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. 1993 Aug;143(2):446–452.

Apoptosis of T lymphocytes in experimental autoimmune encephalomyelitis. Evidence for programmed cell death as a mechanism to control inflammation in the brain.

M Schmied 1, H Breitschopf 1, R Gold 1, H Zischler 1, G Rothe 1, H Wekerle 1, H Lassmann 1
PMCID: PMC1887018  PMID: 8342595

Abstract

In experimental autoimmune encephalomyelitis (EAE) myelin-specific T lymphocytes attack the myelinated tissue of the central nervous system (CNS). In the Lewis rat, EAE as a rule has an acute, monophasic course. With spontaneous clinical recovery the inflammatory CNS infiltrates are cleared from the nervous tissue within a few days. This is well in line with the remarkably low incidence of myelin-specific T cells present in EAE infiltrate. Combining immunocytochemical techniques, ultrastructural criteria and in situ nick translation we found up to 49% of T lymphocytes in EAE lesions showing signs of apoptosis at the time of recovery from disease. Our results suggest that apoptosis of T lymphocytes may be one possible mechanism to eliminate T lymphocytes from inflammatory brain lesions.

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Selected References

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

  1. Ben-Nun A., Wekerle H., Cohen I. R. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol. 1981 Mar;11(3):195–199. doi: 10.1002/eji.1830110307. [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. Bursch W., Kleine L., Tenniswood M. The biochemistry of cell death by apoptosis. Biochem Cell Biol. 1990 Sep;68(9):1071–1074. doi: 10.1139/o90-160. [DOI] [PubMed] [Google Scholar]
  4. Bursch W., Paffe S., Putz B., Barthel G., Schulte-Hermann R. Determination of the length of the histological stages of apoptosis in normal liver and in altered hepatic foci of rats. Carcinogenesis. 1990 May;11(5):847–853. doi: 10.1093/carcin/11.5.847. [DOI] [PubMed] [Google Scholar]
  5. Cohen J. A., Essayan D. M., Zweiman B., Lisak R. P. Limiting dilution analysis of the frequency of antigen-reactive lymphocytes isolated from the central nervous system of Lewis rats with experimental allergic encephalomyelitis. Cell Immunol. 1987 Aug;108(1):203–213. doi: 10.1016/0008-8749(87)90204-8. [DOI] [PubMed] [Google Scholar]
  6. Cohen J. J., Duke R. C. Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. J Immunol. 1984 Jan;132(1):38–42. [PubMed] [Google Scholar]
  7. Cross A. H., Cannella B., Brosnan C. F., Raine C. S. Homing to central nervous system vasculature by antigen-specific lymphocytes. I. Localization of 14C-labeled cells during acute, chronic, and relapsing experimental allergic encephalomyelitis. Lab Invest. 1990 Aug;63(2):162–170. [PubMed] [Google Scholar]
  8. Duke R. C., Chervenak R., Cohen J. J. Endogenous endonuclease-induced DNA fragmentation: an early event in cell-mediated cytolysis. Proc Natl Acad Sci U S A. 1983 Oct;80(20):6361–6365. doi: 10.1073/pnas.80.20.6361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ellis R. E., Yuan J. Y., Horvitz H. R. Mechanisms and functions of cell death. Annu Rev Cell Biol. 1991;7:663–698. doi: 10.1146/annurev.cb.07.110191.003311. [DOI] [PubMed] [Google Scholar]
  10. Fesus L., Davies P. J., Piacentini M. Apoptosis: molecular mechanisms in programmed cell death. Eur J Cell Biol. 1991 Dec;56(2):170–177. [PubMed] [Google Scholar]
  11. Hickey W. F., Hsu B. L., Kimura H. T-lymphocyte entry into the central nervous system. J Neurosci Res. 1991 Feb;28(2):254–260. doi: 10.1002/jnr.490280213. [DOI] [PubMed] [Google Scholar]
  12. Hu Z. Y., Bourreau E., Jung-Testas I., Robel P., Baulieu E. E. Neurosteroids: oligodendrocyte mitochondria convert cholesterol to pregnenolone. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8215–8219. doi: 10.1073/pnas.84.23.8215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jenkins M. K., Pardoll D. M., Mizuguchi J., Chused T. M., Schwartz R. H. Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5409–5413. doi: 10.1073/pnas.84.15.5409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kerr J. F., Wyllie A. H., Currie A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239–257. doi: 10.1038/bjc.1972.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lassmann H., Rössler K., Zimprich F., Vass K. Expression of adhesion molecules and histocompatibility antigens at the blood-brain barrier. Brain Pathol. 1991 Jan;1(2):115–123. doi: 10.1111/j.1750-3639.1991.tb00648.x. [DOI] [PubMed] [Google Scholar]
