Chapter 15 Immunological Tolerance

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 —

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.

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.

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

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

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.

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

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

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

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) ___________________________________________________

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

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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

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

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

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