The document discusses immune tolerance, highlighting its significance in preventing autoimmunity, where the immune system attacks the body's own tissues. It outlines mechanisms such as central and peripheral tolerance, detailing processes like positive and negative selection in lymphocyte maturation and various mechanisms for maintaining tolerance in mature cells. The importance of induced tolerance is also emphasized in preventing allergic reactions and graft rejection, as well as its implications for understanding autoimmune diseases.

1. IMMUNE TOLERANCE
By- Dr Irfan Hussain Gauri
1st
Year Resident
Microbiology Department
SPMC, Bikaner

2. HISTORY
• Early in the 20th
century, Paul Ehrlich realised that the immune system
could go awry.
• Instead of reacting only against foreign antigens, it could focus its
attack on the host.
• This condition which he termed horror autotoxicus can result in a
clinical syndrome generally referred to as autoimmunity.
• This inappropriate response of the immune system, directing humoral
and/or T-cell-mediated immune activity against self components, is
the cause of autoimmune diseases.

3. IMMUNOLOGICAL TOLERANCE
• Immunological tolerance is a mechanism in the body to protect an
individual from self- immune attack.
• This process and mechanism that control it are collectively termed
tolerance, or self tolerance.
• It is mediated by two broad mechanism
1. Central tolerance
2. Peripheral tolerance

4. CENTRAL TOLERANCE
• This refers to the deletion of self-reactive T and B lymphocytes during
there maturation in Central lymphoid organs (i.e. in thymus for T cells
and bone marrow for B cells)
1. IN THYMUS- During the T cell development in thymus, if any self
antigens are encountered, they are processed and presented by
thymic antigen presenting cells(APCs).
i) Positive selection
ii) Negative selection

5. POSITIVE SELECTION
• Cells whose TCR fail to interact with MHC-self peptide molecules
undergo Death by neglect.
• Cells that bind too strongly to MHC self peptide complex also dies.
• Only cells that recognise the MHC molecule with Moderate/Low
affinity survive (POSITIVE SELECTION)

6. NEGATIVE SELECTION
• Cells that bind too strongly to MHC self peptide complex are induced
to undergo programmed cell death (APOPTOSIS).
• This results in self tolerance

7. CENTRAL TOLERANCE
1. IN THYMUS
2. IN BONE MARROW- When developing immature B-cells in the bone
marrow encounter a self antigen during there development, the
tolerance is developed by
i ) Receptor editing
ii) Negative selection

8. i ) RECEPTOR EDITING- A process by which the Ig genes coding light
chains are rearranged so that a different (edited) B cell receptor is
produced. Which no longer reacts to self antigen.
ii) NEGATIVE SELECTION- After receptor editing, if the B cells again
recognise a self antigen, then they are destroyed by subjecting them to
apoptosis.

9. FACTORS THAT PROMOTE TOLERANCE
• Fetal exposure
• High dose of antigen
• Long term persistence of the antigen in the host
• Absence of adjuvants (compounds that enhance the immune
response to antigen)
• Low level of co-stimulation
• Presentation of antigen by immature or inactivated APCs

10. ESCAPE FROM CENTRAL TOLERANCE
TWO FACTORS CONTRIBUTE TO THIS-
1. Not all self antigens are expressed in the central lymphoid organs
where negative selection occurs.
2. There is a threshold requirement for affinity to self antigens before
clonal deletion is triggered.

11. PERIPHERAL TOLERANCE
Mature self-reactive lymphocytes that recognise self antigens in
peripheral tissues are inactivated, killed or supressed. It is done by
various mechanisms.
1. IGNORANCE- The self reactive T cells might never encounter the
self antigen which they recognise and therefore remain in a state of
ignorance.

12. 2. ANERGY- It can be defined as unresponsiveness to antigenic stimulus.
The self reactive T cells interact with APCs presenting the self antigen,
but the co-stimulatory signal is blocked. The B7 molecules on APC bind
to CTLA-4 molecules on T cells instead of CD28 molecules.
3. PHENOTYPIC SKEWING- Self reactive T cells interacting with APCs
presented with self antigens, undergo full activation, but might secrete
non pathogenic cytokines and chemokine receptors profile, although
they are activated, fail to induce autoimmune response.

13. APOPTOTIC CELL DEATH
• Extremely important for maintaining immune homeostasis in healthy
individuals
• mechanism
Activation induced cell death (AICD)- Self reactive T cells are
activated after interacting with APCs presented with self antigen. But
the activation of T cells induces upregulation of Fas ligand which
subsequently interact with the death receptor Fas leading to Apoptosis.

14. REGULATORY T CELLS
• Act in secondary lymphoid tissues and at sites of imflammation.
• Regulatory T cells recognise specific self antigens and also foreign
antigens
• T cells (regulatory) can down regulate the self reactive T cells through
secreting certain cytokines ( IL-10 and TGFβ) or killing by direct cell to
cell contact.

15. DENDRITIC CELLS
• Dendritic cells uptake antigens in there immature state but cant
present to T cells
• Present antigen to T cells only when they are mature
• When certain immature DCs and tolerogenic DCs capture the self
antigen for processing, they act indirectly by induction of regulatory T
cells.

16. SEQUESTRATION OF SELF ANTIGEN
• Self antigen may be sequestrated in some tissues and will never be
available to T cells
• Allows these antigens to avoid encounter with reactive lymphocytes
under normal circumstances
• 2 ways
1. Physical barrier- Location of antigen in privileged sites
2. Immunological barrier- Never processed by functional APCs

17. Privileged SITES
• Cells ignore self antigens if they are expressed in immunologically
privileged sites.
1. The brain
2. The anterior chamber and lens of eye
3. Testes
• In these sites pro inflammatory lymphocytes are controlled by
1. Apoptosis
2. Cytokine secretion

18. EXPERIMENTAL INDUCTION OF
TOLERENCE
• Tolerance can be induced with soluble antigens, when rabbits are
injected with bovine serum albumin (BSA) without adjuvant at birth
and fail to make antibodies against this protein later in life.

19. IMPORTANCE OF INDUCED TOLERANCE
• to protect us from unpleasant, even dangerous, allergic reactions to
such things as food (e.g. peanuts), insect stings, grass pollen (hay
fever)
• to enable transplanted organs (e.g., kidney, heart, liver) to survive in
their new host (graft rejection)
• to reveal the mechanisms of autoimmunity for designing treatments
for systemic lupus erythematosus (SLE) and multiple sclerosis (MS)

20. THANK YOU!!!