  16. Lorenz R. G., Allen P. M. Thymic cortical epithelial cells lack full capacity for antigen presentation. Nature. 1989 Aug 17;340(6234):557–559. doi: 10.1038/340557a0. [DOI] [PubMed] [Google Scholar]
  17. Lublin F. D., Tippett D. L., Maurer P. H. Central nervous system and blood lymphocytes in experimental allergic encephalomyelitis. J Clin Lab Immunol. 1983 Mar;10(3):139–142. [PubMed] [Google Scholar]
  18. Lyman W. D., Abrams G. A., Raine C. S. Experimental autoimmune encephalomyelitis: isolation and characterization of inflammatory cells from the central nervous system. J Neuroimmunol. 1989 Dec;25(2-3):195–201. doi: 10.1016/0165-5728(89)90137-9. [DOI] [PubMed] [Google Scholar]
  19. MacDonald H. R., Lees R. K. Programmed death of autoreactive thymocytes. Nature. 1990 Feb 15;343(6259):642–644. doi: 10.1038/343642a0. [DOI] [PubMed] [Google Scholar]
  20. Male D., Pyrce G., Hughes C., Lantos P. Lymphocyte migration into brain modelled in vitro: control by lymphocyte activation, cytokines, and antigen. Cell Immunol. 1990 Apr 15;127(1):1–11. doi: 10.1016/0008-8749(90)90109-5. [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. Mason D. Genetic variation in the stress response: susceptibility to experimental allergic encephalomyelitis and implications for human inflammatory disease. Immunol Today. 1991 Feb;12(2):57–60. doi: 10.1016/0167-5699(91)90158-P. [DOI] [PubMed] [Google Scholar]
  23. McConkey D. J., Orrenius S., Jondal M. Cellular signalling in programmed cell death (apoptosis). Immunol Today. 1990 Apr;11(4):120–121. doi: 10.1016/0167-5699(90)90048-e. [DOI] [PubMed] [Google Scholar]
  24. Murphy K. M., Heimberger A. B., Loh D. Y. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science. 1990 Dec 21;250(4988):1720–1723. doi: 10.1126/science.2125367. [DOI] [PubMed] [Google Scholar]
  25. Ohmori K., Hong Y., Fujiwara M., Matsumoto Y. In situ demonstration of proliferating cells in the rat central nervous system during experimental autoimmune encephalomyelitis. Evidence suggesting that most infiltrating T cells do not proliferate in the target organ. Lab Invest. 1992 Jan;66(1):54–62. [PubMed] [Google Scholar]
  26. 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]
  27. Pender M. P., McCombe P. A., Yoong G., Nguyen K. B. Apoptosis of alpha beta T lymphocytes in the nervous system in experimental autoimmune encephalomyelitis: its possible implications for recovery and acquired tolerance. J Autoimmun. 1992 Aug;5(4):401–410. doi: 10.1016/0896-8411(92)90001-7. [DOI] [PubMed] [Google Scholar]
  28. Pender M. P., Nguyen K. B., McCombe P. A., Kerr J. F. Apoptosis in the nervous system in experimental allergic encephalomyelitis. J Neurol Sci. 1991 Jul;104(1):81–87. doi: 10.1016/0022-510x(91)90219-w. [DOI] [PubMed] [Google Scholar]
  29. Pette M., Fujita K., Kitze B., Whitaker J. N., Albert E., Kappos L., Wekerle H. Myelin basic protein-specific T lymphocyte lines from MS patients and healthy individuals. Neurology. 1990 Nov;40(11):1770–1776. doi: 10.1212/wnl.40.11.1770. [DOI] [PubMed] [Google Scholar]
  30. Selmaj K., Raine C. S., Farooq M., Norton W. T., Brosnan C. F. Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced by lymphotoxin. J Immunol. 1991 Sep 1;147(5):1522–1529. [PubMed] [Google Scholar]
  31. Smith C. A., Williams G. T., Kingston R., Jenkinson E. J., Owen J. J. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature. 1989 Jan 12;337(6203):181–184. doi: 10.1038/337181a0. [DOI] [PubMed] [Google Scholar]
  32. Sun D., Qin Y., Chluba J., Epplen J. T., Wekerle H. Suppression of experimentally induced autoimmune encephalomyelitis by cytolytic T-T cell interactions. Nature. 1988 Apr 28;332(6167):843–845. doi: 10.1038/332843a0. [DOI] [PubMed] [Google Scholar]
  33. Vass K., Lassmann H., Wekerle H., Wisniewski H. M. The distribution of Ia antigen in the lesions of rat acute experimental allergic encephalomyelitis. Acta Neuropathol. 1986;70(2):149–160. doi: 10.1007/BF00691433. [DOI] [PubMed] [Google Scholar]
  34. Werdelin O., McCluskey R. T. The nature and the specificity of mononuclear cells in experimental autoimmune inflammations and the mechanisms leading to their accumulation. J Exp Med. 1971 Jun 1;133(6):1242–1263. doi: 10.1084/jem.133.6.1242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wyllie A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980 Apr 10;284(5756):555–556. doi: 10.1038/284555a0. [DOI] [PubMed] [Google Scholar]
  36. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]

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