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. 2002 Nov 13;26(1):9–23. doi: 10.1016/0165-5728(90)90115-4

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

Stephen D Miller 1,4,∗, Sheila J Gerety 1, Mary K Kennedy 1, Jeffrey D Peterson 4, John L Trotter 5, Vincent K Tuohy 6, Carl Waltenbaugh 1, Mauro C Dal Canto 2, Howard L Lipton 3,4
PMCID: PMC7119834  PMID: 1688446

Abstract

Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) into susceptible mouse strains produces a chronic demyelinating disease in which mononuclear cell-rich infiltrates in the central nervous system (CNS) are prominent. Current evidence strongly supports an immune-mediated basis for myelin breakdown, with an effector role proposed for TMEV-specific, major histocompatibility complex (MHC) class II-restricted delayed-type hypersensitivity (DTH) responses in which lymphokine-activated macrophages mediate bystander demyelination. The present study examined the possibility that concomitant or later-appearing neuroantigen-specific autoimmune T cell responses, such as those demonstrated in chronic-relapsing experimental allergic encephalomyelitis (R-EAE), may contribute to the demyelinating process following TMEV infection. T cell responses against intact, purified major myelin proteins (myelin basic protein (MBP) and proteolipid protein (PLP), and against altered myelin constituents were readily demonstrable in SJL/J mice with R-EAE, but were not detectable in SJL/J mice with TMEV-induced demyelinating disease. TMEV-infected mice also did not display T cell responses against the peptide fragments of MBP(91–104) and PLP(139–151) recently shown to be encephalitogenic in SJL/J mice. In addition, induction of neuroantigen-specific tolerance to a heterogeneous mixture of CNS antigens, via the i.v. injection of syngeneic SJL/J splenocytes covalently coupled with mouse spinal cord homogenate, resulted in significant suppression of clinical and histologic signs of R-EAE and the accompanying MBP- and PLP-specific DTH responses. In contrast, neuroantigen-specific tolerance failed to alter the development of clinical and histologic signs of TMEV-induced demyelinating disease or the accompanying virus-specific DTH and humoral immune responses. These findings demonstrate that TMEV-induced demyelinating disease can occur in the apparent absence of neuroantigen-specific autoimmune responses. The relationship of the present results to the immunopathology of multiple sclerosis is discussed.

Keywords: Theiler's virus, Relapsing experimental autoimmune encephalomyelitis, Myelin basic protein, Proteolipid apoprotein, Neuroantigen-specific tolerance, Multiple sclerosis

Abbreviations: CMI, cell-mediated immunity; CNS, central nervous system; DTH, delayed-type hypersensitivity; i.c., intracerebral; MBP, myelin basic protein; MDO, mean day of onset; MHC, major histocompatibility complex; MS, multiple sclerosis; MSCH, mouse spinal cord homogenate; MSCH-SP, MSCH-coupled splenocytes; PCFIA, particle concentration fluorescence immunoassay; pfu, plaque-forming unit; p.i., post-infection; PLP, proteolipid apoprotein; R-EAE, chronic-relapsing experimental allergic encephalomyelitis; rfu, relative fluorescence units; TMEV, Theiler's murine encephalomyelitis virus; TDH, delayed-type hypersensitivity T cell(s); Tprlf, T cell proliferation

Footnotes

☆

This work was supported in part by U.S. Public Health Service Grants NS-26543, NS-23349, NS-21913, NS-13011, AI-18755, and National Multiple Sclerosis Society Grants RG-1487 and RG2014-A-2.

