Skip to main content
PMC home page
Elsevier - PMC COVID-19 Collection logoLink to Elsevier - PMC COVID-19 Collection
. 2002 Nov 11;51(1):7–19. doi: 10.1016/0165-5728(94)90123-6

Experimental allergic encephalomyelitis induced by the peptide encoded by exon 2 of the MBP gene, a peptide implicated in remyelination

Benjamin M Segal a,∗, Cedric S Raine b, Dale E McFarlin a,†, Rhonda R Voskuhl a, Henry F McFarland a
PMCID: PMC7119711  PMID: 7512579

Abstract

The discovery of T lymphocytes reactive to the peptide encoded by exon 2 of the myelin basic protein (MBP) gene in multiple sclerosis (MS) patients has drawn attention to MBP isoforms harboring that peptide as candidate autoantigens. Previously, immunological studies in MS had almost exclusively used the more abundant 18.5 kDa isoform of MBP, which does not does not contain the exon 2 peptide. Investigations of experimental allergic encephalomyelitis (EAE) have also focussed on the 18.5 kDa MBP isoform and its peptides. Since EAE is an animal model widely used widly used to study MS, we examined the encephalitogenic potential of exon 2 peptide in the SJL/J mouse. Evidence for increased expression of exon 2-containing isoforms during remyelination in mouse CNS suggested that exon 2-sensitized T cels, with encephalitogenic capacity, might be important in the pertuation of relapsing EAE (rEAE). Our experiments have demonstrated that exon 2 peptide is inherently immunogenic in SJL mice and that EAE could be induced by the adoptive transfer of exon 2-sensitized lymphocytes. Furthermore, the disease could be accentuated by the transfer of short-term exon 2-reactive lines or by a combination of adoptive transfer and antigenic challenge with exon 2 peptide. The immunodominant epitope(s) appeared to localize to the segment bordered by amino acids 59–85.

Keywords: Experimental allergic encephalomyelitis, Myelin basic protein isoforms, Exon 2 peptide

