1. Immunologic Tolerance
Lecture 18
Immunologic Tolerance

2. Importance of Regulation
Inappropriate immune responses can have life-threatening consequences!
Immune Response to self Ags
Tolerance to pathogens
Mechanisms of regulation are not very well understood.

3. Tolerance State of immune system unresponsiveness to an antigen.
Failure to Respond to an antigen
Tolerance to self antigens-Essential feature of the immune system
Loss of tolerance to self: Destruction of self tissues-Autoimmune disease

4. Postulated Mechanisms of Autoimmunity

5. General Features of Immunologic Tolerance
Tolerance is immunologically specific
Induced by inxs. of antigen with antigen receptors
Tolerance to self is learned/acquired
Immature or developing lymphocytes are more susceptible to tolerance induction
Tolerance to foreign antigens is induced even in mature lymphocytes

6. Tolerance Central Tolerance Peripheral Tolerance
Tolerance established in lymphocytes developing in central lymphoid organs
Peripheral Tolerance
Tolerance acquired by mature lymphocytes in the peripheral tissues.

7. Basic Mechanisms of Tolerance
Clonal Deletion
Immature lymphocytes eliminated by apoptosis during T or B cell maturation.
Clonal Anergy
Naive T and B cells exposed to foreign /self Ag are inactivated or rendered unresponsive to restimulation-Functional Inactivation-Tolerogens

9. T Cell Tolerance

10. Mechanisms of T Cell Tolerance
Clonal Deletion
Deletion of self-reactive clones of CD4+ and CD8+ T cells in the thymus by Negative Selection
Clonal Anergy-Peripheral lymphoid organs
Regulatory Lymphocytes-Suppress T Cell Activation
Clonal Ignorance

14. Peripheral T Cell Tolerance
THYMUS
Escape from Clonal Deletion
Suppression by
Regulatory T Cells
PERIPHERY
Autoreactive T cell
(Naïve)
MHC/Ag
No Costim.
Antigen Sequestered
MHC/Ag + Costim.
Clonal Ignorance
Autoimmunity
Clonal Anergy

15. Clonal/Immunological Ignorance

16. Immunologically Privileged Sites
Tissue grafts placed in these sites are not rejected
Antigens are sequestered in immunologically privileged sites
Brain
Anterior chamber of Eye
Cornea
Testis
FasL
Hamster Cheek Pouch

17. T cells specific to Myelin
Transgenic Mouse has
T cells specific to Myelin
Basic protein (MBP)
All the T cells carry the autoreactive TCR
Brain autoantigen, MBP is sequestered in the CNS
Normal, No Autoimmune Disease
Immunological Ignorance

18. is sequestered in the CNS
Transgenic Mouse
TCR specific to Myelin
Basic protein (MBP)
All the T cells carry
the autoreactive TCR
Brain autoantigen, MBP
is sequestered in the CNS
Inject MBP With adjuvant
No Autoimmune Disease
Activation of Autoreactive
T Cells
Immunological Ignorance
Migrate to tissues
Including CNS
Encephalitis and Death
Activated T cells cross BBB and cause CNS disease

19. Trauma to one eye results in the release of sequestered
intraocular antigens
Released intraocular antigens
carried to L. nodes and activates
T cells
Effector T cells return via
blood stream and
encounter antigen in
both eyes
SYMPATHETIC OPTHALMIA

20. Sequestered Antigens DO NOT induce a response by themselves
Sequestered Antigens DO NOT induce a response by themselves. If a response is induced elsewhere they can serve as targets for attack.

21. Tolerance Induction in the Absence of Costimulation

23. Antigen recognition by T cells in the absence of costimulation leads to T cell Tolerance
Naïve T cells recognizing self peptides on tissue cells are not activated, instead they enter a state of anergy/unresponsiveness.

24. T Cell-Mediated Suppression-Regulatory T Cells

25. Suppression of T Cell Responses by Regulatory T Cells

26. Oral Tolerance

27. Experimental allergic
Dominant Immune Suppression
Mouse develops
Experimental allergic
Encephalomyelitis
Brain has
TH1 CD4 cells
Making IFNg
Injected with
adjuvant
Spinal Cord
Homogenate
Brain has
CD4 cells
Making TGFb
Healthy
Mouse
TGF-b suppresses the function of
inflammatory TH1 Cells-Regulatory T Cells
Feed Myelin
Basic Protein
Oral admn. of ag. can lead to protection against autoimmunity

28. B Cell Tolerance
Deletion of Antigen-specific cells may occur as B cells arise in the bone marrow and encounter self antigens before they become functionally competent (immature).
Clonal Anergy

29. Negative Selection and Receptor Editing in Immature B Lymphocytes

30. Thank You and Good Luck