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. 1988 Aug;73(2):242–249.

Deficient interleukin 2 production in rheumatoid arthritis: association with active disease and systemic complications.

G D Kitas 1, M Salmon 1, M Farr 1, J S Gaston 1, P A Bacon 1
PMCID: PMC1541612  PMID: 2972426

Abstract

Interleukin 2 (IL-2) production and proliferative responses of peripheral blood mononuclear cells (PBMC) stimulated with three concentrations of PHA were measured in 75 patients with rheumatoid arthritis (RA) and 25 normal controls. All patients were on a standard therapeutic regime, and were assessed for disease activity by clinical and laboratory criteria. Rheumatoid cells showed significantly lower IL-2 production and proliferation than normal PBMC at all PHA doses. These differences were not attributable to different kinetics. Within the rheumatoid population, both IL-2 levels and proliferation were lower in patients with active disease than those with inactive RA. Patients with extra-articular disease showed the most pronounced defects. Proliferative responses showed an inverse correlation with clinical indices of disease activity but not with measures of the acute phase response. Rheumatoid patients had higher proportions of CD4+, TFR+ and Tac+ lymphocytes than controls. Both proliferative responses and IL2- levels showed a positive relationship with the proportion of CD4+ cells, and an inverse relationship with Tac+ lymphocytes. Monocyte depletion and partial reconstitution resulted in an increase of both proliferation and IL-2 production, which was more marked in RA patients, suggesting that depressed IL-2 production may relate in part to monocyte effects. However, this cannot completely explain the magnitude of the defects observed, because normal monocytes did not increase the responses of rheumatoid lymphocytes, neither did rheumatoid monocytes suppress the responses of normal lymphocytes.