References

  1. Barbarese E., Carson J.H., Braun P.E. Accumulation of teh four myelin basic proteins in teh mouse brain during development. J. Neurochem. 1978;31:779–782. doi: 10.1111/j.1471-4159.1978.tb00110.x. [DOI] [PubMed] [Google Scholar]
  2. Brown A., McFarlin D.E., Raine C.S. Chronic neurophathology of relapsing experimental encephalomyelitis in the mouse. Lab. Invest. 1982;46:171–185. [PubMed] [Google Scholar]
  3. Chou Y.K., Vainiene M., Whitman R., Bourdette D.N., Chou C.H.-J., Hashim G., Offner H., Vandenbark A.A. Response of human T lymphocyte lines to myelin basic protein: association of dominant epitopes with HLA class II restriction molecules. J. Neurosci. Res. 1989;23:207–216. doi: 10.1002/jnr.490230211. [DOI] [PubMed] [Google Scholar]
  4. Chou Y.K., Bourdette D.N., Offner H., Whitman R., Wang R-Y., Hashim G.A., Vandenbark A.A. Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis. J. Neuroimmunol. 1992;38:105–113. doi: 10.1016/0165-5728(92)90095-3. [DOI] [PubMed] [Google Scholar]
  5. Deibler G.E., Martenson R.E., Kies M.W. Large scale preparation of myelin basic protein from central nervous system of several memmalian species. Prep. Biochem. 1972;2:139–165. doi: 10.1080/00327487208061467. [DOI] [PubMed] [Google Scholar]
  6. Fallis R.J., Raine C.S., McFarlin D.E. Chronic relapsing experimental allergic encephalomyelitis in SJL mice following adoptive transfer of an epitope specific T cell line. J. Neuroimmunol. 1989;22:93–105. doi: 10.1016/0165-5728(89)90039-8. [DOI] [PubMed] [Google Scholar]
  7. Fritz R., McFarlin D.E. Encephalitogenic epitopes of myelin basic protein. Chem. Immunol. 1989;46:101–125. [PubMed] [Google Scholar]
  8. Gammon G., Sercarz E., Benichou G. The dominant self and the cryptic self: shaping the autoreactive T cell repertoire. Immun Today. 1991;12:193–195. doi: 10.1016/0167-5699(91)90052-U. [DOI] [PubMed] [Google Scholar]
  9. 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;13:99–108. doi: 10.1016/0165-5728(86)90053-6. [DOI] [PubMed] [Google Scholar]
  10. Jordan C.A., Friedrich V.L., Dubois-Dalcq M. In situ hybridization of myelin gene transcripts in developing mouse spinal cord. J. Neurosci. 1989;9:248–257. doi: 10.1523/JNEUROSCI.09-01-00248.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jordan C.A., Friedrich V.L., DeFerra F., Weismiller D.G., Holmes K.V., Dubois-Dalq M. Differential expression in myelin basic protein transcripts during central nervous system (CNS) remyelination. Cell. Mol. Neurobiol. 1990;10:3–18. doi: 10.1007/BF00733631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kamholtz J., Toffeneti J., Lazzarini R.A. Organization and expression of human myelin basic protein gene. J. Neurosci. Res. 1988;21:62–70. doi: 10.1002/jnr.490210110. [DOI] [PubMed] [Google Scholar]
  13. Kerlero de Rosbo N., Tang S., Bernard C.C.A. Comparative study of myelin basic protein isoforms in developing vertebrate central nervous system: absence of 21.5 and 20.2-kilodalton myelin basic proteins in chickens may point to their importance in mammalian myelinogenesis. Dev. Neurosci. 1991;13:34–40. doi: 10.1159/000112138. [DOI] [PubMed] [Google Scholar]
  14. Kristensson K., Holmes K.V., Duchala C.S., Zeller N.K., Lazzarini R.A., Dubois-Dalq J. Increased levels of myelin basic protein transcripts in virus-induced demyelination. Nature. 1986;322:544–547. doi: 10.1038/322544a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lehmann P.V., Forsthuber T., Miller A., Sercarz E. Spreading of T cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992;358:155–157. doi: 10.1038/358155a0. [DOI] [PubMed] [Google Scholar]
  16. Martin R., Jaraquemada D., Flerlage M., Richert J., Whitaker J., Long E.O., McFarlin D.E., McFarland H.F. Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals. J. Immunol. 1990;145:540–548. [PubMed] [Google Scholar]
  17. Martin R., Whitaker J., Flerlage M., Goodin R.R., McFarlin D.E., McFarland H.F. T cell recognition of a citrulline containing myelin basic protein (Abstract) Neurology. 1991;41(Suppl. 1):257–258. [Google Scholar]
