1. Chapter 15 Immunological Tolerance

2. Outline
1.Concept
Immunological Tolerance: These antigen specific T cells and B cells can not be activated to induce immune response under stimulation of Ag. This phenomenon is called immunological tolerance.
Tolerogen: antigens that induce tolerance.
activation
effect Ag
T/B —

3. 2.Features:
Only play tolerance to definite Ag, but play good immune response to other Ags (immunologically specific) .
Only adaptive immunity has tolerance.
Normal individuals are tolerant of their own antigens(self antigen)----- Self-tolerance.

4. 3.Difference among Immunological tolerance , Immunodeficiency &Immunosuppression
Immunosuppression: The suppression of immune responses to antigens. This can be achieved by various means, including physical and chemical factors ----non-specificity to Ag
Immunodeficiency: Any condition in which there is deficiency in the production of humoral and /or cell-mediated immunity---non-specificity to Ag.
Immune function is disturbed by artificial or non artificial means.

5. 4.Classification of immunological tolerance
According to Ag:
Self tolerance
self Ags
Induced tolerance
foreigen objects，need definite conditions
According to formation region:
Central tolerance
Peripheral tolerance

6. Section I. The development of immunological tolerance
I . Induction of immunologic tolerance to antigen in embryonic period and neonatal period —— maintain lifetime

7. A B Graft of Skin From A to B or From B to A No rejection
Owen first observed phenomenon of immunologic tolerance in Dizygotic bovine twin in 1945 A B
Graft of Skin
From A to B or
From B to A
No rejection
Self –tolerance
Need for tissue and organ graft drove the curiosity to understand the mechanisms of tolerance. The observations a zoologist, Owens, that Dizygotic bovine twins could accept grafts from each other but their siblings from other pregnancies could not tolerate such grafts led Medawar to perform a series of experiments to induce tolerance in mice.
Antigen is introduced into the body early enough in development, the animal would consider it “self” and not react against it.

8. Medawar induced successfully immunologic tolerance in neonate period mice in 1953
Strain B mouse
Strain A mouse
Strain C mouse
Neonate mouse
Bone marrow
8 weeks later
Skin graft
Skin graft
Graft survival
Graft rejected 8

9. II. Induction of immunologic tolerance to
antigen after birth or in adult
(I) Antigen-associated factors
1. Dose of antigen
Inject different dose of BSA to mouse
10-8M
10-7M
10-5M
No Ab
Low dose tolerance
BSA:bovine serum albumin
High level Ab
No Ab
High dose tolerance
Mitchison 1964

10. High-zone tolerance Immune response low zone tolerance
T, B cell tolerance
T cell tolerance
Immune response
low zone tolerance
T cell
antigen low dose，APC cannot form adequate peptide-MHC
high zone tolerance
T cell 、B cell
Induce Ts cell activation or induce apoptosis of responding cell

11. Comparison of T cell tolerance with B cell tolerance
________________________________________________
Contents T cell B cell __________________________________________________________
Tolerance formation easy difficult
Antigens TD -Ag TD- Ag and TI –Ag
Dose of antigens high or low high
Induced time shorter (1-2 days) longer (more than 10 days)
Maintaining time longer (a few months) shorter (a few weeks) ___________________________________________________

12. 2. Types of antigen Large, aggregated, complex molecules
simple small molecules, Soluble, aggregate-free, not processed -tolerance

13. 3. Pathway of antigen entering body
Oral
Mucosa immunization, tolerance in body
Intravenous
Intra-peritoneal
Intramuscular
subcutaneous
Immune response
tolerance

14. 4.Antigen exist persistently
No costimulate signal
Activation
Apoptosis
5. Features of epitope
Some epitope can induce tolerance.
Determinants recognized by Ts or Treg induce tolerance.

15. Host–associated factors
Age and development stage
embryonic period ＞ neonatal period ＞ adult age ＞ old age
Newborn (mice), immunological immature.
Physiological state
Immune suppression
Genetic background
Hepatitis B vaccine

16. Section II. Mechanism of tolerance
I.Mechanism of central tolerance
-Central tolerance：
occurs in the central immune organs as a consequence of immature self-reactive lymphocytes recognizing ubiquitous self-antigen.----negative selection.
-Peripheral tolerance：
Tolerance was induced in peripheral organs as a result of mature self-reactive lymphocytes encountering antigens in vivo or in vitro under particular conditions.

