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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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slide2

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
slide3

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
slide4

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
slide5

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
slide6

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
slide8

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)
slide9

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
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