IMMUNE TOLERANCE 1.pptx

immune tolerance

1. IMMUNE TOLERANCE CANCER AND TRANSPLANTATION IMMUNOLOGY Presenter – Dr. Vaishali T Moderator – Dr. Vedavati B.I

2. IMMUNOLOGICAL TOLERANCE Immunological tolerance is defined as the unresponsiveness of the immune system to an antigen. Normally immune system is self tolerant ( mature B and T cells). This process and mechanism that control it are collectively termed tolerance, or self tolerance. An antigen can become an immunogen or tolerogen depending on Dose , duration and route of antigen administration or exposure. Maturation state of lymphocytes (B and T). Forms and conditions of antigen.

3. It is mediated by two broad mechanism Central tolerance – development of lymphocytes Peripheral tolerance – regulation of lymphocytes in circulation

4. CENTRAL TOLERANCE This refers to the deletion of self-reactive T and B lymphocytes during there maturation in Central lymphoid organs (i.e. in thymus for T cells and bone marrow for B cells) IN THYMUS- During the T cell development in thymus, if any self antigens are encountered, they are processed and presented by thymic antigen presenting cells(APCs). i ) Positive selection ii) Negative selection

5. POSITIVE SELECTION Cells whose TCR fail to interact with MHC-self peptide molecules undergo Death by neglect. Cells that bind too strongly to MHC self peptide complex also dies. Only cells that recognise the MHC molecule with Moderate/Low affinity survive ( POSITIVE SELECTION )

6. NEGATIVE SELECTION and CLONAL DELETION Cells that bind too strongly to MHC self peptide complex are induced to undergo programmed cell death ( APOPTOSIS ). Affects class I and class II MHC restricted T cells – tolerance to CD4 and CD8 cells. This results in self tolerance

7. CENTRAL TOLERANCE IN THYMUS IN BONE MARROW- When developing immature B-cells in the bone marrow encounter a self antigen during there development, the tolerance is developed by i ) Receptor editing ii) Negative selection

8. i ) RECEPTOR EDITING- A process by which the Ig genes coding light chains V(D)J are rearranged so that a different (edited) B cell receptor is produced. Which no longer reacts to self antigen. ii) NEGATIVE SELECTION- After receptor editing, if the B cells again recognise a self antigen, then they are destroyed by subjecting them to apoptosis.

9. ESCAPE FROM CENTRAL TOLERANCE TWO FACTORS CONTRIBUTE TO THIS- Not all self antigens are expressed in the central lymphoid organs where negative selection occurs. There is a threshold requirement for affinity to self antigens before clonal deletion is triggered.

10. PERIPHERAL TOLERANCE Mature self-reactive lymphocytes that recognise self antigens in peripheral tissues are inactivated, killed or supressed. It is done by various mechanisms. Anergy Suppression Deletion

11. ANERGY- It can be defined as unresponsiveness to antigenic stimulus. The self reactive T cells interact with APCs presenting the self antigen, but the co-stimulatory signal (CD28 on T helper cell and CD80/86 on APC) is blocked – no immune response. The B7 molecules on APC bind to CTLA-4 molecules on T cells instead of CD28 molecules.

12. Mechanism of anergy

13. 2. Suppression of T reg cells: These are special subset of CD4 T h cells with high expression of IL-2R α ( CD25). Express high CTLA4 – engages with CD80/86 on APC - IL6, TNF α . APC – IDO (indolamine2,3 dioxygenase – kynurenine – inhibit immune cells. T reg – IL10, TGFβ, IL 35. Supress bystander T cells – linked supression  

14. DENDRITIC CELLS Dendritic cells uptake antigens in there immature state but cant present to T cells Present antigen to T cells only when they are mature When certain immature DCs and tolerogenic DCs capture the self antigen for processing, they act indirectly by induction of regulatory T cells.

15. Deletion Extremely important for maintaining immune homeostasis in healthy individuals. Activate Bim (pro apoptotic) – mitochondrial apoptotic pathway. Activation induced cell death (AICD)- Self reactive T cells are activated after interacting with APCs presented with self antigen. But the activation of T cells induces upregulation of Fas ligand which subsequently interact with the death receptor Fas leading to Apoptosis.

16. SEQUESTRATION OF SELF ANTIGEN Self antigen may be sequestrated in some tissues and will never be available to T cells Allows these antigens to avoid encounter with reactive lymphocytes under normal circumstances 2 ways Physical barrier- Location of antigen in privileged sites Immunological barrier- Never processed by functional APCs

17. Privileged sites Cells ignore self antigens if they are expressed in immunologically privileged sites. The brain The anterior chamber and lens of eye Testes In these sites pro inflammatory lymphocytes are controlled by Apoptosis Cytokine secretion

18. IMPORTANCE OF INDUCED TOLERANCE To protect us from unpleasant, even dangerous, allergic reactions to such things as food (e.g. peanuts), insect stings, grass pollen (hay fever) To enable transplanted organs (e.g., kidney, heart, liver) to survive in their new host (graft rejection) To reveal the mechanisms of autoimmunity for designing treatments for systemic lupus erythematosus (SLE) and multiple sclerosis (MS)