Nature Medicine
3, 1133 - 1136 (1997)
doi:10.1038/nm1097-1133
Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreadingStephen D. Miller1, Carol L. Vanderlugt1, Wendy Smith Begolka1, Winnie Pao1, Robert L. Yauch1, Katherine L. Neville1, Yael Katz-Levy1, Ana Carrizosa2
& Byung S. Kim1
1Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611, USA
2Center for Neurological Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA Correspondence should be addressed to S.D.M. Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease1, which may be initiated by a virus infection2. 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 mononu-clear 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)7, 8, 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)9, 10. Epitope spreading is an important alternate mechanism to explain the etiology of virus-induced organ-specific autoimmune diseases.
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