Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading

Nat Med. 1997 Oct;3(10):1133-6. doi: 10.1038/nm1097-1133.


Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease, which may be initiated by a virus infection. Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a picornavirus that induces a chronic, CD4+ T cell-mediated demyelinating disease with a clinical course and histopathology similar to that of chronic progressive MS (ref. 3). Demyelination in TMEV-infected mice is initiated by a mononuclear inflammatory response mediated by virus-specific CD4+ T cells targeting virus, which chronically persists in the CNS (ref. 4-6). We show that beginning 3-4 weeks after disease onset, T-cell responses to multiple myelin autoepitopes arise in an ordered progression and may play a pathologic role in chronic disease. Kinetic and functional studies show that T-cell responses to the immunodominant myelin proteolipid protein epitope (PLP139-151) did not arise because of cross-reactivity between TMEV and self epitopes (that is, molecular mimicry), but because of de novo priming of self-reactive T cells to sequestered autoantigens released secondary to virus-specific T cell-mediated demyelination (that is, epitope spreading). Epitope spreading is an important alternate mechanism to explain the etiology of virus-induced organ-specific autoimmune diseases.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autoimmunity*
  • CD4-Positive T-Lymphocytes / immunology
  • Cross Reactions
  • Demyelinating Diseases / immunology*
  • Epitopes / immunology*
  • Female
  • Inflammation
  • Kinetics
  • Mice
  • Mice, Inbred Strains
  • Molecular Sequence Data
  • Myelin Proteins / chemistry
  • Myelin Proteins / immunology*
  • Myelin Proteolipid Protein / chemistry
  • Myelin Proteolipid Protein / immunology*
  • Poliomyelitis / immunology*
  • Poliomyelitis / physiopathology
  • Self Tolerance
  • T-Lymphocytes / immunology*
  • Theilovirus*


  • Epitopes
  • Myelin Proteins
  • Myelin Proteolipid Protein