2. What are Autoimmune diseases? T cell development & Self tolerance Breakdown of self tolerance Mouse models on –Self tolerance breakdown –Absence of T cell “education”

3. Immune system attacks own cells Pathogens express antigens that are similar to own cells Immune system attack both non-self and self cells

4. CD4 + T cells - Helper cells - Helper cells –Co-ordinate immune response CD8 + T cells - Cytotoxic cells - Cytotoxic cells –Kills infected cells

5. Cortex Immature T cells –Lack surface molecules –CD3, CD4, CD8 –Double negative thymocytes Medulla –CD4 or CD8 –Macrophages and dendritic cells

6. Positive Selection –Double positive T cells bind self MHC molecules α : β + (TCR) α : β + (TCR) CD3+ CD4+ CD8+ CD3+ CD4+ CD8+ Negative Selection Negative Selection – Eliminate those bind to self antigens on MHC molecules

7. Self tolerance - Lack of response of immune system to self antigens Self tolerance is acquired by - Clonal deletion - Clonal anergy

8. Clonal Deletion –T cell interacts with self antigen Clonal Anergy Clonal Anergy – mature T cells are made unresponsive to antigens Apoptosis (negative selection)

9. Self-Reactive T-Cells Genetic Factors Environmental Factors Virus Trigger Autoimmunity

10. Although T cells selections are stringent, there is still some self reactive T cell released. Although T cells selections are stringent, there is still some self reactive T cell released. –Antigen present in small amounts, negative selection for the peptide unable to occur –Tissue specific antigen that do not trigger clonal deletion

12. No Selection for some Peptide Small amounts of Self reactive T cells released (note: Present in VERY SMALL AMOUNTS) However, normally they will not be activated (immunological ignorance)

13. Different people possess different MHC Different MHC bind with different affinity to antigen Some MHC more susceptible to autoimmunity diseases Diagram

14. Diet – fish containing omega-3 PUFA Sunshine –Trigger skin lesion in Systemic Lupus Erythematosus Butterfly rashes

15. Production of cross reactive antibodies or T cell –Some virus mimics self antigen peptide (molecular mimicry) –E.g. Rheumatic Fever, Diabetes?, Multiple sclerosis? Superantigen –Polyclonal activation of autoreactive T cells –E.g. Rheumatoid arthritis?

16. Nude Mice –Immunological Characteristics –Experimental Applications Experiments –Inducing auto-immune response –Lack of auto-immune response in nude mice

17. Inbred to generate desired qualities –Athymic, i.e. lack thymus –Live in aseptic environment –Homozygous recessive, nu/nu Mutant gene, nu Achieved by inbreeding Lack hair –Hair genes associated with thymic genes

18. Unable to produce mature T-Lymphocytes –Antibody formation –Cell mediated immune responses –Delayed-type hypersensitivity responses –Killing of virus-infected or malignant cells –Graft rejection It’s UNFAIR~!~ Y don’t I have mature T cells?

19. Therefore, –Theoretically unable to cause autoimmune responses in nude mice –What would theoretically cause an autoimmune response in a normal mouse Would not cause one in nude mice.

20. Would be used as a negative control in autoimmune disease experiments –Autoreactive T cells are to be found in normal, healthy mice that show no tendency to develop autoimmune disease HAHA~!~! I don’t have a thymus. You can’t kill me using autoimmune diseases. *BLEAHZ*

22. Nucleoprotein (gene) insert into mouse as a negative control. –“Copy” the small amt of peptide in our body LCMV (Virus) is insert –Induced killing by CD8+ T-Cells –NP expressed cells are also killed

23. Sympathetic Ophthalmia –Disruption of cell / tissue barrier Induction of EAE by adjuvants –Infection of antigen-presenting cell Rheumatic fever / Type I Diabetes –Molecular minicry

24. Accumulating evidence –Regulatory T cells play crucial role in preventing autoimmunity Effectors and suppressors of autoimmunity –Shown to be CD4 + T cells –CD4 + CD25 + T Cells Suppressor –CD4 + CD25 - T Cells Regulatory

25. Distinct Subset of Suppressor T Cells –Able to prevent the development of autoimmune disease Thymectomised mice (d3Tx) –Injected with CD4 + T cell populations that are depleted of CD25 - T cells Autoimmune disease –Reconstituted with CD25+ T cells Autoimmune development prevented

26. X-linked recessive disorder, sf/Y –Thymuses unable to “educate” T cells Die naturally of autoimmune disease

27. Used in experiments to show self-tolerance occurs in thymus by two mechanisms –Clonal anergy –Clonal deletion Shown that –NTx in scurfy nearly doubles its lifespan i.e. prevents (auto)immune response –Crossing with nu/nu produces viable organism

28. Neonates treated with anti-CD4, CD8 mAbs –Anti-CD4 Autoimmune disease –Anti-CD8 Delayed autoimmune response Suggest that –CD4 + T cells Critical mediators of autoimmune disease

29. Elisabeth Suri-Payer, Anna Z. Amar, Angela M. Thornton, and Ethan M. Shevach: CD4 + CD25 + T Cells Inhibit Both the Induction and Effector Function of Autoreactive T Cells and Represent a Unique Lineage of Immunoregulatory Cells. The Journal of Immunology, 1998, 160: 1212–1218 Salomon, B, Lenschow, DJ, Rhee, L, Ashourian, N, Singh, B, Sharpe, A, & Bluestone, JA: B7/CD28 costimulation is essential for the homeostasis of the CD4 + CD25 + immunoregulatory T cells that control autoimmune diabetes. Immunity 2000, 12:431-440 McHugh, RS & Shevach, EM: Cutting edge: depletion of CD4 + CD25 + regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J Immunol 2002, 168:5979-5983 VL Godfrey, JE Wilkinson, EM Rinchik, and LB Russell: Fatal Lymphoreticular Disease in the Scurfy (sf) Mouse Requires T Cells that Mature in a sf Thymic Environment: Potential Model for Thymic Education Proc. Natl. Acad. Sci. USA. 1991 July 1; 88 (13): 5528–5532 Blair PJ, Bultman SJ, Haas JC, Rouse BT, Wilkinson JE, Godfrey VL.: CD4+CD8- T cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse. J Immunol. 1994 Oct 15;153(8):3764-74 Lyon MF, Peters J, Glenister PH, Ball S, Wright E.: The Scurfy Mouse Mutant has Previously Unrecognized Hematological Abnormalities and Resembles Wiskott-Aldrich Syndrome.Proc Natl Acad Sci USA. 1990 Apr 1; 87(7): 2433-2437.