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GENERAL CONCEPTS

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

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GENERAL CONCEPTS

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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 • Immunologically Privileged Site Antigen Sequestration • 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 to allografts • Examples: fetus, brain, anterior chamber of eye • Lymphocytes have access and self antigens exit • Lack of conventional lymphatics • Rich in inhibitory molecules

  7. DELETION • Autoreactive cells killed • Negative selection in thymus Main mechanism of central tolerance • Activation-induced cell death Peripheral tolerance mechanism T cells die during an immune response

  8. Medulla

  9. Thymic Selection • Final outcome depends on both thymic & peripheral environments • Males usually do not have T cells specific for male self antigens, but females do • For bone marrow transplant patients, donor must share some MHC molecules with recipient for donor precursor T cells to become mature cells • Donor T cells will fail to be positively selected on mismatched recipient MHC molecules

  10. Possible Outcomes of Selection Positive Selection If autoreactive, Negative Selection Failure of Positive Selection

  11. What is different? Avidity Model vs. Differential Signaling Model

  12. Not 100% effective

  13. Activation- Induced Cell Death Apoptosis is mediated by Fas pathway. Defect causes fatal multi-organ autoimmune disease

  14. SUPPRESSION • Hallmark Feature: Adoptively transferred with T cells • Infectious Tolerance • Regulatory CD4+ T cells secrete inhibitory cytokines especially TGF-b, and impair presenting cell function • Release of soluble cytokine receptors • Immune Deviation - Change TH1 to TH2 response or reverse

  15. Regulatory T cells • Viewed as most important suppressive mechanism • TH3 in mucosal immune system - defect linked to autoimmune diseases in gut • TR1 generated in culture • TH3 & TR1 are adaptive regulatory T cells • Treg is natural regulatory T cell • Linked suppression

  16. Treg IL-4, IL-10, TGF-b FoxP3 Impair CTLA-4 required for function of Treg cells Mutations in FoxP3 cause fatal multi-organ autoimmune disease in humans

  17. Soluble cytokine receptors neutralize cytokines

  18. Immune Deviation = Cytokine Deviation Subverts main pathological mechanism causing tissue damage and destruction

  19. 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 co-stimulatory signal

  20. Peptide analog acts as partial agonist Generates negative signal

  21. Role of CD4 and CD8 co-receptors in TCR primary signal

  22. Not suppression Impairs primary signal through TCR

  23. Second signal = co-stimulatory Primary signal

  24. 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.

  25. Lack of signal via CD28 renders T cells unable to produce IL-2

  26. B-7’s CD28

  27. CTLA-4 allele increases risk for certain autoimmune diseases in humans

  28. 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 co-stimulatory 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

  29. Two Roles of CTLA-4 in Tolerance • Delivers negative signal to CD8+ cytotoxic T cells and classical CD4+ helper T cells • Overrides positive signals through T cell receptor and co-stimulatory molecules • Critical for function of regulatory T cells that suppress autoimmune responses • CTLA-4 defects cause massive proliferation of classical helper T cells and systemic autoimmune disease

  30. 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

  31. Example of Immunological Ignorance

  32. IMMUNOLOGICAL IGNORANCE • Involvement of 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 to mouse and nothing happens. 2. Administer peptide of mouse cytochrome c, and autoimmune disease develops.

  33. Promising Immunotherapies -To Induce Suppression • Soluble TNF receptor to treat rheumatoid arthritis, ankylosing spondylitis and severe psoriasis Enbrel is FDA-approved • Th1 cytokines to treat IgE-mediated allergies

  34. Promising Immunotherapies - To Induce Anergy • Anti-B7 antibodies to prevent graft rejection • Soluble CTLA-4 to treat autoimmune diseases and prevent graft rejection Orencia is FDA-approved for rheumatoid arthritis • Peptide agonists to treat allergies • Anti-CD4 antibody to prevent graft rejection and treat multiple sclerosis

  35. Promising Immunotherapies for Cancer • Anti-CTLA-4 antibody to boost T cell responses Clinical trials with non-Hodgkin’s lymphoma, and colon & ovarian cancer patients Ipilimumab to treat melanoma, prostate & lung cancer - FDA application pending • Killed tumor cells expressing B7 genes to induce T cell responses Clinical trials with melanoma, renal cell carcinoma, and glioblastoma patients

  36. T

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