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Pharm immuno12 &13 tolerance & autoimmunity


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Pharm immuno12 &13 tolerance & autoimmunity

  1. 1. Pharm-Immuno 12&13 Immunologic Tolerance & Autoimmunity Dr. Saber Hussein
  2. 2. Objectives 1. Define and explain the concept of immunologic tolerance 2. Categorize the conditions that influence tolerance induction 3. Know the mechanisms that induce self-tolerance 4. Know the benefits & disadvantages of tolerance
  3. 3. Tolerance & Anergy Tolerance : The acquisition of a specific nonresponsiveness to a molecule recognized by the immune system as nonself Tolerogen: An otherwise immunogenic substance that, because of its chemical composition, dose, or route of introduction, induces immunologic tolerance rather than immunity Anergy: An absence of cell-mediated immune reaction in supposedly sensitized animals or individuals. No allergic response to an immunogen or allergen In advanced cases of TB, infections with Mycobacterium tuberculosis , the tuberculin test becomes negative
  4. 4. Central & peripheral tolerance to self Ags Central tolerance Immature lymphocytes specific for self Ags may encounter these Ags in the generative lymphoid organs (bone marrow & thymus) and are deleted Peripheral tolerance Mature self-reactive lymphocytes may be inactivated or deleted by encounter with self antigens in peripheral lymphoid tissues
  5. 5. Consequences of the lymphocyte-Ag encounter Naive lymphocytes may be activated to proliferate and differentiate by immunogenic antigens Tolerance is induced when tolerigenic antigens induce functional anergy (unresponsiveness) or apoptosis , leading to an inability of the cells to again respond to the same Ag even in an immunogenic form Some Ags are ignored by lymphocytes, resulting in no response, but the lymphocytes are capable of responding to the same antigen in an immunogenic form Fig 9-1
  6. 6. Tolerance induction Tolerance is a secondary "nothing" response Conditions that influence tolerance induction: The immunologic maturity of an animal & its immune cells The dose of Ag The physico-chemical nature of the Ag Immunogenicity of an Ag Route of Ag administration Kind of recipient
  7. 7. Mechanisms that induce self-tolerance Three principal mechanisms that induce self-tolerance: [1] Physical elimination or clonal deletion [2] Functional inactivation, anergy [3] Regulated inhibition of Ag-reactive T & B cells Induction of self-tolerance can occur at three levels : i. The T-cell level ii. The B-cell level iii. The T-cell-B-cell cooperative level
  8. 8. T Cell Positive & Negative Selection in the Thymus MHC-restriction is not preprogrammed into T cells It is acquired (a) by contact with humoral factors and (b) by physical interaction of TCR-expressing cells with MHC molecule-expressing cells during T-cell development in the thymus Positive and negative thymic selection is a life or death process for the developing T cell: Positive selection for self-MHC-restricted cells Negative selection of autoreactive T cells Mature T cells are self-MHC-restricted and self-tolerant because all thymocytes whose TCRs show strong recognition of self Ags are eliminated
  9. 9. IL-2 synthesis is controlled by costimulatory signals CTLA-4 is a CD28 homologue that is synthesized after the activation of T cell. When CTLA-4 ligates B7 it blocks activation signals that is No more IL-2 is synthesized leading to cell death
  10. 10. Ags can induce any of the following: Clonal abortion : multivalent antigen can , when given in appropriate concentrations, cause immature B cells to abort by preventing their further differentiation  Tolerizability of pre-B cells is high Clonal deletion : very strong negative signals (missing Ag; absence of T H ) can cause deletion of mature B cells Clonal anergy : intermediate concentration of multivalent antigen allows pre-B cells to develop into morphologically normal B cells , with normal numbers of immunoglobulin receptors, but renders them profoundly anergic
  11. 11. T cell & B cell tolerance Because the thymus activity decreases into adulthood most T cell lines are present after birth The clone that dies or becomes tolerant will not or only slowly be replaced with active T cells  T cell tolerance stays for long time B cells are made life long in the bone marrow Later encounter with immunogenic Ag would activate the new B cells  B cell tolerance is shorter
