Basic Medical Sciences Physiology Lecture Immunologic Tolerance

1. IMMUNOLOGIC
TOLERANCE
BY: DR MUHAMMAD KHALID SIDDIQUI

2. What is Immunologic Tolerance?
• State in which the individual is incapable of
developing an immune response to a specific antigen.
• Self tolerance: The immune mechanism normally
recognizes a person’s own tissues as being distinctive
from bacteria or viruses,

3. Classification Immunologic tolerance
• Central tolerance
• Peripheral tolerance

4. What is the difference between central and
peripheral tolerance?
•Central tolerance is a state of immune tolerance that is
induced originally in the thymus and bone marrow.
•Whereas, peripheral tolerance is a state of immune tolerance
that is induced originally in the lymph nodes and other
tissues.

5. Central Tolerance
•Refers to death of self-reactive T- and B-lymphocyte clones
during their maturation in the central lymphoid organs.
•T lymphocytes that bear receptors for self antigens undergo
apoptosis within the thymus during the process of T-cell
maturation

6. • Many autologous protein antigen are processed and
presented by thymic antigen- presenting cells in
association with self MHC proteins.
• Developing T-cells having high affinity receptors for
such antigens are deleted, and therefore the
peripheral T-cell pooling is lacking or deficient in self
reactive cells.

8. Clonal deletion of T-cells & 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 intra thymic 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, co-expressed on activated T-
cells, dampens the immune response by inducing apoptosis
of activated T-cells.

12. 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
apoptosis

13. 2.Clonal anergy
• Refers to a prolonged or irreversible functional inactivation of
lymphocytes, induced by encounter with antigens under certain
conditions.
• Anergy is defined as a cellular state in which lymphocytes fail to
give certain responses upon stimulation through the antigen
receptor

14. •clonal deletion is the removal through apoptosis of B cells
and T cells that have expressed receptors for self before
developing into fully immunocompetent lymphocytes.
•This prevents recognition and destruction of self host cells,
making it a type of negative selection or central tolerance.
•Central tolerance prevents B and T lymphocytes from
reacting to self. Thus, clonal deletion can help protect
individuals against autoimmunity.
•Clonal deletion is thought to be the most common type of
negative selection. It is one method of immune tolerance.
Clonal deletion

15. Activation of T-cells
•Requires 2 signals:-
•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.
•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.

16. • 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 co-stimulatory 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

17. •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

19. 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 auto-
reactivity may be mediated, in part, by the regulated
secretion of cytokinesis

20. Tolerance of self-reactive
• Tolerance of self-reactive T-cells is extremely important for
prevention of autoimmune disease

21. Functions
• T-cell homeostasis
• Cytotoxic T-cell activity: Fas-induced apoptosis and the perforin
pathway are the two main mechanisms by which cytotoxic T
lymphocytes induce cell death in cells expressing foreign antigens.
• Maternal tolerance: Fas ligand may be instrumental in the
prevention of leukocyte trafficking between the mother and the
fetus, although no pregnancy defects have yet been attributed to a
faulty Fas-Fas ligand system.

22. Failure of the Tolerance Mechanism
Causes Autoimmune Diseases.
•It usually occurs after destruction of some of the body’s
own tissues, which releases considerable quantities of self-
antigens that circulate in the body and cause acquired
immunity in the form of activated T cells or antibodies

23. (1) Rheumatic fever,: in which the body becomes immunized against
tissues in the joints and heart, especially the heart valves, after
exposure to a specific type of streptococcal toxin that has an epitope
in its molecular structure similar to the structure of some of the
body’s own self-antigens;
(2) Glomerulonephritis, in which the person becomes immunized
against the basement membranes of glomeruli;
(3) Myasthenia gravis, in which immunity develops against the
acetylcholine receptor proteins of the neuromuscular junction,
causing paralysis;
Autoimmune Disorders

24. • Multiple sclerosis (MS), in which the immune system attacks
the myelin that covers nerve fibers, disrupting nervous
system communication;
• Systemic lupus erythematosus (SLE), in which the person
becomes immunized against many different body tissues at
the same time, a disease that causes extensive damage and
even death when SLE is severe