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Selected References

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  1. Abe T., Takeuchi T., Koide J., Hosono O., Homma M., Morimoto C., Yokohari R. Suppressor T cell function in patients with rheumatoid arthritis complicated by vasculitis. Arthritis Rheum. 1984 Jul;27(7):752–759. doi: 10.1002/art.1780270705. [DOI] [PubMed] [Google Scholar]
  2. Alcocer-Varela J., Laffón A., Alarcón-Segovia D. Differences in the production of and/or the response to interleukin-2 by T lymphocytes from patients with the various connective tissue diseases. Rheumatol Int. 1984;4(1):39–44. doi: 10.1007/BF00683884. [DOI] [PubMed] [Google Scholar]
  3. Arya S. K., Wong-Staal F., Gallo R. C. Dexamethasone-mediated inhibition of human T cell growth factor and gamma-interferon messenger RNA. J Immunol. 1984 Jul;133(1):273–276. [PubMed] [Google Scholar]
  4. Bacon P. A., Salmon M. Modes of action of second-line agents. Scand J Rheumatol Suppl. 1987;64:17–24. doi: 10.3109/03009748709096717. [DOI] [PubMed] [Google Scholar]
  5. Bozdech M. J., Bainton D. F. Identification of alpha-naphthyl butyrate esterase as a plasma membrane ectoenzyme of monocytes and as a discrete intracellular membrane-bounded organelle in lymphocytes. J Exp Med. 1981 Jan 1;153(1):182–195. doi: 10.1084/jem.153.1.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cardenas J. M., Marshall P., Henderson B., Altman A. Human interleukin 2. Quantitation by a sensitive radioimmunoassay. J Immunol Methods. 1986 May 22;89(2):181–189. doi: 10.1016/0022-1759(86)90356-x. [DOI] [PubMed] [Google Scholar]
  7. Cathely G., Amor B., Fournier C. Defective IL2 production in active rheumatoid arthritis. Regulation by radiosensitive suppressor cells. Clin Rheumatol. 1986 Dec;5(4):482–492. [PubMed] [Google Scholar]
  8. Combe B., Pope R. M., Fischbach M., Darnell B., Baron S., Talal N. Interleukin-2 in rheumatoid arthritis: production of and response to interleukin-2 in rheumatoid synovial fluid, synovial tissue and peripheral blood. Clin Exp Immunol. 1985 Mar;59(3):520–528. [PMC free article] [PubMed] [Google Scholar]
  9. Emery P., Gentry K. C., Mackay I. R., Muirden K. D., Rowley M. Deficiency of the suppressor inducer subset of T lymphocytes in rheumatoid arthritis. Arthritis Rheum. 1987 Aug;30(8):849–856. doi: 10.1002/art.1780300802. [DOI] [PubMed] [Google Scholar]
  10. Emery P., Panayi G. S., Nouri A. M. Interleukin-2 reverses deficient cell-mediated immune responses in rheumatoid arthritis. Clin Exp Immunol. 1984 Jul;57(1):123–129. [PMC free article] [PubMed] [Google Scholar]
  11. Gearing A. J., Johnstone A. P., Thorpe R. Production and assay of the interleukins. J Immunol Methods. 1985 Oct 24;83(1):1–27. doi: 10.1016/0022-1759(85)90053-5. [DOI] [PubMed] [Google Scholar]
  12. Gehman L. O., Robb R. J. An ELISA-based assay for quantitation of human interleukin 2. J Immunol Methods. 1984 Nov 16;74(1):39–47. doi: 10.1016/0022-1759(84)90365-x. [DOI] [PubMed] [Google Scholar]
  13. Gelfand E. W., Mills G. B., Cheung R. K., Lee J. W., Grinstein S. Transmembrane ion fluxes during activation of human T lymphocytes: role of Ca2+, Na+/H+ exchange and phospholipid turnover. Immunol Rev. 1987 Feb;95:59–87. doi: 10.1111/j.1600-065x.1987.tb00500.x. [DOI] [PubMed] [Google Scholar]
  14. Hacbarth E., Kajdacsy-Balla A. Low density neutrophils in patients with systemic lupus erythematosus, rheumatoid arthritis, and acute rheumatic fever. Arthritis Rheum. 1986 Nov;29(11):1334–1342. doi: 10.1002/art.1780291105. [DOI] [PubMed] [Google Scholar]
  15. Howard M., Farrar J., Hilfiker M., Johnson B., Takatsu K., Hamaoka T., Paul W. E. Identification of a T cell-derived b cell growth factor distinct from interleukin 2. J Exp Med. 1982 Mar 1;155(3):914–923. doi: 10.1084/jem.155.3.914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kay N. E., Douglas S. D. Monocyte metabolic activation in patients with rheumatoid arthritis. Proc Soc Exp Biol Med. 1979 Jul;161(3):303–306. doi: 10.3181/00379727-161-40541. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Metzger Z., Hoffeld J. T., Oppenheim J. J. Macrophage-mediated suppression. I. Evidence for participation of both hdyrogen peroxide and prostaglandins in suppression of murine lymphocyte proliferation. J Immunol. 1980 Feb;124(2):983–988. [PubMed] [Google Scholar]
