Skip to main content
PMC home page
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1985 Mar;59(3):520–528.

Interleukin-2 in rheumatoid arthritis: production of and response to interleukin-2 in rheumatoid synovial fluid, synovial tissue and peripheral blood.

B Combe, R M Pope, M Fischbach, B Darnell, S Baron, N Talal
PMCID: PMC1576924  PMID: 3921298

Abstract

Several aspects of interleukin-2 (IL-2) generation and function were studied employing mononuclear cells from synovial fluid (SF), synovial tissue (ST) and peripheral blood (PB) of patients with rheumatoid arthritis (RA). Decreased PHA stimulated IL-2 production by lymphocytes from rheumatoid ST, SF (P less than 0.02), and PB (P less than 0.01) was observed when compared to normal blood and SF of patients with gout. The proliferative response of rheumatoid lymphocyte blasts exposed to exogenous IL-2 was also defective (P less than 0.05-0.001). This defect was greater in SF than in rheumatoid PB (P less than 0.05-0.001). In addition to the proliferative response, the effect of IL-2 on interferon-gamma (IFN-gamma) production was also examined. Rheumatoid lymphocytes from both PB and SF produced less IFN-gamma after overnight treatment with IL-2 than did normal PB lymphocytes. This decreased IFN-gamma induction was discordant with the excellent enhancement by IL-2 of natural killer activity. Removal of adherent cells in synovial fluid did not correct this deficit. Abnormalities in the biology of IL-2 and IFN-gamma suggest that impaired T cell function could contribute to the immunopathogenesis of RA.

