医学免疫学课件：免疫耐受

1、免疫耐受免疫耐受 Immune toleranceImmune tolerance *Definition *History （Early observations ) *Mechanism Central Tolerance Peripheral Tolerance *Induction (Acquired tolerance) Immunological Tolerance Immune tolerance or Immunological tolerance is the process by which the Immune system does not attack an anti

2、gen. Specific immunological unresponsiveness to a given antigen. It occurs in 2 forms: natural tolerance (self tolerance) and acquired tolerance (induced tolerance). Definition Immune response vs tolerance Immune Response Immune Tolerance Antigen Yes Yes Latency Yes Yes Antigen specificity + + Memor

3、y + + Response Strong no or weak Function reject non-self protect self Immune tolerance is an active process which is different from immunodeficiency or immunosuppression. Immunodeficiency: A disorder or state in which the Immune systems ability to fight infectious disease is compromised or entirely

4、 absent. Overall Inability of the immune system to respond to a broad range of antigens (genetic reason or AIDS). Immunosuppression: A condition where the activation or efficacy of the immune system is reduced (induced by an immunosuppressant ). Immune tolerance Self tolerance: Individuals normally

5、do not respond to their self“ antigens, i.e., they are tolerant to self. This is the basis for self- non self discrimination by the immune system to ensure immune system not to attack self. Loss of self tolerance can lead to autoimmunity. Natural Tolerance (self tolerance): Induced unresponsiveness

6、to foreign Ags. It can be used to facilitate transplantation or when tolerance is necessary (acquired tolerance) Acquired tolerance Early Observations Ray Owen, 1945 Dizygotic cattle twins that shared the same placenta were blood cell chimaeras, ie contained blood cells of two different haplotypes i

7、n adults and, - these two haplotypes co-existed in the adults without mutual rejection. Ray Owen Such chimaeric cattle will exchange skin grafts without rejection. Normally, if cells of one of the two haplotypes were transferred to an adult cattle of the other haplotype, these were promptly rejected

8、. Thus, tolerance in the dizygotic twins resulted from the sharing of the placenta in fetal life. Early Observations During neonatal stage of life, or when immune system is developing, all Ags present are recognized as self. Immune system becomes tolerant to these Ags. In 1953, Billingham, Brent and

9、 Medawar demonstrated that immunological tolerance could be acquired by introduction of donor cells during fetal development tolerance permanent and Ag specific. Burnets Hypothesis:(1949) Medawars experiment(1953) Early Observations Billingham and Medawar proved Burnets Hypothesis Early Observations

10、 Early Observations Chimeric mice 1960 Nobel Prize Human Immunology Volume 52, Issue 2 *Definition *History-Early observations *Mechanism *Induction Immunological Tolerance Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self during their

11、 development in thymus and bone marrow. Mechanisms (Earlier ) Positive selection: During positive selection Double-Positive T cells that can recognize self MHCs are selected for proliferation, and those T cells that do not recognize self MHC die via Apoptosis. Positive selection assures TCR to recog

12、nize self- peptide/MHC complex and also go with the appropriate CD4 or CD8. For example, TCRs specific for MHC II need to retain CD4, and lose CD8. If the reverse occurs, they will die via apoptosis. The same is true for the T cells that are specific for MHC I, which need to retain CD8, and lose CD4

13、. Thymocytes are positive selected by MHC/self peptides Negative selection: T cells that are strongly activated by self MHC plus self peptides need to be eliminated in the thymus. complex. If they escape this elimination, they may subsequently react against self antigens, and cause Autoimmune diseas

14、e. Central Tolerance is achieved by negative selection Mixture of clones with different affinity to self antigens Positive selected Apoptosis by neglect Apoptosis by AICD - Negative selected Released to Peripheral A Cartoon view of positive and negative selection Avidity Model: Avidity depends on th

15、e affinity of the TCR-peptide/MHC interaction and the density of the peptide/MHC on the thymic epithelial cell. Avidity determines the strength of signal delivered which dictates the outcome. Stronger signals may mean longer signaling or additional signaling. Positive Selection vs Negative Selection

16、 Apoptosis of negative selected cells are mediated by the Bcl apoptosis pathway In summary, Positive selection selects for those T cells that react with MHC: self antigen. Negative selection eliminates those that react strongly with MHC: self antigen. Thus, successful T cell differentiation selects

