Skip to main content
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1993 Aug;93(2):212–217. doi: 10.1111/j.1365-2249.1993.tb07968.x

IL-2 enhances polyclonal IgM but not IgM-rheumatoid factor synthesis by activated human peripheral blood B cells.

M Callaghan 1, A Whelan 1, C Feighery 1, B Bresnihan 1
PMCID: PMC1554842  PMID: 8348746

Abstract

IgM-rheumatoid factor (RF) is thought to be involved in the pathogenesis of rheumatoid arthritis (RA). Several cytokines are known to regulate immunoglobulin synthesis. In this study the effects of IL-2 on polyclonal IgM and IgM RF synthesis were compared. Cytokines were added to peripheral blood B cells from normal subjects and patients with RA after activation by Staphylococcus aureus Cowan 1 (SAC). The addition of IL-2, but not IL-4 or IL-6, resulted in significant enhancement of IgM synthesis in cultures from both healthy subjects and patients with RA. Similar degrees of enhancement were seen in both peripheral blood mononuclear cell and highly purified B cell cultures. IgM-RF was synthesized after activation in cultures from healthy subjects and spontaneously in cultures from RA patients. In contrast to polyclonal IgM synthesis, IL-2 failed to augment IgM-RF synthesis in cell cultures from either healthy subjects or RA patients. This study demonstrates different effects of IL-2 on IgM and IgM-RF synthesis.