Full text

PDF

Selected References

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

  1. Abrahamsen T. G., Froland S. S., Natvig J. B., Pahle J. Elution and characterization of lymphocytes from rheumatoid inflammatory tissue. Scand J Immunol. 1975;4(8):823–830. doi: 10.1111/j.1365-3083.1975.tb03723.x. [DOI] [PubMed] [Google Scholar]
  2. Alcocer-Varela J., Alarcón-Segovia D. Decreased production of and response to interleukin-2 by cultured lymphocytes from patients with systemic lupus erythematosus. J Clin Invest. 1982 Jun;69(6):1388–1392. doi: 10.1172/JCI110579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Altman A., Theofilopoulos A. N., Weiner R., Katz D. H., Dixon F. J. Analysis of T cell function in autoimmune murine strains. Defects in production and responsiveness to interleukin 2. J Exp Med. 1981 Sep 1;154(3):791–808. doi: 10.1084/jem.154.3.791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burmester G. R., Kalden J. R., Peter H. H., Schedel I., Beck P., Wittenborg A. Immunological and functional characteristics of peripheral blood and synovial fluid lymphocytes from patients with rheumatoid arthritis. Scand J Immunol. 1978;7(5):405–417. doi: 10.1111/j.1365-3083.1978.tb00471.x. [DOI] [PubMed] [Google Scholar]
  5. Burmester G. R., Yu D. T., Irani A. M., Kunkel H. G., Winchester R. J. Ia+ T cells in synovial fluid and tissues of patients with rheumatoid arthritis. Arthritis Rheum. 1981 Nov;24(11):1370–1376. doi: 10.1002/art.1780241106. [DOI] [PubMed] [Google Scholar]
  6. Combe B., Pope R., Darnell B., Kincaid W., Talal N. Regulation of natural killer cell activity by macrophages in the rheumatoid joint and peripheral blood. J Immunol. 1984 Aug;133(2):709–713. [PubMed] [Google Scholar]
  7. Dauphinée M. J., Kipper S. B., Wofsy D., Talal N. Interleukin 2 deficiency is a common feature of autoimmune mice. J Immunol. 1981 Dec;127(6):2483–2487. [PubMed] [Google Scholar]
  8. Depper J. M., Bluestein H. G., Zvaifler N. J. Impaired regulation of Epstein-Barr virus-induced lymphocyte proliferation in rheumatoid arthritis is due to a T cell defect. J Immunol. 1981 Nov;127(5):1899–1902. [PubMed] [Google Scholar]
  9. Farrar J. J., Benjamin W. R., Hilfiker M. L., Howard M., Farrar W. L., Fuller-Farrar J. The biochemistry, biology, and role of interleukin 2 in the induction of cytotoxic T cell and antibody-forming B cell responses. Immunol Rev. 1982;63:129–166. doi: 10.1111/j.1600-065x.1982.tb00414.x. [DOI] [PubMed] [Google Scholar]
  10. Fontana A., Hengartner H., Weber E., Fehr K., Grob P. J., Cohen G. Interleukin 1 activity in the synovial fluid of patients with rheumatoid arthritis. Rheumatol Int. 1982;2(2):49–53. doi: 10.1007/BF00541245. [DOI] [PubMed] [Google Scholar]
  11. Galili U., Rosenthal L., Klein E. Activated T cells in the synovial fluid of arthritic patients. II. In vitro activation of the autologous blood lymphocytes. J Immunol. 1981 Aug;127(2):430–432. [PubMed] [Google Scholar]
  12. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  13. Handa K., Suzuki R., Matsui H., Shimizu Y., Kumagai K. Natural killer (NK) cells as a responder to interleukin 2 (IL 2). II. IL 2-induced interferon gamma production. J Immunol. 1983 Feb;130(2):988–992. [PubMed] [Google Scholar]
  14. Hasler F., Bluestein H. G., Zvaifler N. J., Epstein L. B. Analysis of the defects responsible for the impaired regulation of EBV-induced B cell proliferation by rheumatoid arthritis lymphocytes. II. Role of monocytes and the increased sensitivity of rheumatoid arthritis lymphocytes to prostaglandin E. J Immunol. 1983 Aug;131(2):768–772. [PubMed] [Google Scholar]
  15. Hasler F., Bluestein H. G., Zvaifler N. J., Epstein L. B. Analysis of the defects responsible for the impaired regulation of Epstein-Barr virus-induced B cell proliferation by rheumatoid arthritis lymphocytes. I. Diminished gamma interferon production in response to autologous stimulation. J Exp Med. 1983 Jan 1;157(1):173–188. doi: 10.1084/jem.157.1.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Janossy G., Panayi G., Duke O., Bofill M., Poulter L. W., Goldstein G. Rheumatoid arthritis: a disease of T-lymphocyte/macrophage immunoregulation. Lancet. 1981 Oct 17;2(8251):839–842. doi: 10.1016/s0140-6736(81)91107-7. [DOI] [PubMed] [Google Scholar]
  17. Kasahara T., Hooks J. J., Dougherty S. F., Oppenheim J. J. Interleukin 2-mediated immune interferon (IFN-gamma) production by human T cells and T cell subsets. J Immunol. 1983 Apr;130(4):1784–1789. [PubMed] [Google Scholar]