  19. Miyasaka N., Nakamura T., Russell I. J., Talal N. Interleukin 2 deficiencies in rheumatoid arthritis and systemic lupus erythematosus. Clin Immunol Immunopathol. 1984 Apr;31(1):109–117. doi: 10.1016/0090-1229(84)90195-8. [DOI] [PubMed] [Google Scholar]
  20. Moretta A. Frequency and surface phenotype of human T lymphocytes producing interleukin 2. Analysis by limiting dilution and cell cloning. Eur J Immunol. 1985 Feb;15(2):148–155. doi: 10.1002/eji.1830150208. [DOI] [PubMed] [Google Scholar]
  21. Morimoto C., Steinberg A. D., Letvin N. L., Hagan M., Takeuchi T., Daley J., Levine H., Schlossman S. F. A defect of immunoregulatory T cell subsets in systemic lupus erythematosus patients demonstrated with anti-2H4 antibody. J Clin Invest. 1987 Mar;79(3):762–768. doi: 10.1172/JCI112882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ohike Y., Imai M., Tanaka E., Mukaida N., Kasahara T., Tachibana K., Miyakawa Y., Mayumi M. A radioimmunoassay that sandwiches human interleukin-2 between radiolabeled monoclonal antibody and the receptor on a hematopoietic cell line. J Immunol Methods. 1986 Mar 13;87(2):245–249. doi: 10.1016/0022-1759(86)90538-7. [DOI] [PubMed] [Google Scholar]
  23. Peppercorn M. A. Sulfasalazine. Pharmacology, clinical use, toxicity, and related new drug development. Ann Intern Med. 1984 Sep;101(3):377–386. doi: 10.7326/0003-4819-101-3-377. [DOI] [PubMed] [Google Scholar]
  24. Perdue M. H., Gall D. G. Rat jejunal mucosal response to histamine and anti-histamines in vitro. Comparison with antigen-induced changes during intestinal anaphylaxis. Agents Actions. 1986 Oct;19(1-2):5–9. doi: 10.1007/BF01977249. [DOI] [PubMed] [Google Scholar]
  25. Rappaport R. S., Dodge G. R. Prostaglandin E inhibits the production of human interleukin 2. J Exp Med. 1982 Mar 1;155(3):943–948. doi: 10.1084/jem.155.3.943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Salmon M., Bacon P. A. A cellular deficiency in the rheumatoid one-way mixed lymphocyte reaction. Clin Exp Immunol. 1988 Jan;71(1):79–84. [PMC free article] [PubMed] [Google Scholar]
  27. Salmon M., Bacon P. A., Symmons D. P., Blann A. D. Transferrin receptor bearing cells in the peripheral blood of patients with rheumatoid arthritis. Clin Exp Immunol. 1985 Nov;62(2):346–352. [PMC free article] [PubMed] [Google Scholar]
  28. Salmon M., Bacon P. A., Symmons D. P., Walton K. W. Transferrin receptor expression by stimulated cells in mixed lymphocyte culture. Immunology. 1985 Mar;54(3):559–564. [PMC free article] [PubMed] [Google Scholar]
  29. Sette A., Adorini L., Marubini E., Doria G. A microcomputer program for probit analysis of interleukin-2 (IL-2) titration data. J Immunol Methods. 1986 Feb 12;86(2):265–277. doi: 10.1016/0022-1759(86)90463-1. [DOI] [PubMed] [Google Scholar]
  30. Severinson E., Naito T., Tokumoto H., Fukushima D., Hirano A., Hama K., Honjo T. Interleukin 4 (IgG1 induction factor): a multifunctional lymphokine acting also on T cells. Eur J Immunol. 1987 Jan;17(1):67–72. doi: 10.1002/eji.1830170112. [DOI] [PubMed] [Google Scholar]
  31. Sheldon P. J., Webb C., Grindulis K. A. Sulphasalazine in rheumatoid arthritis: pointers to a gut-mediated immune effect. Br J Rheumatol. 1987 Aug;26(4):318–319. doi: 10.1093/rheumatology/26.4.318. [DOI] [PubMed] [Google Scholar]
  32. Shore A., Jaglal S., Keystone E. C. Enhanced interleukin 1 generation by monocytes in vitro is temporally linked to an early event in the onset or exacerbation of rheumatoid arthritis. Clin Exp Immunol. 1986 Aug;65(2):293–302. [PMC free article] [PubMed] [Google Scholar]
  33. Sinigaglia F., Scheidegger D., Talmadge K., Garotta G. A sensitive and quantitative microassay for the detection of mycoplasma contamination: inhibition of IL-2 dependent cell line proliferation. J Immunol Methods. 1985 Jan 21;76(1):85–92. doi: 10.1016/0022-1759(85)90483-1. [DOI] [PubMed] [Google Scholar]
  34. Wang A., Lu S. D., Mark D. F. Site-specific mutagenesis of the human interleukin-2 gene: structure-function analysis of the cysteine residues. Science. 1984 Jun 29;224(4656):1431–1433. doi: 10.1126/science.6427925. [DOI] [PubMed] [Google Scholar]
  35. de Ceulaer C., Papazoglou S., Whaley K. Increased biosynthesis of complement components by cultured monocytes, synovial fluid macrophages and skynovial membrane cells from patients with rheumatoid arthritis. Immunology. 1980 Sep;41(1):37–43. [PMC free article] [PubMed] [Google Scholar]

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