Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Jul 1;182(1):75–85. doi: 10.1084/jem.182.1.75

Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis

PMCID: PMC2192093  PMID: 7540658

Abstract

The role of epitope spreading in the pathology of relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) was examined. Using peripherally induced immunologic tolerance as a probe to analyze the neuropathologic T cell repertoire, we show that the majority of the immunopathologic reactivity during the acute phase of R-EAE in SJL/J mice induced by active immunization with the intact proteolipid (PLP) molecule is directed at the PLP139-151 epitope and that responses to secondary encephalitogenic PLP epitopes may contribute to the later relapsing phases of disease. Intermolecular epitope spreading was demonstrated by showing the development of T cell responses to PLP139- 151 after acute disease in mice in which R-EAE was initiated by the transfer of T cells specific for the non-cross-reactive MBP84-104 determinant. Intramolecular epitope spreading was demonstrated by showing that endogenous host T cells specific for a secondary encephalitogenic PLP epitope (PLP178-191) are demonstrable by both splenic T cell proliferative and in vivo delayed-type hypersensitivity responses in mice in which acute central nervous system damage was initiated by T cells reactive with the immunodominant, non-cross- reactive PLP139-151 sequence. The PLP178-191-specific responses are activated as a result of and correlate with the degree of acute tissue damage, since they do not develop in mice tolerized to the initiating epitope before expression of acute disease. Most importantly, we show that the PLP178-191-specific responses are capable of mediating R-EAE upon adoptive secondary transfer to naive recipient mice. Furthermore, induction of tolerance to intact PLP (which inhibits responses to both the initiating PLP139-151 epitope and to the PLP178-191 epitope) after the acute disease episode is sufficient to prevent relapsing disease. These results strongly support a contributory role of T cell responses to epitopes released as a result of acute tissue damage to the immunopathogenesis of relapsing clinical episodes and have important implications for the design of antigen-specific immunotherapies for the treatment of chronic autoimmune disorders in humans.