  18. Martin R., Utz U., Coligan J.E., Richert J.R., Flerlage M., Robinson E., Stone R., Biddison W.E., McFarlin D.E., McFarland H.F. Diversity in fine specificity and T cell receptor usage of the human CD4+ cytotoxic T cell response specific for the immunodominant myelin basic protein peptide 87–106. J. Immunol. 1992;148:1359–1366. [PubMed] [Google Scholar]
  19. Martin R., McFarland H.F., McFarlin D.E. Immunological aspects of demyelinating diseases. Annu. Rev. Immunol. 1992;10:15–87. doi: 10.1146/annurev.iy.10.040192.001101. [DOI] [PubMed] [Google Scholar]
  20. Moore G.R.W., McCarron R.M., McFarlin D.E., Raine C.S. Chronic relapsing necrotizing encephalomyelitis produced by MBP in mice. Lab. Invest. 1987;57:157–167. [PubMed] [Google Scholar]
  21. Newman S., Kitamura K., Campagnoni A.T. Vol. 84. 1987. Identification of a cDNA coding for a fifth form of myelin basic protein in mouse; pp. 886–890. (Proc. Natl. Acad. Sci. USA). [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ota K., Matsui M., Milford E.L., Mackin G.A., Weiner H.L., Hafler D.A. T cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature. 1990;346:183–187. doi: 10.1038/346183a0. [DOI] [PubMed] [Google Scholar]
  23. Pette M., Fujita K., Kitze B., Whitaker J.N., Albert E., Kappos L., Wekerle H. Myelin basic protein-specific JT lymphocyte lines from MS patients and healthy individuals. Neurology. 1990;40:1770–1776. doi: 10.1212/wnl.40.11.1770. [DOI] [PubMed] [Google Scholar]
  24. Petinelli C.B., McFarlin D.E. Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: requirement for Lyl 1+2- T lymphocytes. J. Immunol. 1981;127:1420–1423. [PubMed] [Google Scholar]
  25. Prineas J.W., Barnard R.O., Kwon E.E., Sharer L.R., Cho E.S. Multiple sclerosis: remyelination of nascent lesions. Ann. Neurol. 1993;33:137–151. doi: 10.1002/ana.410330203. [DOI] [PubMed] [Google Scholar]
  26. Raine C.S. The analysis of autoimmune demyelination: its impact upon multiple sclerosis. Lab. Invest. 1984;50:608–635. [PubMed] [Google Scholar]
  27. Raine C.S., Wu E. Multiple sclerosis: remyelination in acute lesions. J. Neuropath. Exp. Neurol. 1993;52:199–204. [PubMed] [Google Scholar]
  28. Raine C.S., Mokhtarian F., McFarlin D.E. Adoptively transfered chronic relapsing experimental allergic encephalomyelitis in the mouse: neuropathologic analysis. Lab. Invest. 1984;51:534–546. [PubMed] [Google Scholar]
  29. Richert J.R., Reuben-Burnside C.A., Deibler G.E., Kies M.W. Peptide specificities of myelin basic protein-reactive human T cell clones. Neurology. 1988;38:739–742. doi: 10.1212/wnl.38.5.739. [DOI] [PubMed] [Google Scholar]
  30. Roth H.J., Kronquist K.E., Kerlero de Rosbo N., Crandall B.F., Campagnoni A.T. Evidence for the expression of four myelin basic protein variants in developing human spinal cord through cDNA cloning. J. Neurosci. Res. 1987;17:321–328. doi: 10.1002/jnr.490170402. [DOI] [PubMed] [Google Scholar]
  31. Shaw M.K., Kim C., Ho K.-L., Lisak R.P., Tse H.Y. A combination of adoptive transfer and antigenic challenge induces consistent murine experimental allergic encephalomyelitis in C57BL/6 mice and other reputed resistant strains. J. Neuroimmunol. 1992;39:139–150. doi: 10.1016/0165-5728(92)90183-l. [DOI] [PubMed] [Google Scholar]
  32. Sun J., Link H., Olsson T., Xiao B., Andersson G., Ekre H., Linington C., Diener P. T and B cell response to myelin-oligodendrocyte glycoprotein in multiple sclerosis. J. Immunol. 1991;146:1490–1495. [PubMed] [Google Scholar]
  33. Voskuhl R.R., McFarlin D.E., Stone R., McFarland H.F. T-lymphocyte recognition of a portion of myelin basic protein encoded by an exon expressed during myelination. J. Neuroimmunol. 1993;42:187–192. doi: 10.1016/0165-5728(93)90009-N. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Voskuhl R.R., McFarlin D.E., Rhame L., Deibler G., Stone R., Maloni H., McFarland H.F. A novel candidate autoantigen in a multiplex family with multiple sclerosis: prevalence of T-lymphocytes specific for an MBP epitope unique to myelination. J. Neuroimmunol. 1993;46:137–144. doi: 10.1016/0165-5728(93)90243-R. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Neuroimmunology are provided here courtesy of Elsevier

RESOURCES