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

Stephen D. Miller*, Carol L. Vanderlugt, Wendy Smith Begolka, Winnie Pao, Robert L. Yauch, Katherine L. Neville, Yael Katz-Levy, Ana Carrizosa, Byung S. Kim

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

496 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1133-1136
Number of pages4
JournalNature Medicine
Volume3
Issue number10
DOIs
StatePublished - Oct 1997

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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