Immune tolerance

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  1. 1. What is Immune Tolerance? Immune tolerance refers to the state of a biological system where there should be an immune response, but there is none
  2. 2. Tolerance refers to a state of specific unresponsiveness to a specific antigen or failure to mount an immune response to an antigen it is an active response to a particular epitope and is just as specific as an immune response It is induced by prior exposure to that antigen does not necessarily mean total lack of immune response Antigens that induce tolerance are called tolerogens
  3. 3. Highly desirable Tolerance
  4. 4. Undesirable tolerance
  5. 5. In 19th Century, Paul Ehrlich coined the term Horror Autotoxicus means horror of self toxicity it was realized that there must be a mechanism to prevent auto antibody formation a normal body does not mount immune response against its own tissues Implied the need for regulating contrivance to stop production of auto antibodies
  6. 6. Discovery of Immune tolerance In 1938, Traub inoculated mice in Utero with lymphocytic choriomeningitis virus Resulted in symptomless, carrier state Virus was present in blood and other organs, but no antibody was produced If mature virus was inoculated, they produced antibody
  7. 7. Experiment contd. Ray Owen was the first to observe the phenomenon of immunological tolerance in vivo He observed that non-identical dizygotic twin cattle shared each others RBC through their common placenta Each twin had its own red blood cells and a second set of cells derived from the other twin Neither twin made antibodies against the blood cells of the other Owen concluded that exposure of the immature immune system to a foreign antigen resulted in specific tolerance to that antigen
  8. 8. Burnets clonal selection theory Following Owens observation, scientists Burnet and Fenner postulated that age of animal at time of first encounter against non-self antigen is a critical factor Antigens encountered before birth result in deletion of specific clones at some stage in early embryonic development (Clonal deletion) It means that if immune system encounters antigens, while it was immature the relevant lymphocytes become tolerized would ensure that self-reactive antibody-forming cells are physically eliminated before birth and Only antibody-forming cells able to react to not-self persist
  9. 9. Clonal selection (1) A hemapoietic stem cell undergoes differentiation and genetic rearrangement (2) immature lymphocytes are produced with many different antigen receptors (3) Those that bind to antigens from the body's own tissues are destroyed (4) the rest mature into inactive lymphocytes (5) those that encounter a foreign antigen are activated (6) Produce many clones of themselves
  10. 10. Medawars Experiment In 1953, Peter Medawar and his colleagues induced immunological tolerance to skin allografts in mice by neonatal injection of allogenic cells (grafts that are genetically non identical but are from same species) The hypothesis was that mammals and birds never develop, or develop to only a limited degree, the power to react immunologically against foreign homologous tissue cells to which they have been exposed sufficiently early in foetal life Consistent with Burnets theory
  11. 11. Strain A mice normally rejects graft from strain B neonatal injection of spleen cells from strain B into strain A Newborn strain A mice show tolerance to skin grafts from strain B but reject grafts from strain C
  12. 12. Lederbergs modfication of clonal theory Burnets hypothesis implied that all antibody-forming cells (lymphocytes) are generated during fetal development However, it soon became clear that lymphocytes are generated throughout life In 1959, Lederberg suggested modification of Burnets theory
  13. 13. States that, responsiveness is not determined by the developmental stage of individual Rather, It is the state of maturity of the lymphocytes at the time of encountering antigen According to this modification, if lymphocytes contact antigen in its immature stage they are subjected to clonal abortion (removal of immature lymphocytes that interact with antigens, via cell death) If encountered when in mature state, they become activated
  14. 14. The Danger Hypothesis In 1994 Polly Matzinger suggested a new immunologic model states that the immune system does not distinguish between self and nonself discriminates between dangerous and safe by recognition of pathogens or alarm signals from injured or stressed cells and tissues pathogen or cell-associated stress compounds, can induce immune cells
  15. 15. Self vs non-self Immunological SELF implies to all epitopes encoded by the individuals DNA All others are considered non-self Other factors that also determines self or non-self include The stage of differentiation when lymphocytes first encounter the epitopes The site of the encounter The nature of cells presenting the epitopes The number of lymphocytes responding to the epitopes
  16. 16. Ways to prevent responding to self Ag Five possible ways- 1. Self-reactive cells may be deleted at certain stages of development 2. Self reactive cells may be unable to respond 3. Self- reactive T cells in circulation may ignore self Ags 4. Response to self Ag may be suppressed if the Ag is in a privileged site 5. Tolerance can be maintained by immune regulation
  17. 17. Which of these mechanisms would work depends on The stage of maturity of the lymphocyte The affinity of the receptor for the self Ag The nature of the Ag Concentration of the lymphocyte Tissue distribution of lymphocyte Pattern of expression of lymphocyte
  18. 18. The kinds of tolerance Tolerance is classified into 1. Central tolerance: tolerance of T or B cells induced in during development in the primary lymphoid organs (the bone marrow for B cells and the thymus for T cells) 2. Peripheral tolerance: induced in other tissues and lymph nodes The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.
