Understanding of Immunological Tolerance and the mechanisms involved in it.

1. “Tolerance”
Presented by:
Ahmad Aman (Pharm-D)
Riphah Institute of Pharmaceutical
Sciences

2. Tolerance:
“Tolerance is specific immunologic unresponsiveness
(i.e., an immune response to a certain antigen [or
epitope] does not occur, although the immune system is
otherwise functioning normally).”
 In general, antigens that are present during embryonic
life are considered “self ” and do not stimulate an
immunologic response (i.e., we are tolerant to those
antigens).
 The lack of an immune response in the fetus is caused
by the deletion of self-reactive T-cell precursors in the
thymus.

3. Types of Tolerance:
T Cell Tolerance
Central tolerance (inside the thymus)
Peripheral tolerance (outside the thymus)
B Cell Tolerance
Note: Although both B cells and T cells
participate in tolerance, it is T-cell tolerance
that plays the primary role.

4. Types of Tolerance:
Tolerance to “self” acquired within the thymus is
called central tolerance.
Whereas, the tolerance acquired outside the
thymus is called peripheral tolerance. ( mostly in
spleen, lymph nodes)
Peripheral tolerance is necessary because some
antigens are not expressed in the thymus and
therefore some self reactive T cells are not killed
in the thymus.

5. T Cell Tolerance:
Clonal
Deletion
Clonal
Anergy
Clonal
Ignorance

6. Clonal Deletion:
T lymphocytes acquires the ability to distinguish
“self” from “non-self” in the fetal thymus by the
process called clonal deletion.
It is the process that involves the killing of T cells
(“negative selection”) that react against antigens
present in the fetus at that time.
The self reactive cells die by a process of
programmed cell death called apoptosis.
For negative selection and clonal deletion to be
efficient, the thymic epithelial cells must display a
vast repertoire of “self ” proteins.

7. Clonal Deletion:

8. Clonal Deletion:
 A transcriptional regulator called the autoimmune
regulator (AIRE) enhances the synthesis of this array of
self proteins.
 The AIRE transcription factor also functions in the
peripheral lymphoid organs such as the spleen and
lymph nodes, where it contributes to peripheral
tolerance.
 Mutations in the gene encoding the AIRE protein result
in the development of an autoimmune disease called
autoimmune polyendocrinopathy.

9. Polyendocrinopathy:
 APS type 1, also known as APECED (autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy).
 MEDAC (multiple endocrine deficiency autoimmune
candidiasis syndrome).
 Juvenile autoimmune polyendocrinopathy.
 Whitaker's syndrome.

10. Polyendocrinopathy:

11. a) Vitiligo b) Alopecia Areata:

12. Clonal Anergy:
“Clonal anergy is the term used to describe self-
reactive T cells that are not activated because proper
co-stimulation does not occurs.”
Mechanism of clonal anergy:
 Inappropriate presentation of antigen, leading to a
failure of interleukin-2 (IL-2) production.
 Inappropriate presentation is due to a failure of
“co-stimulatory signals”
 For instance, sufficient amounts of IL-1 might not
be made, or cell surface proteins, such as CD28 on
the T cell and B7 on the B cell, might not interact
properly, leading to a failure of signal transduction
by RAS proteins.

13. Normal Activation of T cell:

14. Normal Activation of T cell:

15. Clonal Anergy:
 For example, the inhibitory protein CTLA-4 on the surface
of the T cells may displace CD28 and interact with B7,
resulting in a failure of T-cell activation.

16. Clonal Anergy:
• Furthermore, B7 is an inducible protein, and failure to induce
it in sufficient amounts can lead to anergy.
• In addition, the co-stimulatory proteins, CD40 on the B cell
and CD40L on the helper T cell, may fail to interact properly.

17. Clonal Anergy:
 The failure of co-stimulatory signals most often occurs when there is
an insufficient inflammatory response at the site of infection.
 The presence of microbes typically stimulates the production of pro-
inflammatory cytokines such as Tumor Necrosis Factor and IL-1.
 If the inflammatory response is insufficient (i.e. adjuvant effect of
the cytokines is inadequate, the T cells will not be activated).

18. Clonal Ignorance:
“Clonal ignorance refers to self-reactive T cells that
ignore self antigens.”
 These self-reactive T cells are either kept ignorant by
physical separation from the target antigens (e.g.,
the blood–brain barrier).
 Or ignorance to self antigens may occurs if the
antigens are present in small amounts.

19. Clonal Ignorance:

20. B Cell Tolerance:
Clonal
Deletion
Clonal
Anergy
Receptor
Editing

21. B-Cell Tolerance:
B cells also become tolerant to “self” by two mechanisms:
Clonal Deletion:
 probably while the B-cell precursors are in the bone
marrow.
Clonal Anergy:
 Of B cells in the periphery.
Note: However, tolerance in B cells is less complete than
in T cells, an observation supported by the finding that
most autoimmune diseases are mediated by antibodies.

22. Clonal Deletion:

23. Clonal Anergy:

24. Receptor Editing:
 B cells bearing an antigen receptor for a self protein
can escape clonal deletion (apoptosis) by a process
called receptor editing.
 In this process, a new, different light chain is produced
that changes the specificity of the receptor so that it no
longer recognizes a self protein.
 This reduces the risk of autoimmune diseases and
increases the repertoire of B cells that can react against
foreign proteins.
 It is estimated that as many as 50% of self-reactive B
cells undergo receptor editing. T cells do not undergo
receptor editing.

25. Receptor Editing:

26. B-Cell Tolerance:

27. Induction Of Tolerance:
Whether an antigen will induce tolerance rather than an
immunologic response is largely determined by the following:
The immunologic maturity of the host:
 Neonatal animals are immunologically immature and do
not respond well to foreign antigens.
The structure and dose of the antigen:
 A very simple molecule induces tolerance more readily
than a complex one.
 Very high or very low doses of antigen may result in
tolerance instead of an immune response.
 Purified polysaccharides or amino acid copolymers injected
in very large doses result in “immune paralysis” —a lack of
response.

28. Induction Of Tolerance:
Other aspects of the induction or maintenance of
tolerance are as follows:
 T cells become tolerant more readily and remain
tolerant longer than B cells.
 Administration of a cross-reacting antigen tends to
terminate tolerance.
 Administration of immunosuppressive drugs
enhances tolerance (e.g., in patients who have
received organ transplants).
 Tolerance is maintained best if the antigen to which
the immune system is tolerant continues to be
present.