Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jun 15;97(12):2866–2871. doi: 10.1172/JCI118743

Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice.

R Yung 1, D Powers 1, K Johnson 1, E Amento 1, D Carr 1, T Laing 1, J Yang 1, S Chang 1, N Hemati 1, B Richardson 1
PMCID: PMC507381  PMID: 8675699

Abstract

Current theories propose that systemic lupus erythematosus develops when genetically predisposed individuals are exposed to certain environmental agents, although how these agents trigger lupus is uncertain. Some of these agents, such as procainamide, hydralazine, and UV-light inhibit T cell DNA methylation, increase lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18) expression, and induce autoreactivity in vitro, and adoptive transfer of T cells that are made autoreactive by this mechanism causes a lupuslike disease. The mechanism by which these cells cause autoimmunity is unknown. In this report, we present evidence that LFA-1 overexpression is sufficient to induce autoimmunity. LFA-1 overexpression was induced on cloned murine Th2 cells by transfection, resulting in autoreactivity. Adoptive transfer of the transfected, autoreactive cells into syngeneic recipients caused a lupuslike disease with anti-DNA antibodies, an immune complex glomerulonephritis and pulmonary alveolitis, similar to that caused by cells treated with procainamide. These results indicate that agents or events which modify T cell DNA methylation may induce autoimmunity by causing T cell LFA-1 overexpression. Since T cells from patients with active lupus have hypomethylated DNA and overexpressed LFA-1, this mechanism could be important in the development of human autoimmunity.

Full Text

The Full Text of this article is available as a PDF (298.9 KB).

Selected References

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

  1. Altmann D. M., Hogg N., Trowsdale J., Wilkinson D. Cotransfection of ICAM-1 and HLA-DR reconstitutes human antigen-presenting cell function in mouse L cells. Nature. 1989 Apr 6;338(6215):512–514. doi: 10.1038/338512a0. [DOI] [PubMed] [Google Scholar]
  2. Cornacchia E., Golbus J., Maybaum J., Strahler J., Hanash S., Richardson B. Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. J Immunol. 1988 Apr 1;140(7):2197–2200. [PubMed] [Google Scholar]
  3. Corvetta A., Della Bitta R., Luchetti M. M., Pomponio G. 5-Methylcytosine content of DNA in blood, synovial mononuclear cells and synovial tissue from patients affected by autoimmune rheumatic diseases. J Chromatogr. 1991 May 31;566(2):481–491. doi: 10.1016/0378-4347(91)80265-e. [DOI] [PubMed] [Google Scholar]
  4. Gleichmann E., Van Elven E. H., Van der Veen J. P. A systemic lupus erythematosus (SLE)-like disease in mice induced by abnormal T-B cell cooperation. Preferential formation of autoantibodies characteristic of SLE. