Chap 19 Immunological tolerance - a state of unresponsiveness for a particular antigen

1. Chap 19 Immunological tolerance-a state of unresponsiveness for a particular antigen Trai-Ming Yeh, Ph.D. Department of Medical Laboratory Science and Biotechnology College of Medicine National Cheng Kung University

2. Self tolerance • neonatal tolerance='immune deviation‘ • Transgenic technology has allowed the study of tolerance to authentic self antigens

3. Ways in which self-reactive lymphocytes may be prevented from responding to self antigen • in tissues sequestered from the circulation • in a privileged site • self-reactive cells may be deleted at certain stages of development; • self-reactive cells may be rendered anergic and unable to respond; • a state of tolerance to self antigens can also be maintained by immune regulation.

4. T cell development involves positive and negative selection and lineage commitment

5. T cells are positively selected for 'usefulness' (MHC restriction)

6. T cell selection is compartmentalized in the thymus

7. Medullary thymic epithelial cells can express antigens whose expression was previously thought to be limited to specific organs Aire (autoimmune regulaotry) defect causes autoimmune polyendocrinopathy syndrome type 1 (APS-1) in humans

8. T cell development includes a series of checkpoints • β selection checkpoint - only cells with a rearranged β chain mature from DN to DP cells - this process is not dependent on MHC proteins; • α selection checkpoint - cells expressing an αβ complex must interact with MHC molecules to survive; • lineage commitment checkpoint - cells are instructed to repress expression of either CD4 or CD8 and to develop into SP cells; • negative selection checkpoint - cells that interact strongly with MHC molecules and antigen in the thymus are deleted

10. A VARIETY OF MECHANISMS MAINTAIN TOLERANCE IN PERIPHERAL LYMPHOID ORGANS

11. T cell death can be induced by persistent activation or neglect activation-induced cell death (AICD); and programmed cell death (PCD) Fas is the most important death receptor

12. The Fas pathway is required for peripheral tolerance autoimmune lymphoproliferative syndrome (ALPS), mutations in the Fas gene (ALPS type 1a) or the Fas ligand gene (ALPS type 1b).

13. CD28 signaling enhances cell survival and enhances CD40L expression CTLA-4 pathway inhibits IL-2 synthesis and cell proliferation. CTLA-4 has a higher avidity (100 ×) for CD80 and CD86 than CD28

14. Dendritic cells contribute to peripheral tolerance immature dendritic cells presenting antigen activate T cells, but the outcome is different, resulting in apoptosis, anergy, or the generation of regulatory T cells.

15. Regulatory T cells suppress the activation of other T cells and play a crucial role in controlling autoimmune responses FoxP3 gene were found in the affected members of families with the IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome The ligands for TLRs and cytokines override suppression in potentially overwhelming infection

16. TOLERANCE IS ALSO IMPOSED ON B CELLS. However, anergy in an autoreactive B cell can be overcome

17. Tolerance can be induced articially in vivo by antibodies to co-receptor and co-stimulatory molecules Blocking both B7 molecules with a soluble form of CTLA-4 (CTLA-4-Ig). In combination with an antibody to the ligand for CD40 (CD154) allow long-term skin allograft survival in mice

18. Soluble or oral antigens induce tolerance • tolerance of spleen B cells requires much more time and higher doses of antigen than T cells

19. Chap 20 Autoimmunity and autoimmune disease-breakdown of self tolerance Trai-Ming Yeh, Ph.D. Department of Medical Laboratory Science and Biotechnology College of Medicine National Cheng Kung University

20. Autoimmunity is associated with disease. • Genetic factors play a role in the development of autoimmune diseases. • Self-reactive B and T cells persist even in normal subjects. • Controls on the development of autoimmunity can be bypassed. • In most diseases associated with autoimmunity, the autoimmune process produces the lesions. • Treatment of autoimmune disease has a variety of aims.

21. organ-specific disease-Hashimoto's thyroiditis systemic autoimmune diseases- SLE

23. GENETIC FACTORS PLAY A ROLE IN THE DEVELOPMENT OF AUTOIMMUNITY Certain HLA haplotypes predispose to autoimmunity

24. Molecular mimicry by cross-reactive microbial antigens can stimulate autoreactive B and T cells

25. B cells can be stimulated if the cross-reacting antigen bears a 'foreign' carrier epitope to which the T cells have not been tolerized

26. Cytokine dysregulation, inappropriate MHC expression, and failure of suppression may induce autoimmunity

27. The pathogenic role of autoimmunity can be demonstrated in experimental models • Experimental autoimmune diseases (strain dependent) • Induced by antigen immunization vs. spontaneous. • NOD murine model of IDDM • NZB/NZW model of SLE

28. NZB/NZW mice treatment with anti-CD4

29. Autoantibodies against TSH receptor can give rise to a wide spectrum of clinical thyroid dysfunction

30. A variety of other diseases are associated with autoantibodiesagainst receptor • antibodies to acetylcholine receptor in myathenia gravis

31. Autoantibodies have diagnostic and prognostic value • Antinuclear antibody (ANA) • IFA staining against a variety of Ag within Hep2 cell nucleus • screening tool for SLE

32. Anti-mitochondrial antibodies (AMA) • used in diagnosing primary biliary cirrhosis

34. Anti-parietal cell antibodies(APCA) • Specific fluorescence is seen in stomach parietal cells. Cytoplasm and lumenal border of kidney tubules are negative. (AMA will stain parietal cells and kidney tubules.)

35. Antibodies to the glomerular capillary basement membrane cause Goodpasture's syndrome • kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing a linear deposition of immunoglobulin G along the glomerular basement membrane.

36. Immunocomplex in synovial tissue of RA

37. Rheumatoid factor: Antibodies against IgG Fc • Due to deficiency of terminal galactose of IgG (agalacto IgG)

38. MANY AUTOIMMUNE DISEASES CAN BE TREATED SUCCESSFULLY • anti-TNFα monoclonal antibody plus methotrexate for RA patients

39. Reversal of compromised regulatory T cell function in RA by anti-TNF therapy

40. Anti-CD20 (B cell depletion) in SLE resistant to immunosuppressive drugs

41. Some less well-established approaches to treatment may become practicable