References

  1. Armitage P. John Wiley; New York, NY: 1971. Statistical Methods in Research; p. 207. [Google Scholar]
  2. Bach B.A., Sherman L., Benacerraf B., Greene M.I. Mechanisms of immunoregulation of cell-mediated immunity. II. Induction and suppression of delayed-type hypersensitivity to azobenzenearsonate-coupled syngeneic cells. J. Immunol. 1978;121:1460–1468. [PubMed] [Google Scholar]
  3. 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. J. Neurol. Sci. 1984;66:283–293. doi: 10.1016/0022-510x(84)90017-0. [DOI] [PubMed] [Google Scholar]
  4. Brown A.M., McFarlin D.E. Relapsing experimental allergic encephalomyelitis in the SJL/J mouse. Lab. Invest. 1981;45:278–284. [PubMed] [Google Scholar]
  5. 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 TMEV-specific delayed-type hypersensitivity. J. Immunol. 1985;135:1408–1414. [PubMed] [Google Scholar]
  6. 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. 1986;136:920–927. [PubMed] [Google Scholar]
  7. Clatch R.J., Melvold R.W., Dal Canto M.C., Miller S.D., Lipton H.L. The Theiler's murine encephalomyelitis virus (TMEV) model for multiple sclerosis shows a strong influence of the murine equivalents of HLA-A, B, and C. J. Neuroimmunol. 1987;15:121–135. doi: 10.1016/0165-5728(87)90087-7. [DOI] [PubMed] [Google Scholar]
  8. Corradin G., Etlinger H.M., Chiller J.M. Lymphocyte specificity to protein antigens. I. Characterization of the antigen-induced in vitro T cell-dependent proliferative response with lymph node cells from primed mice. J. Immunol. 1977;199:1048–1053. [PubMed] [Google Scholar]
  9. Dal Canto M.C., Lipton H.L. Primary demyelination in Theiler's virus infection. Lab. Invest. 1976;33:626–637. [PubMed] [Google Scholar]
  10. Dal Canto M.C., Lipton H.L. Ultrastructural immunohistochemical localization of virus in acute and chronic demyelinating Theiler's virus infection. Am. J. Pathol. 1982;106:20–29. [PMC free article] [PubMed] [Google Scholar]
  11. Fontana A., Fierz W., Wekerle H. Astrocytes present myelin basic protein to encephalitogenic T-cell lines. Nature. 1984;307:273–276. doi: 10.1038/307273a0. [DOI] [PubMed] [Google Scholar]
  12. 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 and treatment. J. Virol. 1987;61:898–903. doi: 10.1128/jvi.61.3.898-903.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fujinami R.S., Oldstone M.B.A. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science. 1985;230:1043–1045. doi: 10.1126/science.2414848. [DOI] [PubMed] [Google Scholar]
  14. Greene M.I., Sugimoto M., Benacerraf B. Mechanisms of immunoregulation of cell-mediated immune responses. I. Effect of route of immunization with TNP-coupled syngeneic cells on the induction and suppression of contact sensitivity to picryl chloride. J. Immunol. 1978;120:1604–1611. [PubMed] [Google Scholar]
  15. Hafler D.A., Benjamin D.S., Burks J., Weiner H.L. Myelin basic protein and proteolipid reactivity of brain and cerobrospinal fluid-derived T cell clones in multiple sclerosis and postinfectious encephalomyelitis. J. Immunol. 1987;139:68–72. [PubMed] [Google Scholar]
  16. Houghten R.A. Vol. 82. 1985. General method for the rapid solid-phae synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids; pp. 5131–5136. (Proc. Natl. Acad. Sci. U.S.A.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Houghten R.A., DeGraw S.T., Bray M.K., Hoffmann S.R., Frizzell N.D. Simultaneous multiple peptide synthesis: the rapid preparation of large numbers of discrete peptides for biological, immunological, and methodological studies. Biotechniques. 1986;4:522–530. [Google Scholar]
  18. Kennedy M.K., Clatch R.J., Dal Canto M.C., Trotter J.L., Miller S.D. Monoclonal antibody-induced inhibition of relapsing EAE in SJL/J mice correlates with inhibition of neuroantigen-specific cell-mediated immune responses. J. Neuroimmunol. 1987;16:345–364. doi: 10.1016/0165-5728(87)90110-x. [DOI] [PubMed] [Google Scholar]
  19. Kennedy M.K., Dal Canto M.C., Trotter J.L., Miller S.D. Specific immunoregulation of relapsing experimental allergic encephalomyelitis in mice. J. Immunol. 1988;141:2986–2993. [PubMed] [Google Scholar]
