cell & B cells).
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Dr. Fadwah Al-Ghalib
Diagnostic Immunology
3rd Year
A ) T-Cell Central Tolerance:
1. T cells develop in the thymus
2. The immune system generates a vast array of TCRs.
3. T cells are not only effector cells but are also regulators of the immune system.
4. T cell become educated in the thymus and become dependent on self MHC for
survival.
5. T cell development involves positive and negative selection and lineage
commitment. (See figure 12.3 in Roitt's Book)
T cell selection is compartmentalized in the thymus:
a. Immature lymphocytes are found in the cortical region associated with
cortical epithelial cells.
b. In the outer cortex cells are proliferating immature cells
c. In the inner cortex are more mature double positive (DP) cells under-going
positive selection.
d. The medulla contains mature single positive (SP) lymphocytes, medullary
epithelial cells and bone marrow derived macrophages and dendritic cells.
Q 1: How could the thymus express all the antigens that a T cell might encounter outside
the thymus?
T cell development is subjected to several checkpoints:
1-  selection checkpoint:
Only cells with a rearranged  chain mature from double negative to double positive cells.
It is Independent on MHC.
2-  selection checkpoint:
Cells expressing an  complex must interact with MHC to survive.
3- Lineage commitment checkpoint:
Cells are instructed to repress expression of either CD4 or CD8 and to develop into single
positive cells.
4- Negative selection checkpoint:
Cells that interact strongly with MHC and antigen in the thymus are deleted.
B) T cell peripheral Tolerance:
Many autoreactive T cells escape central tolerance due to :
a. Antigens are absent
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Dr. Fadwah Al-Ghalib
Diagnostic Immunology
3rd Year
b. Antigens are insufficient to induce tolerance in the thymus.
Tolerance is maintained by various mechanisms in the peripheral lymphoid organs:T cells cells are capable of making a response but are unaware of the
presence of their
auto-antigens. Due to 2 reasons:
1- Sequestration of antigen in some tissues: Many self antigens are hidden in the
tissues away from T lymphocytes either because of their location or may never
processed by functional APCs. OR antigen is present in too low concentrations in
which it will not trigger a response.
2- Privileged sites are protected by regulatory mechanisms: Examples of such
"privileged sites":



interior of the eye
testes
the brain
3- Receiving of Death Signals: by two processes either :
a- Activation-induced cell death (AICD):
Some cells of the body express the Fas ligand, FasL. Activated T cells always
express Fas. When they encounter these cells, binding of Fas to FasL triggers
their death by apoptosis.
b- passive cell death (PCD):
Many activated cells die by PCD because their antigen is eliminated (following
clearance of an infection). The removal of the antigen deprives cells of essential
survival stimuli including growth factors.
4- Control by Regulatory T Cells:
Both low and high doses of antigen may induce suppressor T cells which can
specifically suppress immune responses of both B and T cells, either directly or by
production of cytokines, most importantly, TGF-beta and IL-10.
A minor population of CD4+ T cells, called regulatory T cells, suppresses the
activity of other T cells. They may be important players in protecting the body
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Dr. Fadwah Al-Ghalib
Diagnostic Immunology
3rd Year
from attack by its other T cells. [ Th1 cells produce cytokines e.g. INF  and
TNF- that has a role in autoimmune diseases] [Th2 cells produce cytokines e.g.
IL-4, IL-5, IL-6, & IL-10, support Antibody production]
SUMMARY OF MECHANISMS OF CENTRAL & PERIPHERAL TOLERANCE
Thymus
Deletion
Escape
Sequestration
Antigen
Privileged sites
Deletion By
Prevention by
Fas
And cytokines
Activationinduced cell
death
Hidden from
immune system
Immune
regulation
by Supressive T
cells
And Cytokines
e.g IL-2
T-Cell Anergy:
•
Auto-reactive T cells, when exposed to antigenic peptides which do not
possess co-stimulatory molecules (B7-1 or B7-2), become anergic to the
antigen. (see fig- 1.2)
B Cell Tolerance:
-High affinity IgG production is T cell dependent
-Without help from T cells B cells remain harmless (non-self reactive).
Central Tolerance
B cells are formed and mature in the bone marrow. In humans, over half of the
developing B cells produce a BCR able to bind self components.
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Dr. Fadwah Al-Ghalib
Diagnostic Immunology
3rd Year
Self-reactive B cells are either:
a- undergo receptor editing
Any cells that produce a receptor for antigen (BCR) that would bind self components
too tightly undergo a process of receptor editing.(IgM receptor on immature B cell
reacts with self antigen further cell differentiation is blocked. If IgM receptor does not
react with self antigen in bone marrow, B cell development can proceed).
b- or undergo apoptosis
if receptor editing has failed to eliminate auto-reactive B cells they are likely to be
eliminated by apoptotic death.
Peripheral Tolerance:
Self-reactive B cells are eliminated in the spleen by negative selection, as does the
thymus to the unwanted T cells.
Auto-reactive B cells that escape deletion may not find the antigen or the specific
helper T-cells and hence not be activated and die out.
B-cell anergy: (fig: 1.4)
•
•
more than 5%* of the sIgM molecules are normally occupied by monomeric
soluble antigen the B cell becomes anergic.
This anergic state can be recognised in the case of B cells by the
downregulation of surface IgM.
Potential therapeutic applications of tolerance:
Better understanding of tolergenesis could be valuable in many ways:
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is used to promote tolerance of foreign tissue grafts
to control the damaging immune-responses in hypersensitivity states
to control the damaging immune-responses in autoimmune diseases
limit tumor growth.
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Dr. Fadwah Al-Ghalib
Diagnostic Immunology
fig: 1.3
Fig:1.2
fig : 1.4
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3rd Year
Dr. Fadwah Al-Ghalib
Diagnostic Immunology
8
3rd Year