Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1991 Mar;87(3):949–954. doi: 10.1172/JCI115102

Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions.

K Selmaj 1, C S Raine 1, B Cannella 1, C F Brosnan 1
PMCID: PMC329886  PMID: 1999503

Abstract

Multiple sclerosis (MS) brain tissue, spleen, and PBMC were studied using immunocytochemistry and FACS for immunoreactivity for lymphotoxin (LT) and TNF. Both cytokines were identified in acute and chronic active MS lesions but were absent from chronic silent lesions. LT was associated with CD3+ lymphocytes and Leu-M5+ microglia cells at the lesion edge and to a lesser extent, in adjacent white matter. TNF was associated with astrocytes in all areas of the lesion, and with foamy macrophages in the center of the active lesion. In acute lesions, immunoreactivity for TNF in endothelial cells was noted at the lesion edge. No LT or TNF reactivity was detected in Alzheimer's or Parkinson's disease brain tissues but was present at lower levels in central nervous system (CNS) tissue from other inflammatory conditions, except for adrenoleucodystrophy which displayed high levels of LT in microglia. No increase in LT and TNF reactivity was detected in spleen and PBMC of MS patients suggesting specific reactivity within the CNS. These results indicate that LT and TNF may be involved in the immunopathogenesis of MS, and can be detected in both inflammatory cells and cells endogenous to the CNS.

