Abstract
The contribution of autoimmune responses to the pathogenesis of Theiler's virus-induced demyelinating disease was investigated. Delayed-type hypersensitivity responses to myelin were examined in both symptomatic and asymptomatic mice at different times post-infection, in order to determine whether autoreactivity correlates with the development of demyelination. The results indicate that although autoimmune responses probably do not play a major role in the initiation of demyelination at early times post-infection, autoreactivity to myelin antigens dose eventually develop in symptomatic animals, perhaps through the mechanism of epitope spreading. Autoimmunity to myelin components is therefore an additional factor that may contribute to lesion progression in chronically diseased animals.
Full text
PDFImages in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Altintas A., Cai Z., Pease L. R., Rodriguez M. Differential expression of H-2K and H-2D in the central nervous system of mice infected with Theiler's virus. J Immunol. 1993 Sep 1;151(5):2803–2812. [PubMed] [Google Scholar]
- Aubert C., Chamorro M., Brahic M. Identification of Theiler's virus infected cells in the central nervous system of the mouse during demyelinating disease. Microb Pathog. 1987 Nov;3(5):319–326. doi: 10.1016/0882-4010(87)90002-7. [DOI] [PubMed] [Google Scholar]
- Azoulay A., Brahic M., Bureau J. F. FVB mice transgenic for the H-2Db gene become resistant to persistent infection by Theiler's virus. J Virol. 1994 Jun;68(6):4049–4052. doi: 10.1128/jvi.68.6.4049-4052.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Barbano R. L., Dal Canto M. C. Serum and cells from Theiler's virus-infected mice fail to injure myelinating cultures or to produce in vivo transfer of disease. The pathogenesis of Theiler's virus-induced demyelination appears to differ from that of EAE. J Neurol Sci. 1984 Nov-Dec;66(2-3):283–293. doi: 10.1016/0022-510x(84)90017-0. [DOI] [PubMed] [Google Scholar]
- Blakemore W. F., Welsh C. J., Tonks P., Nash A. A. Observations on demyelinating lesions induced by Theiler's virus in CBA mice. Acta Neuropathol. 1988;76(6):581–589. doi: 10.1007/BF00689596. [DOI] [PubMed] [Google Scholar]
- Borrow P., Nash A. A. Susceptibility to Theiler's virus-induced demyelinating disease correlates with astrocyte class II induction and antigen presentation. Immunology. 1992 May;76(1):133–139. [PMC free article] [PubMed] [Google Scholar]
- Borrow P., Tonks P., Welsh C. J., Nash A. A. The role of CD8+T cells in the acute and chronic phases of Theiler's murine encephalomyelitis virus-induced disease in mice. J Gen Virol. 1992 Jul;73(Pt 7):1861–1865. doi: 10.1099/0022-1317-73-7-1861. [DOI] [PubMed] [Google Scholar]
- Bradbury J. M., Campbell R. S., Thompson R. J. Endogenous cyclic AMP-stimulated phosphorylation of a Wolfgram protein component in rabbit central-nervous-system myelin. Biochem J. 1984 Jul 15;221(2):351–359. doi: 10.1042/bj2210351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bureau J. F., Montagutelli X., Lefebvre S., Guénet J. L., Pla M., Brahic M. The interaction of two groups of murine genes determines the persistence of Theiler's virus in the central nervous system. J Virol. 1992 Aug;66(8):4698–4704. doi: 10.1128/jvi.66.8.4698-4704.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cash E., Bandeira A., Chirinian S., Brahic M. Characterization of B lymphocytes present in the demyelinating lesions induced by Theiler's virus. J Immunol. 1989 Aug 1;143(3):984–988. [PubMed] [Google Scholar]
- Cash E., Chamorro M., Brahic M. Minus-strand RNA synthesis in the spinal cords of mice persistently infected with Theiler's virus. J Virol. 1988 May;62(5):1824–1826. doi: 10.1128/jvi.62.5.1824-1826.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cash E., Chamorro M., Brahic M. Theiler's virus RNA and protein synthesis in the central nervous system of demyelinating mice. Virology. 1985 Jul 15;144(1):290–294. doi: 10.1016/0042-6822(85)90327-7. [DOI] [PubMed] [Google Scholar]
- Clatch R. J., Lipton H. L., Miller S. D. Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. II. Survey of host immune responses and central nervous system virus titers in inbred mouse strains. Microb Pathog. 1987 Nov;3(5):327–337. doi: 10.1016/0882-4010(87)90003-9. [DOI] [PubMed] [Google Scholar]
- Clatch R. J., Melvold R. W., Miller S. D., Lipton H. L. Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in mice is influenced by the H-2D region: correlation with TEMV-specific delayed-type hypersensitivity. J Immunol. 1985 Aug;135(2):1408–1414. [PubMed] [Google Scholar]