17. I. Central tolerance T cell central tolerance : formation in thymus
Clonal deletion in negative selection
B cell central tolerance: formation in bone marrow
Clonal deletion
Clonal anergy (clonal inactivation)
Receptor editing

18. 1. T cell central tolerance
T cell Clonal deletion (cell apoptosis)
During maturation of T lymphocytes in the thymus, immature T lymphocytes that recognize ubiquitous self-antigen with high affinity are deleted by mechanism of apoptosis.

19. Clonal deletion: negative selection in the thymus
Clonal deletion: Functionally immature cells of a clone encountering antigen undergo a programmed cell death. For example, auto-reactive T-cell are eliminated in the thymus following interaction with self antigen during their differentiation (negative selection). Clonal deletion has been shown to occur also in the periphery. B cells expressing only IgM (no IgD) on their surface when exposed to antigen are eliminated.
Cortex
Medulla

20. 2. B cell central tolerance
Clonal deletion
During maturation of B lymphocytes in bone marrow , immature lymphocytes that recognize membrane-bound self-antigen with high affinity are deleted by apoptosis.
Clonal anergy (clonal inactivation)
During maturation of B lymphocytes in bone marrow , immature lymphocytes that recognize soluble self-antigen are not deleted but are inactivated .
Receptor editing
If the BCR of some immature B lymphocyte can bind to the self-antigen at high affinity , the light chain gene of BCR on the other allele will start rearrangement to produce a new BCR to replace the old.

21. Negative selection of B cell in bone marrow (clonal deletion)
Clonal deletion: Functionally immature cells of a clone encountering antigen undergo a programmed cell death. For example, auto-reactive T-cell are eliminated in the thymus following interaction with self antigen during their differentiation (negative selection). Clonal deletion has been shown to occur also in the periphery. B cells expressing only IgM (no IgD) on their surface when exposed to antigen are eliminated. 21 21

22. Clonal anergy in B cells
Also, B cells when exposed to large amounts of soluble antigen down regulate their surface IgM and become anergic and short lived. These cells also up regulate Fas molecules on their surface. An interaction of these B cells with Fas-ligand bearing cells result in their death via apoptosis.

23. II . Mechanisms of Peripheral Tolerance
Clonal deletion
Immune ignore
Clonal anergy
The function of immunoregulation cells
Immunologically privileged sites

24. 1.Clonal deletion:
-self Ags at high concentration and affinity can induce self-reactive T cells clonal deletion.
2.Immunological ignorance:
-self Ag at low concentration or affinity can induce self-reactive T cells clonal ignorance. When Ag concentration increasing , this tolerance can be stopped.

25. Immunological ignorance
Self-reactive T cell clones
Corresponding tissue specific Ag
No response
No clonal deletion
No clonal anergy
Too low
Immunological ignorance
Self-reactive T cell clones
Corresponding tissue specific Ags
Enough
T cell reponse
Immunological response

26. 4. The function of regulatory T cells (CD4+CD25+T、Tr1、Th3)
3. Clonal anergy
-Self Ag can not activate DC, which can not supply the secondary signal to T cells.
4. The function of regulatory T cells (CD4+CD25+T、Tr1、Th3)
Cell-cell contacting
CK（IL-10,TGF-β）
Treg
Inhibit T cell response

27. 5. Immunological privileged sites
Under physiological condition, Antigens in immunologically privileged sites can not induce immune response.
-Physiologic barrier
brain, anterior chamber of eye(crystalline lens), didymus , placenta
-promote Th2 inhibit Th1
-FasL induce lymphocytes with Fas apotosis
Immunosupressive cytokines
TGF-、IL-4、IL-10

28. Section III. Immunologic Tolerance and Clinic Medicine
To induce immunologic tolerance
Prevent the rejection of organ allografts and xenografts
Treat autoimmune diseases
Treat allergic diseases
2. To terminate immunologic tolerance
To treat tumor: enhance first signal or second signal
To treat infection diseases

29. Exercise Immunological tolerance definition and feature.
Comparison of T cell tolerance with B cell tolerance
Mechanism of central tolerance and periphery tolerance?