  20. Kono D.H., Urban J.L., Horvath S.J., Ando D.G., Saavedra R.A., Hood L. Two minor determinants of myelin basic protein induce experimental allergic encephalomyelitis in SJL/J mice. J. Exp. Med. 1988;168:213–227. doi: 10.1084/jem.168.1.213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kurtke J.F., Hyllested K. Multiple sclerosis in the Faroe Islands. II. Clinical update, transmission, and the nature of MS. Neurology. 1986;36:307–328. doi: 10.1212/wnl.36.3.307. [DOI] [PubMed] [Google Scholar]
  22. Lang W., Wiley C., Lampert P. Theiler's virus encephalomyelitis is unaffected by treatment with myelin components. J. Neuroimmunol. 1985;9:109–113. doi: 10.1016/s0165-5728(85)80011-4. [DOI] [PubMed] [Google Scholar]
  23. Lees M.B., Sakura J.D. Preparation of proteolipids. In: Marks N., Rodnight R., editors. Vol. 4. Plenum Press; New York, NY: 1978. pp. 345–370. (Research Methods in Neurochemistry). [Google Scholar]
  24. Lehrich J.R., Arnason B.G.W., Hochberg F. Demyelinative myelopathy in mice induced by the DA virus. J. Neurol. Sci. 1976;29:149–160. doi: 10.1016/0022-510x(76)90167-2. [DOI] [PubMed] [Google Scholar]
  25. Liebert U.G., Linington C., ter Meulen V. Induction of autoimmune reactions to myelin basic protein in measles virus encephalitis in Lewis rats. J. Neuroimmunol. 1988;17:103–118. doi: 10.1016/0165-5728(88)90018-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Linington C., Lassmann H. Antibody responses in chronic relapsing experimental allergic encephalomyelitis: correlation of serum demyelinating activity with antibody titre to the myelin/oligodendrocyte glycoprotein (MOG) J. Neuroimmunol. 1987;17:61–69. doi: 10.1016/0165-5728(87)90031-2. [DOI] [PubMed] [Google Scholar]
  27. Lipton H.L. Theiler's virus infection in mice: an unusual biphasic disease process leading to demyelination. Infect. Immun. 1975;11:1147–1155. doi: 10.1128/iai.11.5.1147-1155.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lipton H.L., Dal Canto M.C. Chronic neurologic disease in Theiler's virus infection of SJL/J mice. J. Neurol. Sci. 1976;30:201–207. doi: 10.1016/0022-510x(76)90267-7. [DOI] [PubMed] [Google Scholar]
  29. Lipton H.L., Dal Canto M.C. Theiler's virus induced demyelination: prevention by immunosuppression. Science. 1976;192:62–64. doi: 10.1126/science.176726. [DOI] [PubMed] [Google Scholar]
  30. Lipton H.L., Friedman A. Purification of Theiler's murine encephalomyelitis virus and analysis of the structural virion polypeptides: correlation of the polypeptide profile with virulence. J. Virol. 1980;33:1165–1172. doi: 10.1128/jvi.33.3.1165-1172.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lipton H.L., Kratochvil J., Sethi P., Dal Canto M.C. Theiler's virus antigen detected in mouse spinal cord 212 years after infection. Neurology. 1984;34:1117–1119. doi: 10.1212/wnl.34.8.1117. [DOI] [PubMed] [Google Scholar]
  32. Londei M., Lamb J.R., Bottazzo G.F., Feldmann M. Epithelial cells expressing aberrant MHC class II determinants can present antigen to cloned human T cells. Nature. 1984;312:639–641. doi: 10.1038/312639a0. [DOI] [PubMed] [Google Scholar]
  33. Melvold R.W., Jokinen D.M., Knobler R., Lipton H.L. Variations in genetic control of susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. I. Differences between susceptible SJL/J and resistant BALB/c strains map near the T cell B chain constant genes on chromosome 6. J. Immunol. 1987;138:1429–1433. [PubMed] [Google Scholar]
  34. Miller S.D., Claman H.N. The induction of hapten-specific T cell tolerance using hapten-modified lymphoid cells. I. Characteristics of tolerance induction. J. Immunol. 1976;117:1519–1526. [PubMed] [Google Scholar]
  35. Miller S.D., Sy M.S., Claman H.N. The induction of hapten-specific T cell tolerance using hapten-modified lymphoid cells. II. Relative roles of suppressor T cells and clone inhibition in the tolerant state. Eur. J. Immunol. 1977;7:165–170. doi: 10.1002/eji.1830070310. [DOI] [PubMed] [Google Scholar]
  36. Miller S.D., Wetzig R.P., Claman H.N. The induction of cell-mediated immunity and tolerance with protein antigens coupled to syngeneic lymphoid cells. J. Exp. Med. 1979;149:758–773. doi: 10.1084/jem.149.3.758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Miller S.D., Clatch R.J., Pevear D.C., 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;138:3776–3784. [PubMed] [Google Scholar]
  38. Nathanson N., Miller A. Epidemiology of multiple sclerosis: critique of evidence for a viral etiology. Am. J. Epidemiol. 1978;107:451–461. doi: 10.1093/oxfordjournals.aje.a112564. [DOI] [PubMed] [Google Scholar]