- Dal Canto M. C., Lipton H. L. Primary demyelination in Theiler's virus infection. An ultrastructural study. Lab Invest. 1975 Dec;33(6):626–637. [PubMed] [Google Scholar]
- Fiette L., Aubert C., Brahic M., Rossi C. P. Theiler's virus infection of beta 2-microglobulin-deficient mice. J Virol. 1993 Jan;67(1):589–592. doi: 10.1128/jvi.67.1.589-592.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fiette L., Aubert C., Müller U., Huang S., Aguet M., Brahic M., Bureau J. F. Theiler's virus infection of 129Sv mice that lack the interferon alpha/beta or interferon gamma receptors. J Exp Med. 1995 Jun 1;181(6):2069–2076. doi: 10.1084/jem.181.6.2069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Friedmann A., Frankel G., Lorch Y., Steinman L. Monoclonal anti-I-A antibody reverses chronic paralysis and demyelination in Theiler's virus-infected mice: critical importance of timing of treatment. J Virol. 1987 Mar;61(3):898–903. doi: 10.1128/jvi.61.3.898-903.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gerety S. J., Rundell M. K., Dal Canto M. C., Miller S. D. Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus-induced demyelinating disease. VI. Potentiation of demyelination with and characterization of an immunopathologic CD4+ T cell line specific for an immunodominant VP2 epitope. J Immunol. 1994 Jan 15;152(2):919–929. [PubMed] [Google Scholar]
- Graves M. C., Bologa L., Siegel L., Londe H. Theiler's virus in brain cell cultures: lysis of neurons and oligodendrocytes and persistence in astrocytes and macrophages. J Neurosci Res. 1986;15(4):491–501. doi: 10.1002/jnr.490150406. [DOI] [PubMed] [Google Scholar]
- Hafler D. A., Benjamin D. S., Burks J., Weiner H. L. Myelin basic protein and proteolipid protein reactivity of brain- and cerebrospinal fluid-derived T cell clones in multiple sclerosis and postinfectious encephalomyelitis. J Immunol. 1987 Jul 1;139(1):68–72. [PubMed] [Google Scholar]
- Johnson D., Hafler D. A., Fallis R. J., Lees M. B., Brady R. O., Quarles R. H., Weiner H. L. Cell-mediated immunity to myelin-associated glycoprotein, proteolipid protein, and myelin basic protein in multiple sclerosis. J Neuroimmunol. 1986 Nov;13(1):99–108. doi: 10.1016/0165-5728(86)90053-6. [DOI] [PubMed] [Google Scholar]
- 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. 1995 Jul 15;155(2):947–957. [PubMed] [Google Scholar]
- Lehmann P. V., Sercarz E. E., Forsthuber T., Dayan C. M., Gammon G. Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol Today. 1993 May;14(5):203–208. doi: 10.1016/0167-5699(93)90163-F. [DOI] [PubMed] [Google Scholar]
- Lipton H. L. Theiler's virus infection in mice: an unusual biphasic disease process leading to demyelination. Infect Immun. 1975 May;11(5):1147–1155. doi: 10.1128/iai.11.5.1147-1155.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lisak R. P., Zweiman B. In vitro cell-mediated immunity of cerebrospinal-fluid lymphocytes to myelin basic protein in primary demyelinating diseases. N Engl J Med. 1977 Oct 20;297(16):850–853. doi: 10.1056/NEJM197710202971602. [DOI] [PubMed] [Google Scholar]
- Massa P. T., Dörries R., ter Meulen V. Viral particles induce Ia antigen expression on astrocytes. Nature. 1986 Apr 10;320(6062):543–546. doi: 10.1038/320543a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miller S. D., Clatch R. J., Pevear D. C., Trotter J. L., Lipton H. L. Class II-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. 1987 Jun 1;138(11):3776–3784. [PubMed] [Google Scholar]
- Miller S. D., Gerety S. J., Kennedy M. K., Peterson J. D., Trotter J. L., Tuohy V. K., Waltenbaugh C., Dal Canto M. C., Lipton H. L. Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. III. Failure of neuroantigen-specific immune tolerance to affect the clinical course of demyelination. J Neuroimmunol. 1990 Jan;26(1):9–23. doi: 10.1016/0165-5728(90)90115-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miller S. D., McRae B. L., Vanderlugt C. L., Nikcevich K. M., Pope J. G., Pope L., Karpus W. J. Evolution of the T-cell repertoire during the course of experimental immune-mediated demyelinating diseases. Immunol Rev. 1995 Apr;144:225–244. doi: 10.1111/j.1600-065x.1995.tb00071.x. [DOI] [PubMed] [Google Scholar]
- Miller S. D., Vanderlugt C. L., Begolka W. S., Pao W., Yauch R. L., Neville K. L., Katz-Levy Y., Carrizosa A., Kim B. S. Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading. Nat Med. 1997 Oct;3(10):1133–1136. doi: 10.1038/nm1097-1133. [DOI] [PubMed] [Google Scholar]