  12. 12. Advantages & disadvantages of tolerance Advantages Self-tolerance is essential for the function of the immune system Tolerance to foreign tissue grafts Gene therapy Control of damaging immune responses such as: i. Hypersensitivity Autoimmune diseases Disadvantages Tolerance to certain foreign antigens that cause disease such as bacterial infections Tolerance to some self-antigens associated with cancer
  13. 13. Autoimmunity/Objectives Define autoimmunity Know the multiple etiologies for autoimmune disease and the central role of helper T cells Describe cell-mediated autoimmunity leading to autoimmune disease antibody-mediated autoimmunity leading to autoimmune disease List other factors that may lead to autoimmune disease Discuss some of the approaches used in the treatment of autoimmune diseases; appreciate the preventive approaches to specifically eliminate the causes
  14. 14. Autoimmunity, definition, mechanism Autoimmunity: The immune response of the body with antibodies or cell-mediated immunity to self-tissues or antigens , resulting in pathological consequences and autoimmune disease
  15. 15. Etiologies of autoimmune diseases Genetic factors : Involvement of genetics is evidenced by the fact that monozygotic twins, dizygotic twins and family members have increased predisposition for certain diseases. Such inheritance is polygenic. Examples: SLE (anti-dsDNA Abs) Type 1 diabetes (>14 genes are involved) HLA genes are associated with several autoimmune diseases Environmental factors : They trigger autoimmune diseases. There are Ags that are sequestered from the lymphoid system. Examples: Lens and uveal proteins of the eye Spermatozoa. Accidents might end the sequestration of such Ags leading to autoimmunity
  16. 16. Tolerance Autoimmunity Absence of T H cells: Low dose of Ag  T-cell tolerance B cells are not affected but because T H is lacking  No auto-Ab production Control by Ts Absence of MHC II on potential target cells Bypass of T H absence leads to autoimmunity Impairment of Ts can lead to autoimmune response as result of primary immunodeficiency or anti-Ts Abs Gaining the ability of presenting their Ag to T H  They become APC
  17. 17. Mechanisms of bypassing the absence of T H cells Provision of an altered determinant capable of activating T H cells Polyclonal activation of B cells Bacterial & viral infections: Streptococcal infections elicit Ab that cross-reacts with normal tissue of the heart leading to autoimmune disease Bacteria and EBV can act as adjuvant leading to polyclonal activation and autoimmune response
  18. 18. Postulated mechanisms of autoimmunity In this proposed model of an organ-specific T cell-mediated auto-immune disease, various genetic loci may confer susceptibility to autoimmunity, probably by influencing the maintenance of self-tolerance Environmental triggers, such as infections and other inflammatory stimuli promote the influx of lymphocytes into tissues and the activation of self-reactive T cells , resulting in tissue injury Fig 9-3
  19. 19. Central T cell tolerance Negative selection, or deletion Strong recognition of self antigens by immature T cells in the thymus may lead to death of the cells Development of regulatory T cells that enter peripheral tissues May result from self-antigen recognition in the thymus Fig 9-4 ( CD4 & DC8 )
  20. 20. T cell anergy An antigen presented by costimulator-expressing antigen-presenting cells (APCs) induces a normal T cell response . If the T cell recognizes antigen without costimulation , or in the presence of CTLA-4-B7 interactions, the T cell fails to respond and is rendered incapable of responding even if the antigen is subsequently presented by costimulator-expressing APCs Fig 9-5
  21. 21. Activation-induced death of T cells T cells respond to Ag presented by normal APCs by secreting IL-2 , expressing anti-apoptotic proteins , and undergoing proliferation and differentiation . Restimulation of recently activated T cells by Ag leads to: coexpression of Fas and FasL , engagement of Fas, and apoptotic death of the T cells FasL on one T cell may engage Fas either on a neighboring cell or on the same cell Fas-independent activation-induced cell death of immature T cell results from expression of intracellular pro-apoptotic proteins because of Ag recognition by T cells without costimulation or innate immunity Fig9-6 1 2 3 Death R .