Full Text

The Full Text of this article is available as a PDF (1.9 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allegretta M., Nicklas J. A., Sriram S., Albertini R. J. T cells responsive to myelin basic protein in patients with multiple sclerosis. Science. 1990 Feb 9;247(4943):718–721. doi: 10.1126/science.1689076. [DOI] [PubMed] [Google Scholar]
  2. Brown A. M., McFarlin D. E. Relapsing experimental allergic encephalomyelitis in the SJL/J mouse. Lab Invest. 1981 Sep;45(3):278–284. [PubMed] [Google Scholar]
  3. Cannella B., Cross A. H., Raine C. S. Upregulation and coexpression of adhesion molecules correlate with relapsing autoimmune demyelination in the central nervous system. J Exp Med. 1990 Nov 1;172(5):1521–1524. doi: 10.1084/jem.172.5.1521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cross A. H., Tuohy V. K., Raine C. S. Development of reactivity to new myelin antigens during chronic relapsing autoimmune demyelination. Cell Immunol. 1993 Feb;146(2):261–269. doi: 10.1006/cimm.1993.1025. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Fatenejad S., Mamula M. J., Craft J. Role of intermolecular/intrastructural B- and T-cell determinants in the diversification of autoantibodies to ribonucleoprotein particles. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):12010–12014. doi: 10.1073/pnas.90.24.12010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fritz R. B., Chou C. H., McFarlin D. E. Relapsing murine experimental allergic encephalomyelitis induced by myelin basic protein. J Immunol. 1983 Mar;130(3):1024–1026. [PubMed] [Google Scholar]
  8. Greer J. M., Kuchroo V. K., Sobel R. A., Lees M. B. Identification and characterization of a second encephalitogenic determinant of myelin proteolipid protein (residues 178-191) for SJL mice. J Immunol. 1992 Aug 1;149(3):783–788. [PubMed] [Google Scholar]
  9. Kaufman D. L., Clare-Salzler M., Tian J., Forsthuber T., Ting G. S., Robinson P., Atkinson M. A., Sercarz E. E., Tobin A. J., Lehmann P. V. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature. 1993 Nov 4;366(6450):69–72. doi: 10.1038/366069a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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 Nov;16(3):345–364. doi: 10.1016/0165-5728(87)90110-x. [DOI] [PubMed] [Google Scholar]
  11. Kennedy M. K., Tan L. J., Dal Canto M. C., Miller S. D. Regulation of the effector stages of experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance induction. J Immunol. 1990 Jul 1;145(1):117–126. [PubMed] [Google Scholar]
  12. Kennedy M. K., Tan L. J., Dal Canto M. C., Tuohy V. K., Lu Z. J., Trotter J. L., Miller S. D. Inhibition of murine relapsing experimental autoimmune encephalomyelitis by immune tolerance to proteolipid protein and its encephalitogenic peptides. J Immunol. 1990 Feb 1;144(3):909–915. [PubMed] [Google Scholar]
  13. Kennedy M. K., Torrance D. S., Picha K. S., Mohler K. M. Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J Immunol. 1992 Oct 1;149(7):2496–2505. [PubMed] [Google Scholar]
  14. Kurtzke J. F. Epidemiologic evidence for multiple sclerosis as an infection. Clin Microbiol Rev. 1993 Oct;6(4):382–427. doi: 10.1128/cmr.6.4.382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lehmann P. V., Forsthuber T., Miller A., Sercarz E. E. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992 Jul 9;358(6382):155–157. doi: 10.1038/358155a0. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Link H., Baig S., Olsson O., Jiang Y. P., Höjeberg B., Olsson T. Persistent anti-myelin basic protein IgG antibody response in multiple sclerosis cerebrospinal fluid. J Neuroimmunol. 1990 Aug;28(3):237–248. doi: 10.1016/0165-5728(90)90017-h. [DOI] [PubMed] [Google Scholar]
  18. Malotky M. K., Pope L., Miller S. D. Epitope and functional specificity of peripheral tolerance induction in experimental autoimmune encephalomyelitis in adult Lewis rats. J Immunol. 1994 Jul 15;153(2):841–851. [PubMed] [Google Scholar]
  19. Mamula M. J., Fatenejad S., Craft J. B cells process and present lupus autoantigens that initiate autoimmune T cell responses. J Immunol. 1994 Feb 1;152(3):1453–1461. [PubMed] [Google Scholar]
  20. McCarron R. M., Fallis R. J., McFarlin D. E. Alterations in T cell antigen specificity and class II restriction during the course of chronic relapsing experimental allergic encephalomyelitis. J Neuroimmunol. 1990 Sep-Oct;29(1-3):73–79. doi: 10.1016/0165-5728(90)90149-h. [DOI] [PubMed] [Google Scholar]
  21. McRae B. L., Kennedy M. K., Tan L. J., Dal Canto M. C., Picha K. S., Miller S. D. Induction of active and adoptive relapsing experimental autoimmune encephalomyelitis (EAE) using an encephalitogenic epitope of proteolipid protein. J Neuroimmunol. 1992 Jun;38(3):229–240. doi: 10.1016/0165-5728(92)90016-e. [DOI] [PubMed] [Google Scholar]
  22. Miller S. D., Karpus W. J. The immunopathogenesis and regulation of T-cell-mediated demyelinating diseases. Immunol Today. 1994 Aug;15(8):356–361. doi: 10.1016/0167-5699(94)90173-2. [DOI] [PubMed] [Google Scholar]
  23. Miller S. D., Tan L. J., Pope L., McRae B. L., Karpus W. J. Antigen-specific tolerance as a therapy for experimental autoimmune encephalomyelitis. Int Rev Immunol. 1992;9(3):203–222. doi: 10.3109/08830189209061791. [DOI] [PubMed] [Google Scholar]
