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Lymphocyte Selection and Tolerance Chander Raman 2004

Lymphocyte Selection and Tolerance Chander Raman 2004. Lecture Focus: Lymphocyte Selection: Central Tolerance T-cell selection B-cell selection Peripheral Tolerance Peripheral control of autoreactivity. Breakdown of tolerance Autoimmune diseases Restoration of tolerance

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Lymphocyte Selection and Tolerance Chander Raman 2004

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  1. Lymphocyte Selection and ToleranceChander Raman2004

  2. Lecture Focus: • Lymphocyte Selection: Central Tolerance • T-cell selection • B-cell selection • Peripheral Tolerance • Peripheral control of autoreactivity. • Breakdown of tolerance • Autoimmune diseases • Restoration of tolerance • Treatment of autoimmune diseases

  3. Tolerance: Inability to respond to antigen stimulation OR Immunological unresponsiveness. • Why do we need tolerance? • Initial T-cell receptor rearrangement or B-cell receptor rearrangement leads to generation of repertoire that has the potential to recognize all antigens – • DOES NOT DISCRIMINATE BETWEEN SELF-REACTIVITY AND REACTIVITY TO FOREIGN ANTIGENS

  4. Tolerance: • Central tolerance • Negative selection of immature lymphocytes by clonal deletion of self reactive clones during development. • T cells – thymus • B cells – bone marrow Clonal deletion occurs by induction of programmed cell death or apoptosis

  5. T-Cell Selection - Overview Double Negative (Positive selection for ability to recognize antigen) Death by Neglect Double Positive CD4+CD8+ (Negative Selection) Single Positive CD4+ or CD8+ (Positive selection based on MHC reactivity) Negative Selection

  6. Death by Neglect B Menu F

  7. B Menu F

  8. B Menu F

  9. Evidence for Requirement for Central Tolerance • AIRE (autoimmune regulator) Transcription Factor –”Master” Regulator of Ectopic Expression of Peripheral Tissue- Restricted Antigens in stromal cells of the thymic Medulla. • Originally identified as a human autosomal recessive disorder known as APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. • AIRE-/- mice exhibit wide spread organ-specific autoimmunity, such as ovary, retina testis, stomach. (Anderson et al, Science)

  10. Loss of Thymic Selection lead to Autoimmunity AIRE-Deficient Mice Normal Mice Autoantibodies to different organs shown in GREEN in AIRE-deficient mice

  11. AIRE allows for the expression of antigens to which T-cells are negatively selected.

  12. B-Cell Development Sensitive to Negative Selection – Central Tolerance

  13. B-Cell Selection in the Bone Marrow Binding to self molecules in the bone marrow can lead to the deletion or inactivation of immature B cells.

  14. Factors That Regulate Central Tolerance • Most Important – Strength of Signals initiated by antigen receptor • Intracellular signal strength is dependent on: • Avidity of interaction of between antigen and antigen receptor • Affinity of interaction between antigen and antigen receptor • Co-stimulatory signals that enhance signal strength (CD28) • Signals that attenuate signals strength – Inhibitory receptors (CD5)

  15. Survival Death by Neglect Negative selection Positive selection Death Signal Strength Co-stimulation Inhibition (attenuation)

  16. Peripheral Tolerance • Not all self-reactive T or B cells are deleted during development. Reasons include: • Need for a peripheral repertoire that will protect from pathogens • Peripheral tissue specific antigens not expressed in the thymus. • Expression of neo-antigens occurring as a result of tissue damage. • Expression of specific endopeptidases that modify peptides in thymus. • Positive selection of specificities that exhibit weak self-reactivity but with the propensity for pathogenic autoreactivity. Control of autoreactive T cells in the periphery is termedPeripheral Tolerance

  17. Peripheral Tolerance • Peripheral control of autoreactivity

  18. Peripheral Tolerance: • Clonal deletion, clonal anergy or clonal ignorance of mature self-reactive T and mature or transitional B cells. • Regulated by: • Co-stimulatory molecules (signal 2) • Cytokines (signal 3) • Inhibitory molecules • T-regulatory cells (Tr), T-suppressor cells (Ts) • Dendritic cells.

  19. Anergy and/or Apoptosis

  20. T Regulatory Cells (Tr) CD4+ CD25+ Maloy and Powrie, Nature Immunol. 2:816

  21. T suppressor cells and Inhibitory Molecules Feinberg & Silvestri, Nature Immunol, 3:215

  22. Tolerance Induction by Dendritic Cells Lutz and Schuler, Trends Immunol: 23:9

  23. Immunity vs Tolerance in Peripheral B Cells

  24. Breakdown of tolerance • Autoimmune diseases

  25. Venn Diagram: Requirements for the Development of Autoimmune Disease Focus on Autoimmunity Nature Immunology, Sept 2001 (Vol 2) www.nature.com/ni

  26. Development of Autoimmunity

  27. Autoimmune Diseases • Organ specific autoimmune diseases: • Immune response directed to a specific organ leading to cellular damage and organ destruction • Diabetes – Cell mediated immune response to pancreatic islet beta cells. • Goodpasture’s syndrome – Antibody to basement membrane of kidney glomeruli. • Graves disease – Stimulating antibody to thyroid stimulating hormone receptor (TSHr)

  28. Autoimmune Diseases • Systemic autoimmune diseases: • Immune response to wide variety of antigens involving several organs and tissues. Often involves both cell-mediated and humoral. • Systemic lupus erythematosus (SLE) – Primary antibody response to DNA and nucleoproteins and progressive development of antibodies to other tissues. • Rheumatoid arthritis (RA) – IgM antibodies to Fc portion of IgG. • Multiple sclerosis (MS) – T cell response to myelin basic protein

  29. Organ Specific and Systemic Autoimmune Diseases in Human

  30. Hypothesis for the Development of Type 1 Diabetes

  31. Systemic Lupus Erythematosus

  32. Susceptibility to Autoimmune Diseases • Genetic Predisposition • MHC genes – eg. HLA DR4 in Diabetes • Other susceptibility genes • Sex Differences

  33. Contribution of Susceptibility Gene Alleles to Development of Autoimmunity

  34. Therapeutic Intervention • Conventional therapeutic approaches • Anti-inflammatories, immunosuppressive drugs, Cytotoxic drugs • New therapies • TNFr (EMBREL – etanerecept) • anti-CD20 (depletes B-cells – treatment of SLE) • Experimental/New approaches • TNF receptor family agonists/antagonists • Blys/BlysR(s) (Inhibition of activation and differentiation) • TRAIL/TRAILR(s) (Apoptosis inducing)

  35. Decoy Receptors in Regulation of Lymphocyte Activation and Autoimmunity Soluble Receptor Agonist or antagonist antibody Pharmacological Inhibitors Ware, Nature. 404:949

  36. Decoy Receptors In Treatment of Autoimmune Diseases

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