Full text

PDF
950

Images in this article

Selected References

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

  1. Beck J., Rondot P., Catinot L., Falcoff E., Kirchner H., Wietzerbin J. Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand. 1988 Oct;78(4):318–323. doi: 10.1111/j.1600-0404.1988.tb03663.x. [DOI] [PubMed] [Google Scholar]
  2. Carswell E. A., Old L. J., Kassel R. L., Green S., Fiore N., Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666–3670. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cavender D. E., Edelbaum D., Ziff M. Endothelial cell activation induced by tumor necrosis factor and lymphotoxin. Am J Pathol. 1989 Mar;134(3):551–560. [PMC free article] [PubMed] [Google Scholar]
  4. Chung I. Y., Benveniste E. N. Tumor necrosis factor-alpha production by astrocytes. Induction by lipopolysaccharide, IFN-gamma, and IL-1 beta. J Immunol. 1990 Apr 15;144(8):2999–3007. [PubMed] [Google Scholar]
  5. Cuturi M. C., Murphy M., Costa-Giomi M. P., Weinmann R., Perussia B., Trinchieri G. Independent regulation of tumor necrosis factor and lymphotoxin production by human peripheral blood lymphocytes. J Exp Med. 1987 Jun 1;165(6):1581–1594. doi: 10.1084/jem.165.6.1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Esparza I., Männel D., Ruppel A., Falk W., Krammer P. H. Interferon gamma and lymphotoxin or tumor necrosis factor act synergistically to induce macrophage killing of tumor cells and schistosomula of Schistosoma mansoni. J Exp Med. 1987 Aug 1;166(2):589–594. doi: 10.1084/jem.166.2.589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Franciotta D. M., Grimaldi L. M., Martino G. V., Piccolo G., Bergamaschi R., Citterio A., Melzi d'Eril G. V. Tumor necrosis factor in serum and cerebrospinal fluid of patients with multiple sclerosis. Ann Neurol. 1989 Dec;26(6):787–789. doi: 10.1002/ana.410260618. [DOI] [PubMed] [Google Scholar]
  8. Frei K., Siepl C., Groscurth P., Bodmer S., Schwerdel C., Fontana A. Antigen presentation and tumor cytotoxicity by interferon-gamma-treated microglial cells. Eur J Immunol. 1987 Sep;17(9):1271–1278. doi: 10.1002/eji.1830170909. [DOI] [PubMed] [Google Scholar]
  9. Gallo P., Piccinno M. G., Krzalic L., Tavolato B. Tumor necrosis factor alpha (TNF alpha) and neurological diseases. Failure in detecting TNF alpha in the cerebrospinal fluid from patients with multiple sclerosis, AIDS dementia complex, and brain tumours. J Neuroimmunol. 1989 Jun;23(1):41–44. doi: 10.1016/0165-5728(89)90071-4. [DOI] [PubMed] [Google Scholar]
  10. Garrett I. R., Durie B. G., Nedwin G. E., Gillespie A., Bringman T., Sabatini M., Bertolini D. R., Mundy G. R. Production of lymphotoxin, a bone-resorbing cytokine, by cultured human myeloma cells. N Engl J Med. 1987 Aug 27;317(9):526–532. doi: 10.1056/NEJM198708273170902. [DOI] [PubMed] [Google Scholar]
  11. Hofman F. M., Hinton D. R., Johnson K., Merrill J. E. Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med. 1989 Aug 1;170(2):607–612. doi: 10.1084/jem.170.2.607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kaushansky K., Broudy V. C., Harlan J. M., Adamson J. W. Tumor necrosis factor-alpha and tumor necrosis factor-beta (lymphotoxin) stimulate the production of granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and IL-1 in vivo. J Immunol. 1988 Nov 15;141(10):3410–3415. [PubMed] [Google Scholar]
  13. Lachman L. B., Brown D. C., Dinarello C. A. Growth-promoting effect of recombinant interleukin 1 and tumor necrosis factor for a human astrocytoma cell line. J Immunol. 1987 May 1;138(9):2913–2916. [PubMed] [Google Scholar]
  14. Lieberman A. P., Pitha P. M., Shin H. S., Shin M. L. Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6348–6352. doi: 10.1073/pnas.86.16.6348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Merrill J. E., Strom S. R., Ellison G. W., Myers L. W. In vitro study of mediators of inflammation in multiple sclerosis. J Clin Immunol. 1989 Mar;9(2):84–96. doi: 10.1007/BF00916935. [DOI] [PubMed] [Google Scholar]
  16. Pober J. S., Lapierre L. A., Stolpen A. H., Brock T. A., Springer T. A., Fiers W., Bevilacqua M. P., Mendrick D. L., Gimbrone M. A., Jr Activation of cultured human endothelial cells by recombinant lymphotoxin: comparison with tumor necrosis factor and interleukin 1 species. J Immunol. 1987 May 15;138(10):3319–3324. [PubMed] [Google Scholar]
  17. 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]
  18. Pukel C., Baquerizo H., Rabinovitch A. Destruction of rat islet cell monolayers by cytokines. Synergistic interactions of interferon-gamma, tumor necrosis factor, lymphotoxin, and interleukin 1. Diabetes. 1988 Jan;37(1):133–136. doi: 10.2337/diab.37.1.133. [DOI] [PubMed] [Google Scholar]
  19. Robbins D. S., Shirazi Y., Drysdale B. E., Lieberman A., Shin H. S., Shin M. L. Production of cytotoxic factor for oligodendrocytes by stimulated astrocytes. J Immunol. 1987 Oct 15;139(8):2593–2597. [PubMed] [Google Scholar]
  20. Ruddle N. H., Homer R. The role of lymphotoxin in inflammation. Prog Allergy. 1988;40:162–182. [PubMed] [Google Scholar]
  21. Selmaj K. W., Farooq M., Norton W. T., Raine C. S., Brosnan C. F. Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor. J Immunol. 1990 Jan 1;144(1):129–135. [PubMed] [Google Scholar]
  22. Selmaj K. W., Raine C. S. Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol. 1988 Apr;23(4):339–346. doi: 10.1002/ana.410230405. [DOI] [PubMed] [Google Scholar]
  23. Shinjo K., Tsuda S., Hayami T., Asahi T., Kawaharada H. Increase in permeability of human endothelial cell monolayer by recombinant human lymphotoxin. Biochem Biophys Res Commun. 1989 Aug 15;162(3):1431–1437. doi: 10.1016/0006-291x(89)90834-6. [DOI] [PubMed] [Google Scholar]
  24. Sica A., Wang J. M., Colotta F., Dejana E., Mantovani A., Oppenheim J. J., Larsen C. G., Zachariae C. O., Matsushima K. Monocyte chemotactic and activating factor gene expression induced in endothelial cells by IL-1 and tumor necrosis factor. J Immunol. 1990 Apr 15;144(8):3034–3038. [PubMed] [Google Scholar]
  25. Waksman B. Mechanisms in multiple sclerosis. Nature. 1985 Nov 14;318(6042):104–105. doi: 10.1038/318104a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES