1. IMMUNOLOGIC
TOLERANCE
By:-
Robin Gulati

2. Contents
Definition
Central tolerance
Peripheral tolerance
Back up mechanisms

3. What is Immunologic Tolerance?
State in which the individual is incapable
of developing an immune response to a
specific antigen.
Self tolerance: refers to the lack of
individual’s antigens.
Affects the ability to live in harmony with
our own cells and tissues.

4. Classification
Immunologic
tolerance
Central Peripheral
tolerance tolerance

5. Central Tolerance
Refers to death (deletion) of self-reactive T-
and B-lymphocyte clones during their
maturation in the central lymphoid organs
(the thymus for T cells and the bone
marrow for B cells).
Experiments with transgenic mice provide
abundant evidence that T lymphocytes that
bear receptors for self antigens undergo
apoptosis within the thymus during the
process of T-cell maturation

7.  T-cells that bear receptors for self antigen
undergo apoptosis within the thymus during
the process of T-cell maturation.
 Many autologous protein antigen are
processed and presented by thymic antigen-
presenting cells in association with self MHC
(major histocompatibility complex) proteins.
 Developing T-cells having high affinity
receptors for such antigens are negatively
selected, or deleted, and therefore the
peripheral T-cell pooling is lacking or
deficient in self reactive cells.
 The developing thymocytes express high
levels of Fas causing negative selection.

8. Clonal deletion of T-cells also affects B-
cells.
When developing B-cells encounter a
membrane-bound antigen within the bone
marrow, they undergo apoptosis.
No self antigen present in the thymus: T-
cells and B-cells slip into the periphery.
B-cells bearing receptors for thyroglobulin,
collagen and DNA can be found in the
periphery.

9. PERIPHERAL TOLERANCE
T-cells that escape intrathymic negative
selection can cause tissue injury unless
they are deleted or muzzled in the
peripheral tissues.
3 “back up” mechanisms that silence
such potentially autoreactive T-cells are:-
1.Clonal deletion by activation-induced cell
death
2.Clonal anergy
3.Peripheral suppression by T-cells

10. 1. Clonal deletion by activation-
induced cell death
Mechanism to prevent uncontrolled T-cell
activation during normal immune response
involves apoptotic death of activated T-
cells by Fas-Fas ligand system.
Expression of Fas (CD95) is upregulated in
antigen activated T-cells.
Engagement of Fas by Fas L, coexpressed
on activated T-cells, dampens the immune
response by inducing apoptosis of
activated T-cells.

11. The self antigens that are abundant
in the peripheral tissues cause
repeated and persistent stimulation
of self-antigen-specific T-cells
leading eventually to their
elimination via Fas mediated
apoptotis.

13. 2.Clonal anergy
Refers to a prolonged or irreversible
functional inactivation of
lymphocytes, induced by encounter with
antigens under certain conditions.

14. Activation of T-cells requires 2
signals:-
a.Recognition of peptide antigen in
association with self MHC molecules on
the surface of antigen-presenting cells
and set of costimulatory signals
provided by antigen-presenting cells.
b.To initiate second signals, certain T-cells
associated molecules, such as CD28,
must bind to their ligand, a negative
signal is delivered, and the cell
becomes anergic.

15. Such a cell then fails to be activated
even if the relevant antigen is presented
by component antigen presenting cells
that can deliver costimulation.
Since costimulatory molecules are not
expressed or are weekly expressed on
most normal tissues, the encounter
between auto reactive T-cells and their
specific antigen leads to clonal anergy.
Also affects B-cells.

16. B-cells encounter antigen in the
absence of specific helper T-cells,
the antigen-receptor complex is
down regulated, and such cells
never re-express their
immunoglobin receptors.
Such cells are unable to respond to
subsequent antigenic stimulation.

18. 3.Peripheral stimulation of
T-cells
Focus is on suppressor T-cells with the
ability to downregulate the function of
other autoreactive T-cells.
Molecular mechanisms by which
suppressor T-cells recognize antigens and
exert their suppressive effects are little
understood.
Some evidence is that peripheral
suppression of autoreactivity may be
mediated, in part, by the regulated
secretion of cytokinesis.

19. Tolerance of self-reactive T-cells is
extremely important for prevention
of autoimmune disease.

20. THANK
YOU!