- Musette P., Bureau J. F., Gachelin G., Kourilsky P., Brahic M. T lymphocyte repertoire in Theiler's virus encephalomyelitis: the nonspecific infiltration of the central nervous system of infected SJL/J mice is associated with a selective local T cell expansion. Eur J Immunol. 1995 Jun;25(6):1589–1593. doi: 10.1002/eji.1830250618. [DOI] [PubMed] [Google Scholar]
- Nicholson S. M., Dal Canto M. C., Miller S. D., Melvold R. W. Adoptively transferred CD8+ T lymphocytes provide protection against TMEV-induced demyelinating disease in BALB/c mice. J Immunol. 1996 Feb 1;156(3):1276–1283. [PubMed] [Google Scholar]
- Oleszak E. L., Kuzmak J., Good R. A., Platsoucas C. D. Immunology of Theiler's murine encephalomyelitis virus infection. Immunol Res. 1995;14(1):13–33. doi: 10.1007/BF02918495. [DOI] [PubMed] [Google Scholar]
- Pullen L. C., Miller S. D., Dal Canto M. C., Kim B. S. Class I-deficient resistant mice intracerebrally inoculated with Theiler's virus show an increased T cell response to viral antigens and susceptibility to demyelination. Eur J Immunol. 1993 Sep;23(9):2287–2293. doi: 10.1002/eji.1830230935. [DOI] [PubMed] [Google Scholar]
- Pullen L. C., Miller S. D., Dal Canto M. C., Van der Meide P. H., Kim B. S. Alteration in the level of interferon-gamma results in acceleration of Theiler's virus-induced demyelinating disease. J Neuroimmunol. 1994 Dec;55(2):143–152. doi: 10.1016/0165-5728(94)90004-3. [DOI] [PubMed] [Google Scholar]
- Richert J. R., McFarlin D. E., Rose J. W., McFarland H. F., Greenstein J. I. Expansion of antigen-specific T cells from cerebrospinal fluid of patients with multiple sclerosis. J Neuroimmunol. 1983 Dec;5(3):317–324. doi: 10.1016/0165-5728(83)90052-8. [DOI] [PubMed] [Google Scholar]
- Rodriguez M., Dunkel A. J., Thiemann R. L., Leibowitz J., Zijlstra M., Jaenisch R. Abrogation of resistance to Theiler's virus-induced demyelination in H-2b mice deficient in beta 2-microglobulin. J Immunol. 1993 Jul 1;151(1):266–276. [PubMed] [Google Scholar]
- Rodriguez M., Lafuse W. P., Leibowitz J., David C. S. Partial suppression of Theiler's virus-induced demyelination in vivo by administration of monoclonal antibodies to immune-response gene products (Ia antigens). Neurology. 1986 Jul;36(7):964–970. doi: 10.1212/wnl.36.7.964. [DOI] [PubMed] [Google Scholar]
- Rodriguez M., Pavelko K., Coffman R. L. Gamma interferon is critical for resistance to Theiler's virus-induced demyelination. J Virol. 1995 Nov;69(11):7286–7290. doi: 10.1128/jvi.69.11.7286-7290.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rodriguez M., Pierce M. L., Howie E. A. Immune response gene products (Ia antigens) on glial and endothelial cells in virus-induced demyelination. J Immunol. 1987 May 15;138(10):3438–3442. [PubMed] [Google Scholar]
- Roos R. P., Wollmann R. DA strain of Theiler's murine encephalomyelitis virus induces demyelination in nude mice. Ann Neurol. 1984 May;15(5):494–499. doi: 10.1002/ana.410150516. [DOI] [PubMed] [Google Scholar]
- Rosenthal A., Fujinami R. S., Lampert P. W. Mechanism of Theiler's virus-induced demyelination in nude mice. Lab Invest. 1986 May;54(5):515–522. [PubMed] [Google Scholar]
- Rueckert R. R., Pallansch M. A. Preparation and characterization of encephalomyocarditis (EMC) virus. Methods Enzymol. 1981;78(Pt A):315–325. [PubMed] [Google Scholar]
- Tournier-Lasserve E., Hashim G. A., Bach M. A. Human T-cell response to myelin basic protein in multiple sclerosis patients and healthy subjects. J Neurosci Res. 1988;19(1):149–156. doi: 10.1002/jnr.490190120. [DOI] [PubMed] [Google Scholar]
- Watanabe R., Wege H., ter Meulen V. Adoptive transfer of EAE-like lesions from rats with coronavirus-induced demyelinating encephalomyelitis. Nature. 1983 Sep 8;305(5930):150–153. doi: 10.1038/305150a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Welsh C. J., Tonks P., Nash A. A., Blakemore W. F. The effect of L3T4 T cell depletion on the pathogenesis of Theiler's murine encephalomyelitis virus infection in CBA mice. J Gen Virol. 1987 Jun;68(Pt 6):1659–1667. doi: 10.1099/0022-1317-68-6-1659. [DOI] [PubMed] [Google Scholar]
- Welsh J., Sapatino B., Rosenbaum B., Smith R., Linthicum S. Correlation between susceptibility to demyelination and interferon-gamma induction of major histocompatibility complex class II antigens on murine cerebrovascular endothelial cells. J Neuroimmunol. 1993 Oct;48(1):91–97. doi: 10.1016/0165-5728(93)90062-4. [DOI] [PubMed] [Google Scholar]