Full text

PDF
212

Selected References

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

  1. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  2. Bertolini J. N., Benson E. M. The role of human interleukin-6 in B-cell isotype regulation and differentiation. Cell Immunol. 1990 Jan;125(1):197–209. doi: 10.1016/0008-8749(90)90074-2. [DOI] [PubMed] [Google Scholar]
  3. Boyd A. W., Fisher D. C., Fox D. A., Schlossman S. F., Nadler L. M. Structural and functional characterization of IL 2 receptors on activated human B cells. J Immunol. 1985 Apr;134(4):2387–2392. [PubMed] [Google Scholar]
  4. De Groot C., Braun J., Mevissen M. L., Wormmeester J. Contrasting effects of interleukin 4 (IL-4) on the in vitro proliferation of human B cells is due to the presence of B cell subsets in different activation states. Lymphokine Res. 1990 Fall;9(3):321–332. [PubMed] [Google Scholar]
  5. Dziarski R. Preferential induction of autoantibody secretion in polyclonal activation by peptidoglycan and lipopolysaccharide. I. In vitro studies. J Immunol. 1982 Mar;128(3):1018–1025. [PubMed] [Google Scholar]
  6. Engvall E., Perlmann P. Enzyme-linked immunosorbent assay, Elisa. 3. Quantitation of specific antibodies by enzyme-labeled anti-immunoglobulin in antigen-coated tubes. J Immunol. 1972 Jul;109(1):129–135. [PubMed] [Google Scholar]
  7. Faith A., Pontesilli O., Unger A., Panayi G. S., Johns P. ELISA assays for IgM and IgG rheumatoid factors. J Immunol Methods. 1982 Dec 17;55(2):169–177. doi: 10.1016/0022-1759(82)90029-1. [DOI] [PubMed] [Google Scholar]
  8. Firestein G. S., Xu W. D., Townsend K., Broide D., Alvaro-Gracia J., Glasebrook A., Zvaifler N. J. Cytokines in chronic inflammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. J Exp Med. 1988 Nov 1;168(5):1573–1586. doi: 10.1084/jem.168.5.1573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fong S., Tsoukas C. D., Frincke L. A., Lawrance S. K., Holbrook T. L., Vaughan J. H., Carson D. A. Age-associated changes in Epstein-Barr virus-induced human lymphocyte autoantibody responses. J Immunol. 1981 Mar;126(3):910–914. [PubMed] [Google Scholar]
  10. Galanaud P., Karray S., Llorente L. Regulatory effects of IL-4 on human B-cell response to IL-2. Eur Cytokine Netw. 1990 May-Jun;1(2):57–64. [PubMed] [Google Scholar]
  11. Goldstein R., Karsh J. In vitro synthesis of IgM rheumatoid factor in response to Staphylococcus aureus, by lymphocytes from healthy adults. Arthritis Rheum. 1986 Dec;29(12):1440–1445. doi: 10.1002/art.1780291204. [DOI] [PubMed] [Google Scholar]
  12. Hang L., Slack J. H., Amundson C., Izui S., Theofilopoulos A. N., Dixon F. J. Induction of murine autoimmune disease by chronic polyclonal B cell activation. J Exp Med. 1983 Mar 1;157(3):874–883. doi: 10.1084/jem.157.3.874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hanly J. G., Hassan J., Moriarty M., Whelan A., Feighery C., Bresnihan B. Lymphoid irradiation in intractable rheumatoid arthritis: effects on the production of immunoglobulins and rheumatoid factors. Clin Exp Immunol. 1985 Dec;62(3):647–656. [PMC free article] [PubMed] [Google Scholar]
  14. Hanly J. G., Hassan J., Whelan A., Feighery C., Bresnihan B. Effects of gold therapy on the synthesis and quantity of serum and synovial fluid IgM, IgG, and IgA rheumatoid factors in rheumatoid arthritis patients. Arthritis Rheum. 1986 Apr;29(4):480–487. doi: 10.1002/art.1780290404. [DOI] [PubMed] [Google Scholar]
  15. Hardy R. R., Hayakawa K., Shimizu M., Yamasaki K., Kishimoto T. Rheumatoid factor secretion from human Leu-1+ B cells. Science. 1987 Apr 3;236(4797):81–83. doi: 10.1126/science.3105057. [DOI] [PubMed] [Google Scholar]
  16. Harris E. D., Jr Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990 May 3;322(18):1277–1289. doi: 10.1056/NEJM199005033221805. [DOI] [PubMed] [Google Scholar]
  17. Hassan J., Feighery C., Bresnihan B., Whelan A. Prevalence of anti-Fab antibodies in patients with autoimmune and infectious diseases. Clin Exp Immunol. 1992 Sep;89(3):423–426. doi: 10.1111/j.1365-2249.1992.tb06974.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hirohata S., Inoue T., Ito K. Frequency analysis of human peripheral blood B cells producing autoantibodies: differential activation requirements of precursors for B cells producing IgM-RF and anti-DNA antibody. Cell Immunol. 1991 Dec;138(2):445–455. doi: 10.1016/0008-8749(91)90168-b. [DOI] [PubMed] [Google Scholar]
