Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Wekerle, H. Immunopathogenesis of multiple sclerosis. Acta Neurol. 13, 197–204 (1991).
Kurtzke, J.F. Epidemiologic evidence for multiple sclerosis as an infection. Clin.Microbiol. Rev. 6, 382–427 (1993).
Miller, S.D. & Gerety, S.J. Immunologic aspects of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. Semin. Virol. 1, 263–272 (1990).
Clatch, R.J., Lipton, H.L. & Miller, S.D. Characterization of Theiler's murine encephalomyelitis virus (TMEV)-specific delayed-type hypersensitivity responses in TMEV-induced demyelinating disease: Correlation with clinical signs. J. Immunol. 136, 920–927 (1986).
Clatch, R.J., Miller, S.D., Metzner, R., Dal Canto, M.C. & Lipton, H.L. Monocytes/ macrophages isolated from the mouse central nervous system contain infectious Theiler's murine encephalomyelitis virus (TMEV). Virology 176, 244–254 (1990).
Pope, J.G., Karpus, W.J., Vanderlugt, C. & Miller, S.D. Flow cytometric and functional analyses of CNS-infiltrating cells in SJL/J mice with Theiler's virus-induced demyelinating disease: Evidence for a CD4+ T cell-mediated pathology. J. Immunol. 156, 4050–4058 (1996).
Fujinami, R.S. & Oldstone, M.B. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: Mechanism for autoimmunity. Science 230, 1043–1045 (1985).
Wucherpfennig, K.W. & Strominger, J.L. Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995).
Lehmann, P.V., Forsthuber, T., Miller, A. & Sercarz, E.E. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 358, 155–157 (1992).
McRae, B.L., Vanderlugt, C.L., Dal Canto, M.C. & Miller, S.D. Functional evidence for epitope spreading in the relapsing pathology of EAE in the SJL/J mouse. J. Exp. Med. 182, 75–85 (1995).
Ota, K. et al. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 346, 183–187 (1990).
Bernard, C.C. & de Rosbo, N.K. Immunopathological recognition of autoantigens in multiple sclerosis. Acta Neurol. 13, 171–178 (1991).
Scherer, M.T., Ignatowicz, L., Winslow, G.M., Kappler, J.W. & Marrack, P., Super antigens:Bacterial and viral proteins that manipulate the immune system. Annu. Rev. Cell Biol. 9, 101–128 (1993).
Miller, S.D., Clatch, R.J., Pevear, D.C., Trotter, J.L. & Lipton, H.L. Class ll-restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. I. Cross-specificity among TMEV substrains and related picornaviruses, but not myelin proteins. J. Immunol. 138, 3776–3784 (1987).
Kennedy, M.K. et al. Inhibition of murine relapsing experimental autoimmune encephalomyelitis by immune tolerance to proteolipid protein and its encephalitogenic peptides. J. Immunol. 144, 909–915 (1990).
Karpus, W.J., Pope, J.G., Peterson, J.D., Dal Canto, M.C. & Miller, S.D. Inhibition of Theiler's virus-mediated demyelination by peripheral immune tolerance induction. J. Immunol. 155, 947–957 (1995).
Miller, S.D. et al. Class ll-restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. III. Failure of neuroantigenspecific immune tolerance to affect the clinical course of demyelination. J. Neuroimmunol. 26, 9–23 (1990).
Yu, M., Johnson, J.M. & Tuohy, V.K. A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: A basis for peptide-specific therapy after onset of clinical disease. J. Exp. Med. 183, 1777–1788 (1996).
Rose, N.R. & Hill, S.L. The pathogenesis of postinfectious myocarditis. Clin. Immunol. Immunopathol. 80, S92–S99 (1996).
Kyu, B. et al. Cardiac persistence of cardioviral RNA detected by polymerase chain reaction in a murine model of dilated cardiomyopathy. Circulation 86, 522–530 (1992).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Miller, S., Vanderlugt, C., Begolka, W. et al. Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading. Nat Med 3, 1133–1136 (1997). https://doi.org/10.1038/nm1097-1133
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm1097-1133
This article is cited by
-
Non-mutational neoantigens in disease
Nature Immunology (2024)
-
The impact of the gut microbiome on extra-intestinal autoimmune diseases
Nature Reviews Immunology (2023)
-
ASC- and caspase-1-deficient C57BL/6 mice do not develop demyelinating disease after infection with Theiler’s murine encephalomyelitis virus
Scientific Reports (2023)
-
The Functional Adaptability of Hyporesponsive T Cells and Its Impact on Transplant Outcomes
Current Transplantation Reports (2023)
-
Rethinking peripheral T cell tolerance: checkpoints across a T cell’s journey
Nature Reviews Immunology (2021)