Molecular mimicry between neurons and an intracerebral pathogen induces a CD8 T cell-mediated autoimmune disease

J Immunol. 2008 Jun 15;180(12):8421-33. doi: 10.4049/jimmunol.180.12.8421.

Abstract

To identify basic mechanisms of how infections may induce a neuron-specific autoimmune response, we generated mice expressing OVA as neuronal autoantigen under control of the neuron-specific enolase promoter (NSE-OVA mice). Intracerebral, but not systemic, infection with attenuated Listeria monocytogenes-secreting OVA induced an atactic-paretic neurological syndrome in NSE-OVA mice after bacterial clearance from the brain, whereas wild-type mice remained healthy. Immunization with attenuated Listeria monocytogenes-secreting OVA before intracerebral infection strongly increased the number of intracerebral OVA-specific CD8 T cells aggravating neurological disease. T cell depletion and adoptive transfer experiments identified CD8 T cells as decisive mediators of the autoimmune disease. Importantly, NSE-OVA mice having received OVA-specific TCR transgenic CD8 T cells developed an accelerated, more severe, and extended neurological disease. Adoptively transferred pathogenic CD8 T cells specifically homed to OVA-expressing MHC class I(+) neurons and, corresponding to the clinical symptoms, approximately 30% of neurons in the anterior horn of the spinal cord became apoptotic. Thus, molecular mimicry between a pathogen and neurons can induce a CD8 T cell-mediated neurological disease, with its severity being influenced by the frequency of specific CD8 T cells, and its induction, but not its symptomatic phase, requiring the intracerebral presence of the pathogen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoantigens / administration & dosage*
  • Autoantigens / genetics
  • Autoantigens / immunology
  • Brain Diseases / enzymology
  • Brain Diseases / genetics
  • Brain Diseases / immunology*
  • Brain Diseases / microbiology
  • CD4-Positive T-Lymphocytes / enzymology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / enzymology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / microbiology
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Chickens
  • Humans
  • Listeria monocytogenes / genetics
  • Listeria monocytogenes / immunology
  • Listeriosis / enzymology
  • Listeriosis / genetics
  • Listeriosis / immunology*
  • Listeriosis / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Mimicry / immunology*
  • Nervous System Autoimmune Disease, Experimental / enzymology
  • Nervous System Autoimmune Disease, Experimental / genetics
  • Nervous System Autoimmune Disease, Experimental / microbiology*
  • Nervous System Autoimmune Disease, Experimental / pathology
  • Neurons / enzymology
  • Neurons / immunology*
  • Neurons / metabolism
  • Neurons / microbiology*
  • Ovalbumin / administration & dosage
  • Ovalbumin / biosynthesis
  • Ovalbumin / genetics
  • Ovalbumin / metabolism
  • Phosphopyruvate Hydratase / administration & dosage
  • Phosphopyruvate Hydratase / biosynthesis
  • Phosphopyruvate Hydratase / genetics
  • Promoter Regions, Genetic
  • Rats

Substances

  • Autoantigens
  • Ovalbumin
  • Phosphopyruvate Hydratase