1. Chapter 13 Immunological Tolerance (3)
I. Introduction
Concept
Natural tolerance
Acquired tolerance
II. Factors Affecting Tolerogenicing of
Antigen
III. Mechanisms of Tolerance Induction
IV. Clinical significance of immunologic tolerance

2. Concept
Immunological tolerance is a state of unresponsiveness that is specific for a particular antigen; it is induced by prior exposure to that antigen.

3. II. Factors Affecting Tolerogenicing of Ag
1. The structure of antigen
2. The antigen dosage
3. The route of administration

4. Low –zone tolerance High –zone tolerance
Tolerance cells T cells T and B cells
Speeds hours slow ( 1-2 weeks)
Time long (months) short (weeks)
Antigens TD-Ag (low-dose) all Ag (high-dose)

5. Experimental induction of tolerance at low and high doses of antigen
Serum anti-BAS
Response to secondary
immunogenic dose of
BSA% of control
Priming dose of BSA,g
100%
Low-zone
tolerance
High-zone
Immunity
Control: signal
Immunogenic
Dose of BSA
Experimental induction of tolerance at low and high doses of antigen

6. III. Mechanisms of Tolerance Induction
1. Clonal deletion therapy
Central thymic tolerance to self Ags-positive and negative selection.
2. Clonal anergy
a.  Lack of signal of activation can cause unresponsiveness
b. The blocking of immunocompetent cells
c. Lack of helper cells
3. The Suppressant effect of various cells

7. Mechanisms of Tolerance Induction
Clonal deletion: physically deleting cells from the repertoire at come stage during their lifespan.
Clonal anergy: downregulating the intrinsic mechaism of the immune response.
Suppression: inhibiting cellular activity through interaction with other cells, such as those producing inhibitory cytokines or idiotype-specific lymphocytes which recognize the antigen receptor itself.

8. B
(A)
(C)
(B)
Blocking of BCR

9. IV. Clinical significance of immunologic tolerance
1. The induction and maintenance of immunologic tolerance
2. The elimination of immunologic tolerance

10. Chapter14 Regulation of the Immune Response (4)
Regulation by antigen
Regulation by antibody
Regulation by lymphocytes
Idiotypic modulation of responses
Neuroendocrine modulation of
immune responses

11. Regulation by antigen
A decline in Ag levels ultimately results in diminished clonal proliferation and a decline in further homuoral or cell-mediated responses.

12. suppress enhance APC B Immune regulation by immune complexes
FcR
BCR
suppress
enhance
Immune regulation by immune complexes

13. Immune regulation by TH
IFN-
IFN-R M
TH2
IL-10
IL-10R
TNF-
IL-2
IL-4
IL-5
IL-6
IL-13
Immune regulation by TH B7
IL-12

14. Idiotypic modulation of responses
According to the network theory, a series (or network) of anti-idiotype antibodies are induced during an immune response; these anti--idiotype antibodies act to upregulate the immune response in some cases and to downregulate it in other cases.

15. Idiotypic modulation of responses
Anti-idiotype 2 4 3 1
Internal image group
Nonspecific parallel group
idiotype Ag
1：ARC（antigen reaction cell）
2：ARC stimulate cells
3：ARC suppress cells
4：idiotype and ARC same cells

16. Neuroendocrine modulation of immune responses
It has long been known that stressful conditions may lead to a suppression of immune functions, for example, reducing the ability to recover from infection. There is considerable evidence demonstrating that the nervous, endocrine and immune systems are interconnected. Broadly, there are two main routes.
a.  Most lymphoid tissues receive direct sympathetic innervation, both to the blood vessels passing through the tissues, and directly to the lymphocytes themselves.
b. The nervous system directly or indirectly controls the output of various hormones, in particular, corticosteroids, growth hormone, thyroxine and adrenaline.

17. Neuroendocrine modulation of immune responses hypothalamus anterior
pituitary
thyroid
thymus
gonads
islets
Lymphoid
tissue
adrenal
interleukin-1
T cells
thymic
hormones
insulin
Sex hormones
corticosteroids
catecholamines
Groeth hormone
Neuroendocrine
modulation of
immune responses