The document discusses immunological tolerance, its mechanisms, and types, including central and peripheral tolerance. It defines self-tolerance and self-reactivity, factors influencing tolerance, and historical milestones in understanding these concepts. Additionally, it outlines B cell tolerance, its development, and potential therapeutic applications for promoting tolerance in various medical contexts.

1. TOLERANCE
TOLERANCE
Dr kenneth Lado Lino
Dr kenneth Lado Lino
School of Medicine
School of Medicine
,
,
University of Juba
University of Juba
.
.

2. Tolerance
Tolerance
Topic:
Topic: Immunological Tolerance
Immunological Tolerance
Objectives:
Objectives:
 Define Immunological tolerance
Define Immunological tolerance
 Discuss mechanism of tolerance induction
Discuss mechanism of tolerance induction
 Know types of tolerance
Know types of tolerance
 Central thymic
Central thymic
 Peripheral post thymic
Peripheral post thymic
 Explain B cell tolerance to self antigens
Explain B cell tolerance to self antigens
 Discuss artificial induction of tolerance
Discuss artificial induction of tolerance
 Know therapeutic applications of tolerance
Know therapeutic applications of tolerance

3. Immune tolerance
Immune tolerance or
or
immunological tolerance
immunological tolerance

is the process by which the
is the process by which the immune system
does not attack an
does not attack an antigen.
.
 It can be either :
It can be either :
1) Natural' or 'self tolerance
1) Natural' or 'self tolerance', where the body
', where the body
does not mount an immune response to self
does not mount an immune response to self
antigens.
antigens.
2) Induced tolerance
2) 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 tolerance.
peripheral tolerance and acquired tolerance.

4. Definitions
Definitions
:
:
 Tolerance
Tolerance is a state of unresponsiveness that is
is a state of unresponsiveness that is
specific for a particular antigen
specific for a particular antigen
 Self tolerance
Self tolerance is the mechanisms by which the
is the mechanisms by which the
body is prevented from mounting an immune
body is prevented from mounting an immune
response against its own tissues.
response against its own tissues.
 Self reactivity
Self reactivity is prevented by processes during
is prevented by processes during
development rather than being programmed.
development rather than being programmed.

5. Factors influencing tolerance
Factors influencing tolerance
 Molecule structure
Molecule structure
 Stage of differentiation when
Stage of differentiation when
lymphocyte first encounter the epitopes
lymphocyte first encounter the epitopes
 The site of the encounter
The site of the encounter
 The nature of the cell presenting the
The nature of the cell presenting the
epitopes
epitopes
 Number of responding lymphocytes
Number of responding lymphocytes
Q. What is an epitope?
Q. What is an epitope?

6. History
History

Trub
Trub (1938):
(1938):
Inutero
Inutero mice against choriomeningitis virus
mice against choriomeningitis virus
 Medawar
Medawar (1953)
(1953)
Induced immunological tolerance to skin allograft
Induced 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 rise to
selected by an antigen and then divides to give rise to
clone of daughter cells with the same specificity
clone of daughter cells with the same specificity

7. Leaderburg
Leaderburg (1959)
(1959)
Modification of Clonal selection theory ( Stage of cell
Modification of Clonal selection theory ( Stage of cell
maturation)
maturation)
Key discoveries of
Key discoveries of (1960)
(1960)
a)
a) Role of thymus in development of the immune
Role of thymus in development of the immune
system
system
a)
a) Existence of two interacting subsets of lymphocytes
Existence of two interacting subsets of lymphocytes

10. Types of Tolerance
Types of Tolerance
 Central Tolerance
Central 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.

