Autoimmunity

1. Autoimmunity A breakdown of mechanisms responsible for tolerance. The auto-reactivity may result in disease.

2. Contents: • General introduction • Immunologic pathogenesis involved in autoimmune diseases • Proposed mechanisms for induction of autoimmunity • Treatment of autoimmune diseases

3. Autoimmunity: An acquired immune reactivity against self antigens. Autoimmunity can be found in normal persons.

4. Autoimmune diseases Tissue damage caused by autoimmune responses. The autoantibodies and autoreactive T cells against self antigens exist in all the individuals with autoimmune disease.

5. Effector mechanisms of autoimmune damage • Specific components: • Antibodies • T cells • Nonspecific components: • Complement • Phagocytes (PMN and macrophages) • NK and other cells

6. Tissues and organs involved • Organ-specific diseases • Damage is confined to the organ against which the immune response is mounted • Non-organ-specific diseases • Immune response against antigens which are not associated with the organ involved

9. Tissues and organs involved

10. Immunologic pathogenesis involved in typical autoimmune diseases • Direct cellular damage (CDC, Opsonization, ADCC) • Stimulatory autoantibodies • Blocking autoantibodies

11. Type II hypersensitivityrole of complement and phagocytes

12. Anti microsomal antibodies inHashimoto’s disease

13. Goodpasture’s syndrome

14. Insulin-dependent diabetes mellitus

15. Grave’s disease

16. Myasthenia gravisthe mechanism

17. Rheumatoid arthritis Characterized by the presence of rheumatoid factor (antibodies against IgG)

18. Staining for immune complexes in lupus nephritis (left) and Anti-renal basement membrane antibody In Goodpasture's nephritis (right) Immunofluorescent detection of antinuclear antibody in the serum of an SLE patient Systemic lupus erythematosus

19. Multiple Sclerosis

20. Proposed mechanisms for induction of autoimmunity • Release of sequestered autoantigens • Infections (bystander activation, molecular mimicry, epitope spreading) • Abnormal immunoregulation • Genetic factors

21. Release of sequestered antigens Any tissue antigens that are sequestered from the circulation, and therefore not seen by the developing T cells in the thymus, will not induce self-tolerance. Exposure of mature T cells to such normally sequestered antigens at a later time might result in their activation. Myelin basic protein (MBP) Sperm, lens protein, heart-muscle antigens

22. Infection (Bystander activation)

23. Infection (Molecular mimicry)

25. Epitope spreading

26. Abnormal immunoregulation • Abnormal expression of MHC II molecules • Deviation of Th1 and Th2 balance • Polyclonal action of B cells and T cells • Abnormal expression of Fas/FasL

27. Abnormal expression of Fas/FasL The role of Fas and FasL can be understood by two mouse strains. One is called MRL/lpr/lpr(Lpr has been identified as a defective Fas gene), Another is called MRL/gld (mutation of FasL)

28. Genetic factors Most autoimmune diseases are polygenic, and affected individuals inherit genetic polymorphisms that contribute to disease susceptibility.

29. Susceptibility loci for autoimmune diseases

30. Among the genes that are associated with autoimmunity, the strongest associations are with MHC genes, especially class II MHC genes.

31. Examples of HLA-linked immunologic Diseases

32. Studies with knockout mice and patients have identified several genes that influence the maintenance of tolerance to self antigens.

33. Examples of Gene mutations that results in autoimmunity

34. Treatment of autoimmune diseases • Ideally, treatment for autoimmune diseases should be aimed at reducing only the autoimmune response while leaving the rest of the immune system intact. • To date, this idea has not been reached.

35. Methods • Immunosuppression • T-cell vaccination • Peptide blockade • Monoclonal antibodies • Oral tolerance

36. Immunosuppression • Nonspecific suppressive drugs: corticosteroids, azathioprine, cyclophosphamide • More selective suppressive drugs: cyclosporin A, FK506 • Thymectomy • Plasmapheresis

37. T cell vaccination When irradiated self-reactive T cells are infused to the blood, these T cells apparently elicit regulatory T cells specific for TCR variable-region determinants.

38. Proliferation Energy • Peptide blockade altered antigen peptide

39. Monoclonal antibodies • Anti-CD4 • Anti-CD25 • Anti-MHC • Anti-TCR

41. Inducing tolerance by oral antigen Mice fed MBP do not develop EAE after subsequent injection of MBP, However, the human clinical trials are in the early stages.

42. Summary • Autoimmunity results from a failure of self-tolerance, which mediated by autoantibodies and autoreactive T cells. • Autoimmune reactions may be triggered by environmental stimuli, such as infections, in genetically susceptible individuals.

43. Indicate whether each of the following statements is true or false. If you think a statement is false, explain why. a. Th1 cells have been associated with development of autoimmunity. b. Immunization of mice with IL-12 prevents induction of EAE by injection of myelin basic protein plus adjuvant. c. The presence of the HLA-B27 allele is diagnostic for ankylosing spondylitis, an autoimmune disease affecting the vertebrae. d. Individuals with pernicious anemia produce antibodies to intrinsic factor. e. A defect in the gene encoding Fas can reduce programmed cell death by apoptosis