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Autoimmune

Autoimmune . Disease. Overview. What are Autoimmune diseases? T cell development & Self tolerance Breakdown of self tolerance Mouse models on Self tolerance breakdown Absence of T cell “education”. Autoimmune disease. Immune system attacks own cells

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Autoimmune

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  1. Autoimmune Disease

  2. Overview • 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. Autoimmune disease • Immune system attacks own cells • Pathogens express antigens that are similar to own cells • Immune system attack both non-self and self cells

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

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

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

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

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

  9. Factors Leading to Autoimmune Disease • Self-Reactive T-Cells • Genetic Factors • Environmental Factors • Virus Trigger Autoimmunity

  10. Self Reactive T-cell 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

  11. Diagram

  12. Self Reactive T-cell 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. Genetic Factors • Different people possess different MHC • Different MHC bind with different affinity to antigen • Some MHC more susceptible to autoimmunity diseases • Diagram

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

  15. Viruses trigger autoimmunity • 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. Mouse Model • Nude Mice • Immunological Characteristics • Experimental Applications • Experiments • Inducing auto-immune response • Lack of auto-immune response in nude mice

  17. Nude Mouse • 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. Immunological Characteristics • 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. Immunological Characteristics • 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. Experimental Applications • 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*

  21. Mouse Model for Viral Activation

  22. Viral Activation • 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. Viral Activation • 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. Suppression of T Cells in Mouse Models • Accumulating evidence • Regulatory T cells play crucial role in preventing autoimmunity • Effectors and suppressorsof autoimmunity • Shown tobe CD4+ T cells • CD4+CD25+ T Cells • Suppressor • CD4+CD25- T Cells • Regulatory

  25. CD4+CD25+ T Cells • 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. Scurfy Mouse • X-linked recessive disorder, sf/Y • Thymuses unable to “educate” T cells • Die naturally of autoimmune disease

  27. Studies on Scurfy • 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. Studies on Scurfy • 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. References • 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.

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