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GENERAL CONCEPTS Immune system distinguishes between self ...

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  • 1. GENERAL CONCEPTS • Immune system distinguishes between self (auto) and non-self (foreign) antigens • V genes encode TCR’s and BCR’s with anti-self reactivity • Autoreactive T and B cells are produced • If mature autoreactive T and B cells are activated, autoimmune disease may develop • Self-tolerance mechanisms eliminate or prevent autoreactive cells from responding
  • 2. TOLERANCE • Antigen-specific unresponsiveness • Acquired characteristic - Somatic process • Central tolerance occurs in primary lymphoid organs during lymphocyte maturation • Peripheral tolerance occurs in secondary lymphoid organs involving mature cells • Time dependent • Antigen concentration dependent Low vs. High Zone Tolerance
  • 3. T cells are easier to tolerize than B cells. If helper T cell is tolerant, B cell will not respond. Without T cell help, B cell undergoes apoptosis.
  • 4. Mechanisms of T Cell Tolerance • Antigen Sequestration Immunological Privileged Site • Deletion • Suppression • Anergy • Immunological Ignorance • Receptor Editing NOT important
  • 5. Fetus is an allograft, but no immune response occurs.
  • 6. Immune Privileged Sites • Lack of immune responses • Examples: fetus, brain, anterior chamber of eye • Lymphocytes have access and self antigens exit • Lack of conventional lymphatics • Rich in inhibitory molecules
  • 7. DELETION • Cells killed • Activation-induced cell death Peripheral tolerance mechanism Cells die during an immune response Mediated by Fas pathway • Main mechanism of central tolerance: Negative selection in thymus
  • 8. Activation- Induced Cell Death Apoptosis is mediated by Fas pathway. Defect causes fatal multi-organ autoimmune disease
  • 9. Medulla
  • 10. Implications for bone marrow transplantation patients
  • 11. Avidity Model vs. No Positive Selection Cell Death Differential Signaling Model No Signal DP T Cell Stromal Weak or Partial Cell Positive Selection TCR MHC + Signal Antigen Strong or Full Signal Negative Selection Cell Death
  • 12. SUPPRESSION • Hallmark Feature: Adoptively transferred with T cells • Regulatory CD4+ T cells secrete inhibitory cytokines especially TGF- • Release of soluble cytokine receptors • Immune Deviation - Change TH1 to TH2 response or reverse
  • 13. IL-4, IL-10, TGF- FoxP3 Mutations in FoxP3 cause fatal multi-organ autoimmune disease in humans
  • 14. Soluble cytokine receptors neutralize cytokines
  • 15. Immune Deviation = Cytokine Deviation Subverts main pathological mechanism causing the autoimmune disease
  • 16. ANERGY • Peripheral tolerance mechanism • Cells functionally inactivated and not capable of responding to antigen • Low or no interleukin-2 secretion is one main effect • Cells remain alive • Long-term effect • Caused by improper primary signal or lack of costimulatory signal
  • 17. Peptide analog acts as partial agonist delivering negative signa
  • 18. Not suppression
  • 19. Second Primary signal = signal co-stimulatory
  • 20. Naive T cells interact with professional antigen-presenting cells for a primary response Other cell types lack MHC class II and co-stimulatory molecules and cause anergy.
  • 21. Lack of signal via CD28 renders T cells unable to produce IL-2
  • 22. B-7’s CD28
  • 23. Particular CTLA-4 allele increases risk for certain autoimmune diseases in humans
  • 24. SUMMARY OF ANERGY • Analog peptides act as partial agonist and generate negative signal • Disruption of CD4 or CD8 co-receptors impairs primary signal • Lack of costimulatory signal from non- professional antigen-presenting cells No CD28 signal renders T cells unable to produce IL-2 • CTLA-4 generates negative signal Blocks IL-2 production
  • 25. IMMUNOLOGICAL IGNORANCE • Peripheral tolerance mechanism • Cells are alive and capable of responding • Cells “ignorant” of antigen and do not respond • Occurs if TCR has low affinity and/or antigen concentration is low • Increase in antigen concentration may lead to a response
  • 26. Example of Immunological Ignorance
  • 27. IMMUNOLOGICAL IGNORANCE • One Mechanism involves Antigen Processing • Peptide of intact self protein antigen is not made by antigen-presenting cells during antigen processing • T cells are not tolerant to that self peptide • Example: 1. Administer intact mouse cytochrome c, and nothing happens. 2. Administer peptide of mouse cytochrome c, and autoimmune disease develops.
  • 28. Promising Immunotherapies • Peptide agonists to treat allergies • Anti-B7 antibodies to prevent graft rejection • Soluble CTLA-4 to treat autoimmune diseases and prevent graft rejection • Anti-CD4 antibody to prevent graft rejection and treat multiple sclerosis • Th1 cytokines to treat IgE-mediated allergies • Soluble TNF receptor (Enbrel) to treat rheumatoid arthritis, ankylosing spondylitis and severe psoriasis - FDA approved
  • 29. Promising Immunotherapies - Continued • Anti-CTLA-4 antibody to boost T cell responses to melanoma and prostate cancer • Tumors transfected with B7 genes to induce T cell responses to tumors One published clinical trial with melanoma and glioblastoma patients
  • 30. T

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