  19. Hirohata S., Inoue T., Miyamoto T. Frequency analysis of human peripheral blood B cells producing IgM-rheumatoid factor. Differential effects of stimulation with monoclonal antibodies to CD3 and Staphylococcus aureus. J Immunol. 1990 Sep 15;145(6):1681–1686. [PubMed] [Google Scholar]
  20. Houssiau F. A., Devogelaer J. P., Van Damme J., de Deuxchaisnes C. N., Van Snick J. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum. 1988 Jun;31(6):784–788. doi: 10.1002/art.1780310614. [DOI] [PubMed] [Google Scholar]
  21. Husby G., Williams R. C., Jr Synovial localization of tumor necrosis factor in patients with rheumatoid arthritis. J Autoimmun. 1988 Aug;1(4):363–371. doi: 10.1016/0896-8411(88)90006-6. [DOI] [PubMed] [Google Scholar]
  22. Jelinek D. F., Lipsky P. E. Inhibitory influence of IL-4 on human B cell responsiveness. J Immunol. 1988 Jul 1;141(1):164–173. [PubMed] [Google Scholar]
  23. Jelinek D. F., Splawski J. B., Lipsky P. E. The roles of interleukin 2 and interferon-gamma in human B cell activation, growth and differentiation. Eur J Immunol. 1986 Aug;16(8):925–932. doi: 10.1002/eji.1830160809. [DOI] [PubMed] [Google Scholar]
  24. Jokinen I., Poikonen K., Möttönen T., Hannonen P., Oka M., Ilonen J., Surcel H. M., Karttunen R., Arvilommi H. Analysis of impaired in vitro immunoglobulin synthesis in rheumatoid arthritis. Ann Rheum Dis. 1990 Jul;49(7):507–511. doi: 10.1136/ard.49.7.507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Keogan M. T., Callaghan M., Yanni G., Mulherin D., Feighery C., Brown D. L., Fitzgerald M. X., Bresnihan B. Spontaneous in vitro production of rheumatoid factor during infectious exacerbations of cystic fibrosis: correlation with circulating immune complex levels. Clin Exp Immunol. 1993 Mar;91(3):462–466. doi: 10.1111/j.1365-2249.1993.tb05925.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Klinman D. M., Steinberg A. D. Systemic autoimmune disease arises from polyclonal B cell activation. J Exp Med. 1987 Jun 1;165(6):1755–1760. doi: 10.1084/jem.165.6.1755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Koch A. E., Kunkel S. L., Burrows J. C., Evanoff H. L., Haines G. K., Pope R. M., Strieter R. M. Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. J Immunol. 1991 Oct 1;147(7):2187–2195. [PubMed] [Google Scholar]
  28. Koopman W. J., Schrohenloher R. E. In vitro synthesis of IgM rheumatoid factor by lymphocytes from healthy adults. J Immunol. 1980 Aug;125(2):934–939. [PubMed] [Google Scholar]
  29. Lee H. K., Xia X., Choi Y. S. IL-4 blocks the up-regulation of IL-2 receptors induced by IL-2 in normal human B cells. J Immunol. 1990 May 1;144(9):3431–3436. [PubMed] [Google Scholar]
  30. Levinson A. I., Tar L., Carafa C., Haidar M. Staphylococcus aureus Cowan I. Potent stimulus of immunoglobulin M rheumatoid factor production. J Clin Invest. 1986 Sep;78(3):612–617. doi: 10.1172/JCI112617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Maher D. W., Pike B. L., Boyd A. W. The response of human B cells to interleukin 4 is determined by their stage of activation and differentiation. Scand J Immunol. 1990 Dec;32(6):631–640. doi: 10.1111/j.1365-3083.1990.tb03205.x. [DOI] [PubMed] [Google Scholar]
  32. Mittler R., Rao P., Olini G., Westberg E., Newman W., Hoffmann M., Goldstein G. Activated human B cells display a functional IL 2 receptor. J Immunol. 1985 Apr;134(4):2393–2399. [PubMed] [Google Scholar]
  33. Miyasaka N., Sato K., Goto M., Sasano M., Natsuyama M., Inoue K., Nishioka K. Augmented interleukin-1 production and HLA-DR expression in the synovium of rheumatoid arthritis patients. Possible involvement in joint destruction. Arthritis Rheum. 1988 Apr;31(4):480–486. doi: 10.1002/art.1780310404. [DOI] [PubMed] [Google Scholar]
  34. Mogensen C. E. The glomerular permeability determined by dextran clearance using Sephadex gel filtration. Scand J Clin Lab Invest. 1968;21(1):77–82. doi: 10.3109/00365516809076979. [DOI] [PubMed] [Google Scholar]
  35. Muraguchi A., Kehrl J. H., Longo D. L., Volkman D. J., Smith K. A., Fauci A. S. Interleukin 2 receptors on human B cells. Implications for the role of interleukin 2 in human B cell function. J Exp Med. 1985 Jan 1;161(1):181–197. doi: 10.1084/jem.161.1.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nakagawa N., Nakagawa T., Volkman D. J., Ambrus J. L., Jr, Fauci A. S. The role of interleukin 2 in inducing Ig production in a pokeweed mitogen-stimulated mononuclear cell system. J Immunol. 1987 Feb 1;138(3):795–801. [PubMed] [Google Scholar]
