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

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

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

Low –zone tolerance High –zone tolerance Tolerance cells T cells T and B cells Speeds 24 hours slow ( 1-2 weeks) Time long (months) short (weeks) Antigens TD-Ag (low-dose) all Ag (high-dose)

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% 10-12 10-9 10-6 10-3 1.0 Low-zone tolerance High-zone Immunity Control: signal Immunogenic Dose of BSA Experimental induction of tolerance at low and high doses of antigen

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

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.

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

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

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

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

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

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

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.

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

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.

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