17、for MHC restricted TCRs with low affinity for self antigens. The rationale here is that a T cell that binds weakly to self MHC/self Antigen will not be activated but will be activated by a stronger binding to self MHC/ foreign Antigen Summary of central tolerance Kisielow and von Boehmer 1988 - HY t

18、ransgenic mice HY transgenic mice made by isolating TCR a and b chain cDNAs from CD8+ CTL clone derived from H-2b female mouse. This TCR recognizes a male-specific peptide bound to H-2Db. The HY TCR transgene promotes the development of SP CD8 but not CD4 T cells in H-2d/b but not in H-2d/d mice. Ev

19、idence for positive selection Female H-2d/b Female H-2d/d “selecting” “non-selecting” Background Backgrounds Evidence for Negative selection. Kisielow and von Boehmer 1988 - HY transgenic mice Harald von Boehmer Harvard Medical School Ligands for Positive and Negative Selection Ligands are necessary

20、 for both positive and negative selection. (self-endogenous peptide/MHC complexes presented by stromal and hematopoietic cells） low dose high dose Paradox: It is critical to delete thymocytes expressing TCRs that would react with self peptides presented by MHC molecules on BM-derived APCs in the per

21、iphery. Some peptides are derived from circulating blood cells or serum components. Deletion of T cells in the thymus also requires local expression of the tissue specific antigens (e.g. insulin, MBP). What cell in the thymus is expressing self-proteins? What makes this particular cell to express al

22、l these tissue-specific genes? Central tolerance The answer: A large variety of tissue specific proteins are expressed in the thymus by MEC (medullary epithelial cell) Central tolerance Tissue-restrictive genes expressed by MECs But How? Central tolerance AIRE(autoimmune regulator): transcription fa

23、ctor that enables ectopic expression in the thymus of genes usually considered tissue-specific Normal AIRE knockout From M. Anderson, et al. (Laboratory of C. Benoist and D. Mathis). Joslin Diabetes Center and Harvard Medical School; Science 298:1395, 2002 Spontaneous Autoimmune disease in AIRE knoc

24、kout mice Autoantibodies Spontaneous Autoimmune disease in AIRE knockout mice Organ-Specific lymphocyte infiltrations Deletion of self-reactive T cells in the thymus AIRE (autoimmune regulator) is a putative transcription factor that stimulates expression of many self antigens in in the thymus Diane

25、 Mathis and Christophe Benoist Central tolerance Diane and Chris visiting ZJU 2012 TSAs presentation in thymus Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystro

26、phy (APECED)。 APECED, also known as autoimmune polyendocrine syndrome-type 1(APS-1), is a polyglandular disorder that classically manifests as spontaneous autoimmunity against the parathyroid and/or adrenal glands, and/or by a mucocutaneous candidiasis infection. Other common ailments include autoim

27、mune forms of premature ovarian failure, hepatitis, anemia, diabetes, alopecia, and vitiligo. It seemed reasonable to hypothesize that APECED patients develop multiorgan autoimmunity because a defect in AIRE prevents or modifies ectopic transcription of genes encoding peripheral tissue-restricted an

28、tigens in thymic MECs. APECED in human AIRE Structure Fas surface expression is normal Heterozygous Fas splice mutation resulting in loss of exons 3, 4 (AA 52-96) WT Fas PT 2 28 66 128 174 214 298 51 97 del 52-96 TM TM Peripheral T cell tolerance Regulatory cells Peripheral T cell tolerance IPEX Dis

29、ease characteristics. IPEX syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life. The majority of affected males die within the first year of life of either metabolic derangements or sepsis; a few survive into the second or third decade. Diagnos

30、is/testing. Diagnosis is based on clinical findings. FOXP3 is the only gene currently known to be associated with IPEX syndrome. Approximately 50% of males with IPEX syndrome have mutations identified in FOXP3. Molecular genetic testing is clinically available. Other Peripheral tolerance determinant

31、s Cytokines： 1. Limited supply of pro-survival cytokines (IL7 for T cell and BAFF for B cells)； 2. Secretion of suppressive cytokines TGF-beta, IL10 Signaling pathways: Inhibitory receptors; negative regulators including Phosphotases、 Ubiqutin Ligases。 *Definition *History-Early observations *Mechanism *Induction （acquired tolerance） Immunological Tolerance 1. Establish immune tolerance will facilitate organ transplantation, reduce the chance or autoimmune disease. 2. Breakdown of immune tolerance to enhance anti-tumor immune response or some viral