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  1. 1. AUTOIMMUNITY FE A. BARTOLOME, MD, FPASMAP Department of Microbiology Our Lady of Fatima University
  2. 2. IMMUNOLOGICAL TOLERANCE <ul><li>State in which the individual is incapable of developing an immune response to a specific antigen </li></ul><ul><li>Self-tolerance  lack of responsiveness to an individual’s antigens </li></ul><ul><li>Central tolerance & peripheral tolerance </li></ul>
  3. 3. CENTRAL TOLERANCE <ul><li>Clonal deletion of self-reactive T and B lymphocytes during their maturation in the central lymphoid organs </li></ul>
  4. 4. CENTRAL TOLERANCE <ul><li>T cells </li></ul><ul><li>T lymphocytes that bear high-affinity receptors for self-antigens are negatively selected or deleted  undergo apoptosis </li></ul><ul><li>occur during fetal development </li></ul>
  5. 5. CENTRAL TOLERANCE <ul><li>B cells </li></ul><ul><li>Also undergo clonal deletion </li></ul><ul><li>Developing B cells encounter a membrane-bound antigen within the bone marrow  B cells undergo apoptosis </li></ul><ul><li>Occur throughout life </li></ul>
  6. 6. PERIPHERAL TOLERANCE <ul><li>Self-reactive T cells that escape </li></ul><ul><li>intrathymic negative selection are </li></ul><ul><li>deleted or muzzled in the peripheral tissues </li></ul>
  7. 7. PERIPHERAL TOLERANCE <ul><li>MECHANISMS: </li></ul><ul><ul><li>Clonal deletion by activation-induced cell death </li></ul></ul><ul><ul><li>Clonal anergy </li></ul></ul><ul><ul><li>Peripheral suppression by T cells </li></ul></ul>
  8. 8. PERIPHERAL TOLERANCE <ul><li>Clonal deletion by activation-induced cell death </li></ul><ul><ul><li>Apoptotic death of activated T cells by the Fas-FasL system </li></ul></ul><ul><ul><li>Self-antigens abundant in peripheral tissue (e.g. collagen, thyroglobulin)  repeated & persistent stimulation of self-antigen-specific T cells  activation of Fas-mediated apoptosis </li></ul></ul>
  9. 9. Clonal deletion in thymus A A A Cell death B B B Antigen Two immature T cells (A and B) with different antigen receptors Binding of self antigen to T-cell A in thymus but not to T-cell B Death of self-reacting T-cell A; survival of T-cell B that reacts against foreign antigen
  10. 11. PERIPHERAL TOLERANCE <ul><li>Clonal anergy </li></ul><ul><ul><li>Prolonged or irreversible functional inactivation of lymphocytes </li></ul></ul><ul><ul><li>Induced by encounter with antigens </li></ul></ul><ul><ul><li>T cells – due to absence of co-stimulatory molecules on APCs, such as B7-1 & B7-2 </li></ul></ul><ul><ul><li>B cells – due to lack of T cell help for antibody synthesis (T cell anergy or down-regulation of surface IgM) </li></ul></ul>
  11. 12. PERIPHERAL TOLERANCE APC Helper T cell Class II MHC Antigen TCR B7 protein CD28 protein CD4 protein APC Helper T cell Class II MHC Antigen TCR CD28 protein CD4 protein B7 protein on APC interacts with CD28 on helper T cells. Full activation of helper T cells occur. B7 protein on APC is not produced. CD28 on helper T cell does not give a co-stimulatory signal. Anergy occurs.
  12. 14. PERIPHERAL TOLERANCE <ul><li>Peripheral suppression by T cells </li></ul><ul><ul><li>Suppressor T cells – with ability to down-regulate the function of other autoreactive T cells </li></ul></ul><ul><ul><li>Shift immune response from T H 1 to T H 2 </li></ul></ul><ul><ul><li>T H 2 generally immunosuppressive  down-modulate T H 1 response </li></ul></ul>
  13. 16. Factors Affecting Artificially-Induced Tolerance <ul><li>Form, dose & route of administration </li></ul><ul><ul><li>Very simple molecules induce tolerance more readily than a complex one </li></ul></ul><ul><ul><li>Very high or very low doses of an antigen may result in tolerance instead of an immune response </li></ul></ul><ul><ul><li>Purified polysaccharides or amino acid co-polymers injected in very large doses result in “ immune paralysis ” </li></ul></ul>
  14. 17. Factors Affecting Artificially-Induced Tolerance <ul><li>Immunologic “maturity” of the host </li></ul><ul><ul><li>E.g. neonates  immunologically immature  do not respond well to foreign antigens </li></ul></ul><ul><li>Chimerism </li></ul><ul><ul><li>Tolerance induced by inoculation of allogeneic cells into hosts that lack immune competence </li></ul></ul><ul><li>Antibodies to CD4 and CD8 </li></ul><ul><ul><li>Tolerance of transplanted tissues by inoculating graft recipient with monoclonal antibodies against CD4 and CD8 </li></ul></ul>
  15. 18. Factors Affecting Artificially-Induced Tolerance <ul><li>Clonal exhaustion </li></ul><ul><ul><li>Repeated antigenic challenge </li></ul></ul><ul><ul><li>Stimulate B and T cell to differentiate into short-lived end cells </li></ul></ul>
  16. 19. Factors Affecting Artificially-Induced Tolerance <ul><li>Clonal anergy induced by anti-idiotypic antibodies & antagonistic peptides </li></ul><ul><ul><li>Antibody combining site (idiotype) act as antigen  induce formation of anti-idiotypic antibodies  cross-link on B cells  prevent interaction with Ag </li></ul></ul><ul><ul><li>Antagonistic peptides  fit into Ag-binding site of MHC  no activation of T cells </li></ul></ul>