  22. 22. T cell-mediated suppression of immune responses In a normal response, T cells recognize Ag and proliferate and differentiate into effector cells A typical T H 1 response APCs secrete IL-12 , which stimulates differentiation of the naive T cells into T H 1 effectors that produce IFN- γ and activate macrophages in the effector phase of the response Some T cells may differentiate into regulatory cells in the peripheral tissues or the thymus Regulatory cells inhibit the activation and differentiation of naive T cells by contact-dependent mechanisms , or they may secrete cytokines that inhibit the effector phase of T cell responses Fig9-7
  23. 23. Tolerance or activation? Features of protein antigens that influence the choice between T cell tolerance and activation Why the self antigens induce tolerance and microbial antigens stimulate T cell-mediated immune responses? Fig 9-8
  24. 24. Negative selection and receptor editing in immature B lymphocytes An immature B cell that strongly recognizes self antigens E.g. a multivalent self Ag with several epitopes in the bone marrow is killed by apoptosis or Receptor editing: changes its antigen receptor by making a new light chain with different specificity Fig9-9
  25. 25. Peripheral tolerance in B cells A mature B cell that recognizes a self Ag without T cell help is functionally inactivated & becomes incapable of responding to that Ag B cells that are partially activated by recognition of self Ags without T cell help may be excluded from lymphoid follicles and may die by apoptosis because they are deprived of survival stimuli Fig9-10
  26. 26. Autoimmune disease association with alleles of MHC locus Several lines of evidence support such association: Family and linkage studies show that individuals who inherit particular HLA alleles are more likely to develop some autoimmune diseases than individuals lacking these alleles (" relative risk "). Selected examples of HLA disease associations are listed. For instance, individuals who have the HLA-B27 allele are 90 to 100 times more likely to develop the disease ankylosing spondylitis than B27-negative individuals ; other diseases show varying degrees of association with other HLA alleles. Breeding studies in animals have shown that the incidence of some autoimmune diseases correlates strongly with the inheritance of particular MHC alleles (e.g., insulin-dependent [type 1] diabetes mellitus with the mouse class II allele called I-A g7 ). Genome scanning studies have also revealed the association of MHC with autoimmune diseases in humans and mice (e.g., HLA-DR and type 1 diabetes in humans).  See next, Fig9-11:
  27. 27. Ankylosing spondylitis Progressive deformity due to ankylosing spondylitis over a period of 26 years
  28. 28. Association of autoimmune diseases with alleles of the MHC locus MHC II allele Fig9-11 Skin disease characterized by groups of itching blisters
  29. 29. The roles of some non-MHC genes in auto-immunity Some genes other than MHC genes may contribute to the development of autoimmune diseases. Lpr = Mouse mutation "lymphoproliferation" gld = "generalized lymphoproliferative disease“ AICD , activation-induced cell death ALPS , autoimmune lymphoproliferative syndrome A uto I mmune R egulator poly E ndocrine Fig9-12
  30. 30. Mechanisms by which microbes may promote auto-immunity Normal ly, encounter of mature T cells with self Ags presented by resting APCs results in peripheral tolerance by anergy or deletion Microbes may activate the APCs to express costimulators ; and when these APCs present self Ags, the specific T cells are activated rather than rendered tolerant. Some microbial Ags may cross-react with self antigens ( mimicry ) Therefore, immune responses initiated by the microbes may become directed at self cells and tissues Molecular mimicry applies to T cells and self-reactive B cells Fig.9-13
  31. 31. Autoimmune diseases Antibody-mediated autoimmunity Autoimmune hemolytic anemia Myasthenia gravis Graves' disease Immune complex-mediated autoimmunity Systemic lupus erythematosus (SLE) T-Cell-mediated autoimmunity : Multiple sclerosis Type I diabetes mellitus Hashimoto's thyroiditis Antibody- & T-cell-mediated autoimmune disease Rheumatoid arthritis
  32. 32. Myasthenia gravis
  33. 33. Rheumatoid Arthritis Chronic, inflammatory joint disease. Serum and synovial fluid of patients contain Rheumatoid factor IgM and IgG antibodies bound to Fc fragment of normal IgG Synovial membranes and blood vessels contain rheumatoid factor and normal IgG, which attract PMN  causing inflammation In active disease the patients have low titers of complement and high titers of rheumatoid factor