  39. Notkins A.L., Onodera T., Prabhakar E.L. Virus-induced autoimmunity. In: Notkins A.L., Oldstone M.B.A., editors. Vol. 1. Springer-Verlag; New York, NY: 1984. pp. 210–217. (Concepts in Viral Pathogenesis). [Google Scholar]
  40. Oldstone M.B.A., Notkins A.L. Molecular mimicry. In: Notkins A.L., Oldstone M.B.A., editors. Vol. 2. Springer-Verlag; New York, NY: 1986. pp. 195–202. (Concepts in Viral Pathogenesis). [Google Scholar]
  41. Peterson J.D., Kim J.Y., Melvold R.W., Miller S.D., Waltenbaugh C. A rapid method for quantitation of antiviral antibodies. J. Immunol. Methods. 1989;119:83–94. doi: 10.1016/0022-1759(89)90384-0. [DOI] [PubMed] [Google Scholar]
  42. Quarles R.H., Barbarash G.R., MacIntosh T.D. Methods for the identification and characterization of glycoproteins in central and peripheral myelin. In: Marks N., Rodnight R., editors. Vol. 6. Plenum Press; New York, NY: 1985. pp. 303–357. (Research Methods in Neurochemistry). [Google Scholar]
  43. Raine C.S. Experimental allergic encephalomyelitis and experimental allergic neuritis. Handb. Clin. Neurol. 1985;3:429–466. [Google Scholar]
  44. Rapport M.M., Graf L., Autilio L.A., Norton W.L. Immunochemical studies of organ and tumor lipids. 14. Galactocerebroside determinants in the myelin sheath of the central nervous system. J. Neurochem. 1964;11:855–864. doi: 10.1111/j.1471-4159.1964.tb06736.x. [DOI] [PubMed] [Google Scholar]
  45. Rodriguez M., David C.S. Demyelination induced by Theiler's virus: influence of the H-2 complex. J. Immunol. 1985;135:2145–2148. [PubMed] [Google Scholar]
  46. Rodriguez M., Leibowitz J.L., Lampert P.W. Persistent infection of oligodendrocytes in Theiler's virus-induced encephalomyelitis. Ann. Neurol. 1983;13:426–433. doi: 10.1002/ana.410130409. [DOI] [PubMed] [Google Scholar]
  47. Rodriguez M., Leibowitz J., David C.S. Susceptibility to Theiler's virus-induced demyelination. Mapping of the gene within the H-2D region. J. Exp. Med. 1986;163:620–631. doi: 10.1084/jem.163.3.620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Rodriguez M., Lafuse W.P., Liebowitz 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;36:964–970. doi: 10.1212/wnl.36.7.964. [DOI] [PubMed] [Google Scholar]
  49. Roos R.S., Firestone S., Wollmann R., Variakojis D., Arnason B.G.W. The effect of short-term and chronic immunosuppression on Theiler's virus demyelination. J. Neuroimmunol. 1982;2:223–234. doi: 10.1016/0165-5728(82)90057-1. [DOI] [PubMed] [Google Scholar]
  50. Srinivasappa J., Saegusa J., Prabhakar B.S., Gentry M.K., Buchmeier M.J., Wilktor T.J., Koprowski H., Oldstone M.B.A., Notkins A.L. Molecular mimicry: frequency of reactivity of monoclanal antiviral antibodies with normal tissues. J. Virol. 1986;57:397–401. doi: 10.1128/jvi.57.1.397-401.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Swanborg R.H., Swierkosz J.E., Saieg R.G. Studies on the species variability of experimental allergic encephalomyelitis in guinea pigs and rats. J. Immunol. 1974;112:594–600. [PubMed] [Google Scholar]
  52. Tuohy V.K., Lu Z., Sobel R.A., Laursen R.A., Lees M.B. Identification of an encephalitogenic determinant of myelin proteolipid protein for SJL mice. J. Immunol. 1989;142:1523–1527. [PubMed] [Google Scholar]
  53. Waksman B.H. The pathogenetic significance of cross reactions in autoimmune disease of the nervous system. Today. 1984;5:346–348. doi: 10.1016/0167-5699(84)90076-8. [DOI] [PubMed] [Google Scholar]
  54. Waksman B.H., Reynolds W.E. Vol. 175. 1984. Multiple sclerosis as a disease of immune regulation; pp. 282–294. (Proc. Soc. Exp. Biol. Med.). [DOI] [PubMed] [Google Scholar]
  55. Watanabe R., Wege H., ter Meulen V. Adoptive transfer of EAE-like lesions from rats with coronavirus-induced demyelinating encephalomyelitis. Nature. 1983;305:150–153. doi: 10.1038/305150a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Welsh C.J.R., 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;68:1659–1667. doi: 10.1099/0022-1317-68-6-1659. [DOI] [PubMed] [Google Scholar]
  57. Wisnewski H.M., Bloom B.R. Primary demyelination as a nonspecific consequence of a cell-mediated immune reaction. J. Exp. Med. 1975;141:346–354. doi: 10.1084/jem.141.2.346. [DOI] [PMC free article] [PubMed] [Google Scholar]

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