Immunologic Tolerance

1
Immunologic Tolerance

• Lecture 18

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
• 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

8
(No Transcript)
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

11
(No Transcript)
12
(No Transcript)
13
(No Transcript)
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
Clonal Anergy
Autoimmunity
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
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
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. If a response is induced elsewhere
they can serve as targets for attack.
21
Tolerance Induction in the Absence of
Costimulation
22
(No Transcript)
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
Dominant Immune Suppression
Mouse develops Experimental allergic Encephalomyel
itis
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 andGood Luck