  17. 20. Other aspects of induction/maintenance of tolerance <ul><li>T cells become tolerant more readily and remain tolerant longer than B cells. </li></ul><ul><li>Administration of a cross-reacting antigen tends to terminate tolerance. </li></ul><ul><li>Administration of immunosuppressive drugs enhances tolerance. </li></ul><ul><li>Tolerance is maintained best if the antigen to which the immune system is tolerant continues to be present. </li></ul>
  18. 21. AUTOIMMUNITY <ul><li>Immune reaction against self-antigens </li></ul><ul><li>Requirements: </li></ul><ul><ul><li>Presence of an autoimmune reaction </li></ul></ul><ul><ul><li>Clinical or experimental evidence that reaction is not secondary to tissue damage but is of primary pathogenetic significance </li></ul></ul><ul><ul><li>Absence of another well-defined cause of the disease </li></ul></ul>
  19. 22. AUTOIMMUNITY <ul><li>Most important step in production of autoimmune disease: activation of self-reactive CD4 T cells </li></ul><ul><li>Most are antibody-mediated </li></ul>
  20. 23. AUTOIMMUNITY <ul><li>GENETIC FACTORS </li></ul><ul><ul><li>(+) genetic predisposition </li></ul></ul><ul><ul><li>Strong association with HLA specificities, especially class II genes </li></ul></ul><ul><ul><li>Class I MHC-related: ankylosing spondylitis & Reiter’s syndrome; more common in men </li></ul></ul><ul><ul><li>Class II MHC-related: RA, Grave’s disease, SLE; more common in women </li></ul></ul>
  21. 24. AUTOIMMUNITY <ul><li>HORMONAL FACTORS </li></ul><ul><ul><li>Approximately 90% occur in women </li></ul></ul><ul><ul><li>Estrogen  can alter the B-cell repertoire and enhance formation of antibody to DNA </li></ul></ul>
  22. 25. AUTOIMMUNITY <ul><li>ENVIRONMENTAL FACTORS </li></ul><ul><ul><li>Exposure to an environmental agent can trigger a cross-reacting immune response against some component of normal tissue </li></ul></ul><ul><ul><li>Example: S. pyogenes & rheumatic fever </li></ul></ul>
  23. 26. AUTOIMMUNITY: Mechanisms <ul><li>Defects in clonal deletion mechanisms </li></ul><ul><ul><li>Thymic defects that lead to proliferation of self-reactive T cells </li></ul></ul><ul><ul><li>Failure of central tolerance </li></ul></ul>
  24. 27. AUTOIMMUNITY: Mechanisms <ul><li>Polyclonal lymphocyte activation </li></ul><ul><ul><li>Microorganism-derived mitogens stimulate lymphocytes </li></ul></ul><ul><ul><li>Microbial products (e.g. LPS)  act as superantigens  activate a large pool of T and B cells </li></ul></ul>
  25. 28. AUTOIMMUNITY: Mechanisms <ul><li>Molecular mimicry </li></ul><ul><ul><li>Microbial antigens with similar structure to self-antigens  activate autoreactive T cells </li></ul></ul><ul><ul><li>Cross-reactivity-induced immune response </li></ul></ul><ul><ul><li>Example: M protein of S. pyogenes and myosin of cardiac muscle </li></ul></ul>
  26. 29. AUTOIMMUNITY: Mechanisms <ul><li>Release of sequestered antigens </li></ul><ul><ul><li>Immunologically privileged sites ( brain, ant. eye chamber, ovary, placenta, testis, pregnant uterus )  not exposed to immune system </li></ul></ul><ul><ul><li>Damage  release of antigens  elicit immune response </li></ul></ul>
  27. 30. AUTOIMMUNITY: Mechanisms <ul><li>Defects in the regulation of TH 1 and TH 2 cells </li></ul><ul><ul><li>Impaired T suppressor cell immunoregulation </li></ul></ul>
  28. 31. Microbial infections associated with autoimmune diseases Microbe Autoimmune disease BACTERIA Streptococcus pyogenes Campylobacter jejuni Escherichia coli Chlamydia trachomatis Shigella sp. Yersinia enterocolitica Borrelia burgdorferi Rheumatic fever Guillain-Barre syndrome Primary biliary cirrhosis Reiter’s syndrome Reiter’s syndrome Grave’s disease Lyme arthritis VIRUSES Hepatitis B virus Hepatitis C virus Measles virus Cytomegalovirus Multiple sclerosis Mixed cryoglobulinemia Allergic encephalitis Scleroderma
  29. 32. ORGAN-SPECIFIC AUTOIMMUNE DISEASES Type of Immune Response Autoimmune Disease Target of Immune Response Antibody to receptors Myasthenia gravis Grave’s disease Acetylcholine receptor TSH receptor Antibody to cell components other than receptors Pernicious anemia Goodpasture’s synd. IDDM Addison’s disease Male infertility Pemphigus Hashimoto’s Primary myxedema Intrinsic factor and parietal cells BM of kidney & lung Islet cell Adrenal cortex Sperm Desmoglein in tight junctions of skin Thyroglobulin Thyroid peroxidase
  30. 33. NON-ORGAN SPECIFIC AUTOIMMUNE DISEASES Type of Immune Response Autoimmune Disease Target of Immune Response Antibody to cell components other than receptors Rheumatoid arthritis SLE Sjogren’s syndrome (Sicca syndrome) Guillain-Barre synd. IgG in joints dsDNA, histones RNP antigens (SS-A/Ro and SS-B/La) Myelin protein