  24. 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 Mar 1;149(3):758–773. doi: 10.1084/jem.149.3.758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mokhtarian F., McFarlin D. E., Raine C. S. Adoptive transfer of myelin basic protein-sensitized T cells produces chronic relapsing demyelinating disease in mice. Nature. 1984 May 24;309(5966):356–358. doi: 10.1038/309356a0. [DOI] [PubMed] [Google Scholar]
  26. Offner H., Vainiene M., Gold D. P., Celnik B., Wang R., Hashim G. A., Vandenbark A. A. Characterization of the immune response to a secondary encephalitogenic epitope of basic protein in Lewis rats. I. T cell receptor peptide regulation of T cell clones expressing cross-reactive V beta genes. J Immunol. 1992 Mar 15;148(6):1706–1711. [PubMed] [Google Scholar]
  27. Perry L. L., Barzaga-Gilbert E., Trotter J. L. T cell sensitization to proteolipid protein in myelin basic protein-induced relapsing experimental allergic encephalomyelitis. J Neuroimmunol. 1991 Jul;33(1):7–15. doi: 10.1016/0165-5728(91)90029-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Perry L. L., Barzaga M. E. Kinetics and specificity of T and B cell responses in relapsing experimental allergic encephalomyelitis. J Immunol. 1987 Mar 1;138(5):1434–1441. [PubMed] [Google Scholar]
  29. Powell M. B., Mitchell D., Lederman J., Buckmeier J., Zamvil S. S., Graham M., Ruddle N. H., Steinman L. Lymphotoxin and tumor necrosis factor-alpha production by myelin basic protein-specific T cell clones correlates with encephalitogenicity. Int Immunol. 1990;2(6):539–544. doi: 10.1093/intimm/2.6.539. [DOI] [PubMed] [Google Scholar]
  30. Sakai K., Tabira T., Endoh M., Steinman L. Ia expression in chronic relapsing experimental allergic encephalomyelitis induced by long-term cultured T cell lines in mice. Lab Invest. 1986 Mar;54(3):345–352. [PubMed] [Google Scholar]
  31. Sakai K., Zamvil S. S., Mitchell D. J., Lim M., Rothbard J. B., Steinman L. Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein. J Neuroimmunol. 1988 Aug;19(1-2):21–32. doi: 10.1016/0165-5728(88)90032-x. [DOI] [PubMed] [Google Scholar]
  32. Sun J. B., Olsson T., Wang W. Z., Xiao B. G., Kostulas V., Fredrikson S., Ekre H. P., Link H. Autoreactive T and B cells responding to myelin proteolipid protein in multiple sclerosis and controls. Eur J Immunol. 1991 Jun;21(6):1461–1468. doi: 10.1002/eji.1830210620. [DOI] [PubMed] [Google Scholar]
  33. Tan L. J., Kennedy M. K., Dal Canto M. C., Miller S. D. Successful treatment of paralytic relapses in adoptive experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance. J Immunol. 1991 Sep 15;147(6):1797–1802. [PubMed] [Google Scholar]
  34. Tan L. J., Kennedy M. K., Miller S. D. Regulation of the effector stages of experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance induction. II. Fine specificity of effector T cell inhibition. J Immunol. 1992 May 1;148(9):2748–2755. [PubMed] [Google Scholar]
  35. Tisch R., Yang X. D., Singer S. M., Liblau R. S., Fugger L., McDevitt H. O. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature. 1993 Nov 4;366(6450):72–75. doi: 10.1038/366072a0. [DOI] [PubMed] [Google Scholar]
  36. Traugott U., Lebon P. Interferon-gamma and Ia antigen are present on astrocytes in active chronic multiple sclerosis lesions. J Neurol Sci. 1988 Apr;84(2-3):257–264. doi: 10.1016/0022-510x(88)90130-x. [DOI] [PubMed] [Google Scholar]
  37. Traugott U., Raine C. S., McFarlin D. E. Acute experimental allergic encephalomyelitis in the mouse: immunopathology of the developing lesion. Cell Immunol. 1985 Mar;91(1):240–254. doi: 10.1016/0008-8749(85)90047-4. [DOI] [PubMed] [Google Scholar]
  38. Trotter J. L., Clark H. B., Collins K. G., Wegeschiede C. L., Scarpellini J. D. Myelin proteolipid protein induces demyelinating disease in mice. J Neurol Sci. 1987 Jun;79(1-2):173–188. doi: 10.1016/0022-510x(87)90271-1. [DOI] [PubMed] [Google Scholar]
  39. 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 Mar 1;142(5):1523–1527. [PubMed] [Google Scholar]
  40. Vandenbark A. A., Vainiene M., Celnik B., Hashim G. A., Buenafe A., Offner H. Definition of encephalitogenic and immunodominant epitopes of guinea pig myelin basic protein (Gp-BP) in Lewis rats tolerized neonatally with Gp-BP or Gp-BP peptides. J Immunol. 1994 Jul 15;153(2):852–861. [PubMed] [Google Scholar]
  41. Zamvil S. S., Mitchell D. J., Powell M. B., Sakai K., Rothbard J. B., Steinman L. Multiple discrete encephalitogenic epitopes of the autoantigen myelin basic protein include a determinant for I-E class II-restricted T cells. J Exp Med. 1988 Sep 1;168(3):1181–1186. doi: 10.1084/jem.168.3.1181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Zamvil S., Nelson P., Trotter J., Mitchell D., Knobler R., Fritz R., Steinman L. T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination. 1985 Sep 26-Oct 2Nature. 317(6035):355–358. doi: 10.1038/317355a0. [DOI] [PubMed] [Google Scholar]
  43. van der Veen R. C., Trotter J. L., Clark H. B., Kapp J. A. The adoptive transfer of chronic relapsing experimental allergic encephalomyelitis with lymph node cells sensitized to myelin proteolipid protein. J Neuroimmunol. 1989 Feb;21(2-3):183–191. doi: 10.1016/0165-5728(89)90174-4. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES