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. 1994 Mar 1;179(3):973–984. doi: 10.1084/jem.179.3.973

Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis

PMCID: PMC2191414  PMID: 7509366

Abstract

Equal numbers of CD4+ T cells recognizing myelin basic protein (MBP) and proteolipid protein (PLP) are found in the circulation of normal individuals and multiple sclerosis (MS) patients. We hypothesized that if myelin-reactive T cells are critical for the pathogenesis of MS, they would exist in a different state of activation as compared with myelin-reactive T cells cloned from the blood of normal individuals. This was investigated in a total of 62 subjects with definitive MS. While there were no differences in the frequencies of MBP- and PLP- reactive T cells after primary antigen stimulation, the frequency of MBP or PLP but not tetanus toxoid-reactive T cells generated after primary recombinant interleukin (rIL-2) stimulation was significantly higher in MS patients as compared with control individuals. Primary rIL- 2-stimulated MBP-reactive T cell lines were CD4+ and recognized MBP epitopes 84-102 and 143-168 similar to MBP-reactive T cell lines generated with primary MBP stimulation. In the cerebrospinal fluid (CSF) of MS patients, MBP-reactive T cells generated with primary rIL-2 stimulation accounted for 7% of the IL-2-responsive cells, greater than 10-fold higher than paired blood samples, and these T cells also selectively recognized MBP peptides 84-102 and 143-168. In striking contrast, MBP-reactive T cells were not detected in CSF obtained from patients with other neurologic diseases. These results provide definitive in vitro evidence of an absolute difference in the activation state of myelin-reactive T cells in the central nervous system of patients with MS and provide evidence of a pathogenic role of autoreactive T cells in the disease.

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Selected References

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  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. Bourdette D. N., Vainiene M., Morrison W., Jones R., Turner M. J., Hashim G. A., Vandenbark A. A., Offner H. Myelin basic protein specific T cell lines and clones derived from the CNS of rats with EAE only recognize encephalitogenic epitopes. J Neurosci Res. 1991 Oct;30(2):308–315. doi: 10.1002/jnr.490300205. [DOI] [PubMed] [Google Scholar]
  3. Brod S. A., Purvee M., Benjamin D., Hafler D. A. T-T cell interactions are mediated by adhesion molecules. Eur J Immunol. 1990 Oct;20(10):2259–2268. doi: 10.1002/eji.1830201015. [DOI] [PubMed] [Google Scholar]
  4. Brod S. A., Rudd C. E., Purvee M., Hafler D. A. Lymphokine regulation of CD45R expression on human T cell clones. J Exp Med. 1989 Dec 1;170(6):2147–2152. doi: 10.1084/jem.170.6.2147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chou Y. K., Bourdette D. N., Offner H., Whitham 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 May;38(1-2):105–113. doi: 10.1016/0165-5728(92)90095-3. [DOI] [PubMed] [Google Scholar]
  6. Cohen I. R. The cognitive principle challenges clonal selection. Immunol Today. 1992 Nov;13(11):441–444. doi: 10.1016/0167-5699(92)90071-E. [DOI] [PubMed] [Google Scholar]
  7. Deibler G. E., Martenson R. E., Kies M. W. Large scale preparation of myelin basic protein from central nervous tissue of several mammalian species. Prep Biochem. 1972;2(2):139–165. doi: 10.1080/00327487208061467. [DOI] [PubMed] [Google Scholar]
  8. Fallis R. J., Powers M. L., Sy M. S., Weiner H. L. Adoptive transfer of murine chronic-relapsing autoimmune encephalomyelitis. Analysis of basic protein-reactive cells in lymphoid organs and nervous system of donor and recipient animals. J Neuroimmunol. 1987 Mar;14(2):205–219. doi: 10.1016/0165-5728(87)90055-5. [DOI] [PubMed] [Google Scholar]
  9. Fey K., Melchers I., Eichmann K. Quantitative studies on T cell diversity. IV. Mathematical analysis of multiple limiting populations of effector and suppressor T cells. J Exp Med. 1983 Jul 1;158(1):40–52. doi: 10.1084/jem.158.1.40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ford D., Burger D. Precursor frequency of antigen-specific T cells: effects of sensitization in vivo and in vitro. Cell Immunol. 1983 Jul 15;79(2):334–344. doi: 10.1016/0008-8749(83)90075-8. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Hafler D. A., Duby A. D., Lee S. J., Benjamin D., Seidman J. G., Weiner H. L. Oligoclonal T lymphocytes in the cerebrospinal fluid of patients with multiple sclerosis. J Exp Med. 1988 Apr 1;167(4):1313–1322. doi: 10.1084/jem.167.4.1313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hauser S. L., Dawson D. M., Lehrich J. R., Beal M. F., Kevy S. V., Propper R. D., Mills J. A., Weiner H. L. Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J Med. 1983 Jan 27;308(4):173–180. doi: 10.1056/NEJM198301273080401. [DOI] [PubMed] [Google Scholar]
  14. Hünig T., Tiefenthaler G., Meyer zum Büschenfelde K. H., Meuer S. C. Alternative pathway activation of T cells by binding of CD2 to its cell-surface ligand. Nature. 1987 Mar 19;326(6110):298–301. doi: 10.1038/326298a0. [DOI] [PubMed] [Google Scholar]
  15. Jingwu Z., Medaer R., Hashim G. A., Chin Y., van den Berg-Loonen E., Raus J. C. Myelin basic protein-specific T lymphocytes in multiple sclerosis and controls: precursor frequency, fine specificity, and cytotoxicity. Ann Neurol. 1992 Sep;32(3):330–338. doi: 10.1002/ana.410320305. [DOI] [PubMed] [Google Scholar]
  16. KURTZKE J. F. FURTHER NOTES ON DISABILITY EVALUATION IN MULTIPLE SCLEROSIS, WITH SCALE MODIFICATIONS. Neurology. 1965 Jul;15:654–661. doi: 10.1212/wnl.15.7.654. [DOI] [PubMed] [Google Scholar]
  17. LaSalle J. M., Hafler D. A. The coexpression of CD45RA and CD45RO isoforms on T cells during the S/G2/M stages of cell cycle. Cell Immunol. 1991 Nov;138(1):197–206. doi: 10.1016/0008-8749(91)90144-z. [DOI] [PubMed] [Google Scholar]
  18. LaSalle J. M., Tolentino P. J., Freeman G. J., Nadler L. M., Hafler D. A. Early signaling defects in human T cells anergized by T cell presentation of autoantigen. J Exp Med. 1992 Jul 1;176(1):177–186. doi: 10.1084/jem.176.1.177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lamb J. R., Skidmore B. J., Green N., Chiller J. M., Feldmann M. Induction of tolerance in influenza virus-immune T lymphocyte clones with synthetic peptides of influenza hemagglutinin. J Exp Med. 1983 May 1;157(5):1434–1447. doi: 10.1084/jem.157.5.1434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lee S. J., Wucherpfennig K. W., Brod S. A., Benjamin D., Weiner H. L., Hafler D. A. Common T-cell receptor V beta usage in oligoclonal T lymphocytes derived from cerebrospinal fluid and blood of patients with multiple sclerosis. Ann Neurol. 1991 Jan;29(1):33–40. doi: 10.1002/ana.410290109. [DOI] [PubMed] [Google Scholar]
  21. 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 Jul 15;145(2):540–548. [PubMed] [Google Scholar]
  22. Ofosu-Appiah W., Mokhtarian F., Miller A., Grob D. Characterization of in vivo-activated T cell clones from peripheral blood of multiple sclerosis patients. Clin Immunol Immunopathol. 1991 Jan;58(1):46–55. doi: 10.1016/0090-1229(91)90147-3. [DOI] [PubMed] [Google Scholar]
  23. 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 Jul 12;346(6280):183–187. doi: 10.1038/346183a0. [DOI] [PubMed] [Google Scholar]
  24. Poser C. M., Paty D. W., Scheinberg L., McDonald W. I., Davis F. A., Ebers G. C., Johnson K. P., Sibley W. A., Silberberg D. H., Tourtellotte W. W. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983 Mar;13(3):227–231. doi: 10.1002/ana.410130302. [DOI] [PubMed] [Google Scholar]
  25. Robb R. J., Greene W. C., Rusk C. M. Low and high affinity cellular receptors for interleukin 2. Implications for the level of Tac antigen. J Exp Med. 1984 Oct 1;160(4):1126–1146. doi: 10.1084/jem.160.4.1126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schluesener H. J., Wekerle H. Autoaggressive T lymphocyte lines recognizing the encephalitogenic region of myelin basic protein: in vitro selection from unprimed rat T lymphocyte populations. J Immunol. 1985 Nov;135(5):3128–3133. [PubMed] [Google Scholar]
  27. Vandenbark A. A., Offner H., Reshef T., Fritz R., Chou C. H., Cohen I. R. Specificity of T lymphocyte lines for peptides of myelin basic protein. J Immunol. 1985 Jul;135(1):229–233. [PubMed] [Google Scholar]
  28. Waldmann T. A. The structure, function, and expression of interleukin-2 receptors on normal and malignant lymphocytes. Science. 1986 May 9;232(4751):727–732. doi: 10.1126/science.3008337. [DOI] [PubMed] [Google Scholar]
  29. Wucherpfennig K. W., Newcombe J., Li H., Keddy C., Cuzner M. L., Hafler D. A. Gamma delta T-cell receptor repertoire in acute multiple sclerosis lesions. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4588–4592. doi: 10.1073/pnas.89.10.4588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wucherpfennig K. W., Weiner H. L., Hafler D. A. T-cell recognition of myelin basic protein. Immunol Today. 1991 Aug;12(8):277–282. doi: 10.1016/0167-5699(91)90126-E. [DOI] [PubMed] [Google Scholar]
  31. Zamvil S. S., Nelson P. A., Mitchell D. J., Knobler R. L., Fritz R. B., Steinman L. Encephalitogenic T cell clones specific for myelin basic protein. An unusual bias in antigen recognition. J Exp Med. 1985 Dec 1;162(6):2107–2124. doi: 10.1084/jem.162.6.2107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. Zhang J. W., Chou C. H., Hashim G., Medaer R., Raus J. C. Preferential peptide specificity and HLA restriction of myelin basic protein-specific T cell clones derived from MS patients. Cell Immunol. 1990 Aug;129(1):189–198. doi: 10.1016/0008-8749(90)90197-y. [DOI] [PubMed] [Google Scholar]
  34. Zhang J., Weiner H. L., Hafler D. A. Autoreactive T cells in multiple sclerosis. Int Rev Immunol. 1992;9(3):183–201. doi: 10.3109/08830189209061790. [DOI] [PubMed] [Google Scholar]

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