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Introduction to Autoimmunity

Introduction to Autoimmunity. Alon Monsonego, Ph.D. The department of Microbiology and Immunology Tel: 08-647-9052. Topics:. T-cell selection T-cell activation T-cell regulation. The Development and Survival of Lymphocytes. Figure 7-2 part 1 of 2. The development of T cells:.

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Introduction to Autoimmunity

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  1. Introduction to Autoimmunity Alon Monsonego, Ph.D. The department of Microbiology and Immunology Tel: 08-647-9052

  2. Topics: • T-cell selection • T-cell activation • T-cell regulation

  3. The Development and Survival of Lymphocytes

  4. Figure 7-2 part 1 of 2 The development of T cells:

  5. Figure 7-2 part 2 of 2

  6. Figure 7-8 part 1 of 2 The cellular organization of the human Thymus:

  7. Figure 7-9

  8. Figure 7-10 The thymus is critical for T-cell maturation:

  9. Changes in cell surface molecules throughout T-cell maturation in the Thymus: Figure 7-12

  10. Figure 7-14

  11. Figure 7-32 part 1 of 2 Positive selection in the thymus:

  12. Figure 7-32 part 2 of 2

  13. Figure 7-35 Negative selection in the thymus by bone marrow derived cells:

  14. Figure 7-36

  15. Figure 13-9 Expression of AIRE in the thymus shape the immune repertoire:

  16. Summary: • Lymphocytes originate in the bone marrow. • B cells mature in the bone marrow • T cells mature in the thymus • Positive and negative selection mechanisms shape the lymphocyte repertoire

  17. T Cell-Mediated Immunity

  18. Figure 8-3 dictate Distribution of APCs in the lymph nodes:

  19. Figure 8-4 Naïve T cells encounter antigen in the peripheral lymph node:

  20. Figure 8-13 Two signals are required to induce T-cell activation:

  21. Figure 8-14 DC’s maturation as APCs:

  22. Figure 8-15

  23. Figure 8-21 T-cell tolerance to antigens expressed on tissue cells:

  24. Figure 8-24 Activation of CD4 T cells:

  25. Figure 8-31 Effector T cells with different functions:

  26. Figure 8-32 part 1 of 3 T-cell cytokines:

  27. Figure 8-32 part 2 of 3

  28. Figure 8-32 part 3 of 3

  29. Molecular differentiation of Th1,Th2, and Th17 T cells

  30. Summary: • Antigens are processed and presented to T cells by professional APCs (B cells, Mac, and DCs). • Two signals are required to induce T-cell activation by APCs. • The inflammatory environment shapes the activation of both T cells and APCs • The function of T cells (CD4/CD8) differs primarily according to their cytokine profile.

  31. Mechanisms of autoimmune diseases

  32. Figure 13-1

  33. Figure 13-6

  34. Figure 13-31

  35. Figure 13-3 T-cell mediated paralysis in a mouse model of multiple sclerosis:

  36. Figure 13-34

  37. Mechanisms of immune regulation Regulatory T cells

  38. Antigen receptors and the immunological synapse: The principal T cell membrane proteins involved in antigen recognition and in responses to antigens are shown. The functions of these proteins fall into three groups: antigen recognition, signal transduction, and adhesion.

  39. Figure 13-14 By stander suppression

  40. CD4+CD25+ cells: • About 5-10% of CD4 cells. • Generated in the thymus possibly via high affinity interactions with self ligands presented by thymic stromal cells. • Extensive proliferation in vivo; depending on the presence of specific Ag. • Their development and maintenance is highly dependent on costimulation and IL-2. • Express CD25, TNFa receptor, CTLA-4, and Foxp3. • MicroRNAs are involved in their differentiation.

  41. Mechanism of action: • Antigen specificity is unknown but most likely selected and respond to self Ags. • Suppression is contact and also cytokine dependent (TGF-b/ IL-10). • Act in tissues to control inflammation via direct effects on effector T cells or DCs.

  42. Foxp3: • Highly enriched in CD4+CD25+ cells. • Its expression induces Treg activity. • Targeted disruption prevents Treg development and results in autoimmune diseases in mice and humans (IPEX-immune dysregulation, polyendocrinopathy, enteropathy, X-linked). Leads to type-1 diabetes, allergy, and other. • Induced by TGF-b in CD4+CD25- cells and lead to expansion of CD4+CD25+ in vitro and in vivo. • Foxp3 binds other transcrition factors such as NFAT, AML1, RUNx1.

  43. Different subsets of Tregs CD4CD25 10% of CD4

  44. A balance between regulation and activation:

  45. Figure 13-15 part 1 of 2 CD4CD25 regulatory T cells inhibit colitis:

  46. Figure 13-15 part 2 of 2

  47. Anti-ergotypic T cells: CTLA-4-CD80/86 Treg Teff TCR-Ag APC TCR-Ag MHC-Ag TCR Terg TCR-Ag(HSP/CD25)

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