  19. 19. Central tolerance of T cells takes place during their development within the thymus depends on a number of checkpoints through which cells have to pass in order to develop The process of generating new T cell receptors involves gene rearrangement to generate a highly diverse T cell receptors Such a broad variety is necessary to provide protection against different infectious agents
  20. 20. Stages of T cell Development Double Negative (DN) stage Double Positive (DP) Stage Single Positive (SP) stage
  21. 21. Double Negative (DN) Stage Immature T cells enter the thymus and express neither CD4 nor CD8 co-receptors, hence called double negative (DN) cells The TCR b chain genes start recombination
  22. 22. Double Positive (DP) Stage expression of both CD4 and CD8 co-receptors occurs T cells mature into CD4 and CD8 Double positive (DP) cells chain rearrangement initiates TCR structure is completed These cells come into contact with cortical thymic epithelial cells that express high levels of class I and class II MHC molecules on their surface These self-MHC molecules present self-peptides, which are derived from intracellular or extracellular proteins that are degraded in the normal course of cellular metabolism
  23. 23. Thymic Selection of the T cell Repertoire Cells undergo two selection Processes- 1. Positive Selection 2. Negative Selection
  24. 24. Cells whose TCR fail to interact with MHC-self peptide molecules undergo programmed cell death (Death by neglect) Cells that bind too strongly to MHC/self-peptide complexes, also die Only cells that recognize MHC molecules with moderate/low affinity survive (positive selection) Some are able to rescue failed positive selection by receptor editing positive selection ensures that T cells recognize antigen only in association with MHC Positive selection
  25. 25. Negative selection Selected cells then mature to (SP) single positive (CD4 or CD8) T lymphocytes and migrate to the medulla those that bind with high affinity with self-peptide-MHC complexes are induced to undergo apoptosis (clonal deletion) Results in self-tolerance After negative selection, these SP cells pass from the thymus into the circulatory system Only 2% to 5% of DP thymocytes actually exit the thymus as mature T cells
  26. 26. investigations in the late 1990s revealed that the thymus had an extraordinary capacity to express and present proteins from all over the body some medullary epithelial cells of Thymus express a unique protein, AIRE, that allows cells to express, process, and present proteins that are ordinarily only found in other specific organs
  27. 27. Aire promotes the expression of organ-specific genes in medullary thymic epithelial cells (mTECs) These organ-specific proteins are presented on the surface of mTECs by MHC molecules to T cells developing in the thymus Thymocytes that recognize these organ-specific proteins in the context of MHC molecules undergo negative selection Medullary dendritic cells can acquire these antigens by engulfing mTECs, and mediate negative selection The role of Aire is therefore to limit the generation of self reactive T cells
  28. 28. Aire Protein
  29. 29. Checkpoints in T cell development b selection checkpoint- only cells with a rearranged b chain mature from DN to DP a selection checkpoint- cells expressing ab chains must interact with MHC to survive Lineage commitment checkpoint- cells must repress expression of CD4 or CD8 to develop into SP cells Negative selection checkpoint-cells that interact with MHC-self molecules are deleted
  30. 30. The decision to undergo positive or negative selection is directly related to th