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Tolerance and Autoimmunity

Tolerance and Autoimmunity. Autoimmunity: Failure of hosts immune system to distinguish between self and non-self. Results in attack on self by auto-antibodies and self reactive T-cells. Tolerance: Mechanisms to protect an individual from self-reactive lymphocytes

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Tolerance and Autoimmunity

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  1. Tolerance and Autoimmunity

  2. Autoimmunity: Failure of hosts immune system to distinguish between self and non-self. Results in attack on self by auto-antibodies and self reactive T-cells. • Tolerance: Mechanisms to protect an individual from self-reactive lymphocytes • Central: Elimination of T- or B-cell clones before they are allowed to mature • Peripheral: Renders mature T- or B-cells inactive or anergic • Anergic: Unresponsiveness to antigenic stimulus • Systemic Disease: Immune response directed towards a broad range of target antigens and involves a number of organs and tissues • Organ Specific Disease: Target antigen is unique to a single organ

  3. Tolerance • Tolerogens: Antigens that induce tolerance, no immune response • Factors Promoting Tolerance: • High dose of antigen • Persistence of antigen in host • Intravenous/oral introduction • Absence of adjuvants • Low levels of costimulators

  4. Central Tolerance: Negative selection of lymphocytes with autoreactive TCRs or Ig receptors • Peripheral Tolerance: • Mature B-cells require T-cell help • Mature T-cells require co-stimulatory recognition • CD28/B7 • CTLA-4 inhibitory receptor • T-regulatory cell • CD4+ T-cells expressing CD25 that have increased foxp3 expression • Apoptosis: Activated T-cells increase Fas and Fas ligand expression • Antigen Sequestration: Antigen never exposed to immune system

  5. Multiple Sclerosis (MS) • Systemic autoimmune disease • Affected individuals produce auto-reactive T cells against the myelin sheath of nerve fibers • Activated T cells in the cerebrospinal fluid are able to infiltrate the brain tissue producing inflammatory lesions that destroy the myelin sheath • Breakdown of myelin results in numerous neurological dysfunctions including numbness of the limbs, paralysis, and loss of vision

  6. Autoimmunity can be induced in animals • Experimental autoimmune encephalomyelitis (EAE) in mice • Caused by injection of myelin basic protein (MBP), normally sequestered by blood brain barrier • T cells implicated: • Transfer of CD4+ T cells immunized with MBP causes disease • Treatment with CD4+ antibodies can prevent disease • TH1 vs TH2 and cytokine production • T cell involvement requires MHC molecules and TCRs capable of binding self antigens • *This is experimental design for our paper. TH17 is distinct lineage of CD4+ T cells and MOG is used as immunizing agent instead of MBP

  7. TH17 cells: Il-17 producing CD4+ T helper cells • Il-17: Promotes neutrophil recruitment, mediate both pathogenic immune responses as well autoimmune responses • IFNγ: Cytokine produced by T cells and NK cells • CD45: Cell surface marker of lymphocytes • EAE is mouse model for MS • MOG(35-55): myelin oligodendrocyte glycoprotein (aa 35-55 of protein that is normally sequestered from immune system by blood brain barrier, antigen) • CCR6: Chemokine Receptor 6 (expressed by TH17 cells) • CCL20: CCR6 ligand • Choroid Plexus: Site of entry into central nervous system (CNS)

  8. Findings • EAE caused by two waves of T-cell entry into the CNS • CCR6 required for initial T cell entry into the brain tissue (second wave CCR6 independent) • CCL20 expressed choroid plexus epithelium • CCR6/CCL20 found in human nerve tissue, links to MS

  9. Conclusions

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