12. Central thymic Tolerance to Self Antigens
Central thymic Tolerance to Self Antigens
 The immune system generates a vast array of
The immune system generates a vast array of
TCRs
TCRs
 T cells are not only effector cells but are also
T cells are not only effector cells but are also
regulators of the immune system
regulators of the immune system
 T cells become
T cells become “
“educated
educated”
” in the thymus
in the thymus
 They become dependant on self MHC for
They become dependant on self MHC for
survival
survival

16. III-T cell development is subjected to several
III-T cell development is subjected to several
checkpoints
checkpoints
 β
β selection checkpoint:
selection checkpoint:
Only cells with a rearranged
Only cells with a rearranged β
β chain mature
chain mature
from double negative to double positive cells.
from double negative to double positive cells.
Independent on MHC
Independent on MHC
 α
α selection checkpoint:
selection checkpoint:
Cells expressing an
Cells expressing an αβ
αβ complex must interact
complex must interact
with MHC molecules to survive
with MHC molecules to survive

17.  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 cells
into 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 deleted
antigen in the thymus are deleted

19. Peripheral or Post-Thymic Tolerance to
Peripheral or Post-Thymic Tolerance to
Self Antigens
Self 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 absent
Antigens are absent
b)
b) Antigens are insufficient
Antigens are insufficient
However, tolerance is maintained by
However, tolerance is maintained by
mechanisms in peripheral lymphoid organs
mechanisms in peripheral lymphoid organs

20. 1-Sequestration of antigens in some tissues:
1-Sequestration of antigens in some tissues:
Many self antigens are hidden in tissues that are
Many self antigens are hidden in tissues that are
anatomically located away from T lymphocytes
anatomically located away from T lymphocytes
2-
2- Privileged sites are protected by regulatory
Privileged sites are protected by regulatory
mechanisms
mechanisms:
:
Privileged sites include brain, testes and anterior champers
Privileged sites include brain, testes and anterior champers
of the eye
of the eye
In these sites lymphocytes are controlled by apoptosis or
In these sites lymphocytes are controlled by apoptosis or
cytokines such as TNF
cytokines such as TNFβ
β and IL10
and IL10
These mechanisms include:
These mechanisms include:

21. 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 (PCD)
Activated lymphocyte will die by passive cell death (PCD)
when deprived from its antigen
when deprived from its antigen
4- Regulation by suppressive cytokines
4- Regulation by suppressive cytokines
IL-2 and IL-2 receptor regulate sensitivity to Fas mediated
IL-2 and IL-2 receptor regulate sensitivity to Fas mediated
apoptosis
apoptosis

22. Summary of peripheral post thymic
Summary of peripheral post thymic
mechanisms of tolerance
mechanisms of tolerance
:
:
Thymus
Deletion Escape
Immune
regulation
By
Suppressive
cytokines
Deletion
By
activation
-
induced
Cell death
Sequestration
Antigen
hidden from
immune
system
Privileged
sites
Prevention
by Fas
and
cytokines

23. B- Cell Tolerance to Self Antigens
B- Cell Tolerance to Self Antigens
 High affinity IgG production is T cell dependent
High affinity IgG production is T cell dependent
 Lack of T cell leads to non-self reactivity by B
Lack of T cell leads to non-self reactivity by B
cells
cells
 Self reactive B cells either:
Self reactive B cells either:
a)
a) Edit their receptors to become non-reactive
Edit their receptors to become non-reactive
b)
b) Die by the process of apoptosis
Die by the process of apoptosis
 In peripheral B cell tolerance
In peripheral B cell tolerance,
, self reactive cells
self reactive cells
are removed by negative selection in the
are removed by negative selection in the
spleen in a process that is similar to T cell
spleen in a process that is similar to T cell
removal in the thymus.
removal in the thymus.

25. B cell tolerance in the BM
B 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 cells
expressed on 'immature' B cells
 If those cells encounter their target antigen in a form
If those cells encounter their target antigen in a form
which can
which can cross-link
cross-link their IgM then such cells are
their IgM then such cells are
programmed to die
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 polyvalent
polyvalent

27. Potential clinical applications for
Potential clinical applications for
tolerance
tolerance
:
:
 Understanding of tolerance is valuable in
Understanding of tolerance is valuable in
many ways
many ways:
:
 Promote tolerance to tissue graft
Promote tolerance to tissue graft
 Control damaging immune response in
Control damaging immune response in
hypersensitivity
hypersensitivity
 Control damaging in autoimmune disease
Control damaging in autoimmune disease
 Limit tumor growth
Limit tumor growth