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Immunological tolerance
- 2. Antigen • Recognized by immune system • Substance that induces immune response in a body • Can be foreign or self
- 3. Foreign antigen Not part of our body Self antigen Components of our own body
- 4. First line of defense Skin and mucous membrane Second line of defense Defensive cells, Antimicrobial substances, Inflammation, fever Third line of defense T cells, B cells, Antigen presenting cells Foreign Antigen
- 5. BCR TCR Our immune system can generate lymphocytes clones that can virtually recognize any antigen in universe.
- 6. Self antigen Components of our own body Lymphocytes having receptors against self antigens are constantly being generated in our body. Auto-reactive (self-reactive) Lymphocytes How we avoid attack on our own cells and tissues?
- 7. Our immune system has ability to react with enormous and diverse foreign antigens While it is tolerant to self antigen The state of unresponsiveness of the immune system to antigens is known as immunological tolerance The state of unresponsiveness of the immune system to antigens is known as Self tolerance
- 8. Self-Tolerance Achieved by various mechanisms and processes operating on the cell of immune system 1. Central Tolerance • Central refers to primary or central lymphoid organs • T and B lymphocytes first express antigen receptors • Comprises of mechanisms that eliminate most auto-reactive T and B cells during their early development 2. Peripheral Tolerance • Peripheral refers to the secondary or peripheral lymphoid organs • Tolerance induced in mature lymphocytes • Prevent auto-reactive mature lymphocytes from attacking self antigen
- 9. Central T Cell Tolerance Inside Thymus Immature T-cell undergo an elaborate screening process Non-Selection Negative Selection Positive Selection
- 10. Inside Thymus Immature T cell Self peptide: Self MHC molecule Fate of developing T cell depends on…. The strength with which immature T cells interact with Self peptide: Self MHC molecules
- 11. No interaction Apoptosis (of T cells) • Non-functional TCRs • Lack receptors recognizing MHC molecules Non-selection
- 12. Moderate interaction Survival (of T cells) • Interaction is not too strong nor too weak • T cells learn to focus on self-MHC molecules (MHC restriction) Positive selection
- 13. Strong interaction Apoptosis (of T cells) • Potentially auto-reactive cells • Dead cells are phagocytosed by macrophages in the thymus Negative selection
- 14. Peripheral T cell Tolerance Mechanisms: • Peripheral clonal deletion • Anergy • Immune deviation • Immune privilege • Immunosuppressive cytokines • Regulatory T cells Prevent T cell activation Control Immune responses
- 15. Self antigen Danger signals are absent • Co-stimulatory molecules are not expressed. • T cell receives first signal for its activation • No second signal- because co- stimulatory molecules on DCs are absent Peripheral clonal deletion of T cells
- 16. Anergy Some auto-reactive T cells survive But remain INACTIVATED
- 17. What if auto reactive T cells get activated? Other control mechanisms Immune Deviation Potentially harmful immune response is converted into less harmful immune response Regulatory T cells Control the responses of activated T cells Immune privilege Anatomical regions that are less subject to immune responses Immunosuppressive Cytokines IL-10 TGF-β Immunosuppressive effects
- 18. Central B Cell Tolerance Inside Bone marrow Central B cell tolerance uses 3 mechanisms to induce tolerance: Receptor Editing Clonal Deletion Anergy
- 19. Receptor Editing Antigen receptor of autoreactive immature B cell is MODIFIED Immature B cells have ability to rearrange their immunoglobulin genes. Light chain locus
- 20. Receptor Editing Strong cross linking of BCRs and multivalent cells rearranging immunoglobulin genes in the light chain loci Old chain is replaced by new light chain Non self-reactiveSelf-reactive B cell development continues and mature B cell migrate to periphery Apoptosis Clonal Deletion
- 21. Inside Bone marrow B cells become unresponsive Monovalent antigens Interaction with B cells Anergy Monovalent antigens are also present in the bone marrow Anergic cells enter peripheral circulation
- 22. Peripheral B Cell Tolerance Auto-reactive B cell Self antigen B cell becomes unresponsive Absence of signals • B cell requires T cell help for activation • But auto-reactive T cells are eliminated by Central Tolerance • Without T cell help, there is no signals for auto- reactive B cell activation
- 23. Thank you