  37. Nakagawa T., Hirano T., Nakagawa N., Yoshizaki K., Kishimoto T. Effect of recombinant IL 2 and gamma-IFN on proliferation and differentiation of human B cells. J Immunol. 1985 Feb;134(2):959–966. [PubMed] [Google Scholar]
  38. Nakanishi K., Malek T. R., Smith K. A., Hamaoka T., Shevach E. M., Paul W. E. Both interleukin 2 and a second T cell-derived factor in EL-4 supernatant have activity as differentiation factors in IgM synthesis. J Exp Med. 1984 Dec 1;160(6):1605–1621. doi: 10.1084/jem.160.6.1605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Pisetsky D. S., Jelinek D. F., McAnally L. M., Reich C. F., Lipsky P. E. In vitro autoantibody production by normal adult and cord blood B cells. J Clin Invest. 1990 Mar;85(3):899–903. doi: 10.1172/JCI114517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Romagnani S., Giudizi G. M., Almerigogna F., Biagiotti R., Alessi A., Mingari C., Liang C. M., Moretta L., Ricci M. Analysis of the role of interferon-gamma, interleukin 2 and a third factor distinct from interferon-gamma and interleukin 2 in human B cell proliferation. Evidence that they act at different times after B cell activation. Eur J Immunol. 1986 Jun;16(6):623–629. doi: 10.1002/eji.1830160607. [DOI] [PubMed] [Google Scholar]
  41. Roosnek E., Lanzavecchia A. Efficient and selective presentation of antigen-antibody complexes by rheumatoid factor B cells. J Exp Med. 1991 Feb 1;173(2):487–489. doi: 10.1084/jem.173.2.487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Shlomchik M. J., Marshak-Rothstein A., Wolfowicz C. B., Rothstein T. L., Weigert M. G. The role of clonal selection and somatic mutation in autoimmunity. 1987 Aug 27-Sep 2Nature. 328(6133):805–811. doi: 10.1038/328805a0. [DOI] [PubMed] [Google Scholar]
  43. Slaughter L., Carson D. A., Jensen F. C., Holbrook T. L., Vaughan J. H. In vitro effects of Epstein-Barr virus on peripheral blood mononuclear cells from patients with rheumatoid arthritis and normal subjects. J Exp Med. 1978 Nov 1;148(5):1429–1434. doi: 10.1084/jem.148.5.1429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Smiley J. D., Sachs C., Ziff M. In vitro synthesis of immunoglobulin by rheumatoid synovial membrane. J Clin Invest. 1968 Mar;47(3):624–632. doi: 10.1172/JCI105758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Splawski J. B., Jelinek D. F., Lipsky P. E. Immunomodulatory role of IL-4 on the secretion of Ig by human B cells. J Immunol. 1989 Mar 1;142(5):1569–1575. [PubMed] [Google Scholar]
  46. Splawski J. B., McAnally L. M., Lipsky P. E. IL-2 dependence of the promotion of human B cell differentiation by IL-6 (BSF-2). J Immunol. 1990 Jan 15;144(2):562–569. [PubMed] [Google Scholar]
  47. Tanay A., Schiffman G., Strober S. Effect of total lymphoid irradiation on levels of serum autoantibodies in systemic lupus erythematosus and in rheumatoid arthritis. Arthritis Rheum. 1986 Jan;29(1):26–31. doi: 10.1002/art.1780290104. [DOI] [PubMed] [Google Scholar]
  48. WILLIAMS R. C., Jr, KUNKEL H. G. Rheumatoid factor, complement, and conglutinin aberrations in patients with subacute bacterial endocarditis. J Clin Invest. 1962 Mar;41:666–675. doi: 10.1172/JCI104523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Waldmann T. A., Goldman C. K., Robb R. J., Depper J. M., Leonard W. J., Sharrow S. O., Bongiovanni K. F., Korsmeyer S. J., Greene W. C. Expression of interleukin 2 receptors on activated human B cells. J Exp Med. 1984 Nov 1;160(5):1450–1466. doi: 10.1084/jem.160.5.1450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Welch M. J., Fong S., Vaughan J., Carson D. Increased frequency of rheumatoid factor precursor B lymphocytes after immunization of normal adults with tetanus toxoid. Clin Exp Immunol. 1983 Feb;51(2):299–304. [PMC free article] [PubMed] [Google Scholar]
  51. Winchester R. J., Agnello V., Kunkel H. G. Gamma globulin complexes in synovial fluids of patients with rheumatoid arthritis. Partial characterization and relationship to lowered complement levels. Clin Exp Immunol. 1970 May;6(5):689–706. [PMC free article] [PubMed] [Google Scholar]
  52. 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]

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

RESOURCES