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Ch. 16. Tolerance and Autoimmunity Tolerance sometimes is broken

Ch. 16. Tolerance and Autoimmunity Tolerance sometimes is broken - self reactive cells do form, but are usually inactivated or suppressed Failure of tolerance leads to autoimmunity Damage can be antibody-mediated and/or T-cell mediated Systemic vs. organ-specific

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Ch. 16. Tolerance and Autoimmunity Tolerance sometimes is broken

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  1. Ch. 16. Tolerance and Autoimmunity Tolerance sometimes is broken - self reactive cells do form, but are usually inactivated or suppressed Failure of tolerance leads to autoimmunity Damage can be antibody-mediated and/or T-cell mediated Systemic vs. organ-specific Females > males (p.416) Tendency sometimes runs in families If one, may have > one autoimmune disease Ch. 16

  2. Establishment and maintenance of tolerance Tolerance is a state of unresponsiveness to an antigen (Ag); it is specific To establish tolerance, it helps to have: High doses of Ag Soluble form of Ag Persistence of Ag in host Intravenous or oral administration of Ag Absence of adjuvants Low levels of costimulators Ch. 16

  3. Central tolerance Deletion of lymphocytes that react with self Ag’s in the primary lymphid organs (thymus = T cells, bone marrow = B cells) Peripheral tolerance Deletion or rendering anergic any lymphocytes that react with self Ag’s in the secondary lymphoid organs Ch. 16

  4. p. 402 Ch. 16

  5. Ch. 16

  6. p. 403 Ch. 16

  7. Organ-specific target is a molecule unique to that organ Hashimoto’s thyroiditis Th1 cells and autoantibodies specific for thyroid Ag’s  infiltration of thyroid by L, M, and PC’s  hypothyroidism Chronic inflammation and enlargement Others: AIHA, Goodpasture’s syndrome Ch. 16

  8. normal Ch. 16 p. 408

  9. Hashimoto’s thyroiditis Ch. 16

  10. Goodpasture’s syndrome Antibodies to membrane antigens in kidney and alveoli in lungs Complement activation, cell damage, inflammation IDDM (insulin-dependent diabetes mellitus) both T and B cells involved CTLs, autoantibodies subsequent DTH response kills pancreatic beta cells that make insulin Ch. 16

  11. Ch. 16 p. 408

  12. IDDM Ch. 16 p. 409

  13. Antibodies to receptors Grave’s disease Autoantibody mimics TSH, leads to constant thyroid stimulation Myasthenia gravis Autoantibody blocks ACh receptor, eventually destroys it Ch. 16

  14. p. 410 Ch. 16

  15. p. 410 Ch. 16

  16. Systemic diseases- damage is widespread Systemic lupus erythematosis autoantibodies to DNA, RNA, histones, leukocytes, RBC’s, platelets, clotting factors anti-nuclear antibodies (ANA) are diagnostic Type II, III and inflammatory damage; elevated C3a and C5a, vasculitis 10:1 female to male ratio; 20-40 yr-old women Ch. 16

  17. Ch. 16

  18. Multiple sclerosis T cell mediated Myelin sheath of nerves targeted CNS attacked by inflammatory lesions Starts in 20-40 yr. old people Rheumatoid arthritis Chronic inflammation of the joints Starts in 40-60 yr. old women Many produce rheumatoid factors (RF’s), IgM autoAb’s that react with Fc of IgG IgM-IgG complexes deposited in joints  Type III inflammatory reaction Ch. 16

  19. Ch. 16 p. 412

  20. How does autoimmunity occur? Transferred by T cells (CD4+ cells specifically) TH1 cells transfer disease TH2 cells protect against it Ch. 16

  21. p. 413 Ch. 16

  22. In Ab-caused autoimmune diseases, Autoantibody can be transferred from patient to recipient, then symptoms appear in recipient Graves’ disease can be transferred from human to rat Also autoAb’s can go from mother to fetus - child is born with Graves’ disease treated by plasmapheresis Ch. 16

  23. Ch. 16 p. 415

  24. Why does autoimmunity occur? Many possibilities: 1. Release of “sequestered antigens”- seen, so L not deleted in T cell development MBP heart muscle proteins nuclear antigens sperm In animals, can avoid autoimmune disease by injection of sequestered antigen into thymus  tolerance Ch. 16

  25. 2. Molecular mimicry Several viruses and bacteria have ID or similar Ag’s to self- Ag’s 3% of anti-viral mAb’s react with normal tissue Ag’s Post-rabies encephalitis when virus grown in rabbit TC Post-streptococcal rheumatic heart disease Ch. 16

  26. p. 418 Ch. 16

  27. 3. Inappropriate expression of class II MHC • “Wrong” cells induced to express MHC Class II • antigen (and act as APCs) – IDDM, Hahimoto’s • Additional signals, • such as IFN-gamma IL-1 and TNF • Polyclonal B cell activation by CMV, EBV, • and some G-negative bacteria • - T-cell-independent • - Large amounts of IgM produced Ch. 16

  28. Treatment of autoimmune disease Reduce symptoms Immunosuppression Corticosteroids, azathioprine, cyclophosamide Removal of thymus (MG) Plasmapheresis Short-term relief (MG, Grave’s disease, RA, SLE) Ch. 16

  29. Treatment of autoimmune disease (cont’d) Reduce inflammation TNF-alpha blockers (RA, Crohn’s dis., psoriasis) e.g., Enbrel, Remicade, Humira IL-1 receptor antagonist (RA) Ab’s against IL6R and IL-15R Statins, shown to lower CRP (RA, MS) Rituxin = monoclonal Ab = anti-CD20 Eliminates B cells in non-Hodgkins lymphoma (maybe also RA, and other Ab-mediated autoimmune diseases) Ch. 16

  30. Possible experimental approaches Ch. 16

  31. T cell vaccines (against activated Ag-specific T cells) Interfere with antigen presentation (anti-MHC) Monoclonal antibodies against a variety of target antigens Oral induction of tolerance (MS) So far, efforts have been more successful in mice than humans Ch. 16

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