  18. Klareskog L., Forsum U., Scheynius A., Kabelitz D., Wigzell H. Evidence in support of a self-perpetuating HLA-DR-dependent delayed-type cell reaction in rheumatoid arthritis. Proc Natl Acad Sci U S A. 1982 Jun;79(11):3632–3636. doi: 10.1073/pnas.79.11.3632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Klein J. R., Bevan M. J. Secretion of immune interferon and generation of cytotoxic T cell activity in nude mice are dependent on interleukin 2: age-associated endogenous production of interleukin 2 in nude mice. J Immunol. 1983 Apr;130(4):1780–1783. [PubMed] [Google Scholar]
  20. Langford M. P., Stanton G. J., Johnson H. M. Biological effects of staphylococcal enterotoxin A on human peripheral lymphocytes. Infect Immun. 1978 Oct;22(1):62–68. doi: 10.1128/iai.22.1.62-68.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Langford M. P., Weigent D. A., Stanton G. J., Baron S. Virus plaque-reduction assay for interferon: microplaque and regular macroplaque reduction assays. Methods Enzymol. 1981;78(Pt A):339–346. doi: 10.1016/0076-6879(81)78139-4. [DOI] [PubMed] [Google Scholar]
  22. Linker-Israeli M., Bakke A. C., Kitridou R. C., Gendler S., Gillis S., Horwitz D. A. Defective production of interleukin 1 and interleukin 2 in patients with systemic lupus erythematosus (SLE). J Immunol. 1983 Jun;130(6):2651–2655. [PubMed] [Google Scholar]
  23. Miyasaka N., Sauvezie B., Pierce D. A., Daniels T. E., Talal N. Decreased autologous mixed lymphocyte reaction in Sjögren's syndrome. J Clin Invest. 1980 Nov;66(5):928–933. doi: 10.1172/JCI109960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mizel S. B., Dayer J. M., Krane S. M., Mergenhagen S. E. Stimulation of rheumatoid synovial cell collagenase and prostaglandin production by partially purified lymphocyte-activating factor (interleukin 1). Proc Natl Acad Sci U S A. 1981 Apr;78(4):2474–2477. doi: 10.1073/pnas.78.4.2474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Panayi G. S. Response of rheumatoid-synovial-fluid lymphocytes to non-specific mitogens. Lancet. 1973 Sep 1;2(7827):512–513. doi: 10.1016/s0140-6736(73)92121-1. [DOI] [PubMed] [Google Scholar]
  26. ROPES M. W., BENNETT G. A., COBB S., JACOX R., JESSAR R. A. 1958 Revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis. 1958 Dec;9(4):175–176. [PubMed] [Google Scholar]
  27. Seaman W. E., Gindhart T. D., Blackman M. A., Dalal B., Talal N., Werb Z. Natural killing of tumor cells by human peripheral blood cells. Suppression of killing in vitro by tumor-promoting phorbol diesters. J Clin Invest. 1981 May;67(5):1324–1333. doi: 10.1172/JCI110161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sheldon P. J., Papamichail M., Holborow E. J. Studies on synovial fluid lymphocytes in rheumatoid arthritis. Ann Rheum Dis. 1974 Nov;33(6):509–514. doi: 10.1136/ard.33.6.509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Silver R. M., Redelman D., Zvaifler N. J. Studies of rheumatoid synovial fluid lymphocytes. II. A comparison of their behavior with blood mononuclear cells in the autologous mixed lymphocyte reaction and response to TCGF. Clin Immunol Immunopathol. 1983 Apr;27(1):15–27. doi: 10.1016/0090-1229(83)90052-1. [DOI] [PubMed] [Google Scholar]
  30. Torres B. A., Farrar W. L., Johnson H. M. Interleukin 2 regulates immune interferon (IFN gamma) production by normal and suppressor cell cultures. J Immunol. 1982 May;128(5):2217–2219. [PubMed] [Google Scholar]
  31. Wilkins J. A., Warrington R. J., Sigurdson S. L., Rutherford W. J. The demonstration of an interleukin-2 like activity in the synovial fluids of rheumatoid arthritis patients. J Rheumatol. 1983 Feb;10(1):109–113. [PubMed] [Google Scholar]
  32. Wofsy D., Murphy E. D., Roths J. B., Dauphinée M. J., Kipper S. B., Talal N. Deficient interleukin 2 activity in MRL/Mp and C57BL/6J mice bearing the lpr gene. J Exp Med. 1981 Nov 1;154(5):1671–1680. doi: 10.1084/jem.154.5.1671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wood D. D., Ihrie E. J., Dinarello C. A., Cohen P. L. Isolation of an interleukin-1-like factor from human joint effusions. Arthritis Rheum. 1983 Aug;26(8):975–983. doi: 10.1002/art.1780260806. [DOI] [PubMed] [Google Scholar]
  34. Yamamoto J. K., Farrar W. L., Johnson H. M. Interleukin 2 regulation of mitogen induction of immune interferon (IFN gamma) in spleen cells and thymocytes. Cell Immunol. 1982 Jan 15;66(2):333–341. doi: 10.1016/0008-8749(82)90183-6. [DOI] [PubMed] [Google Scholar]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology

RESOURCES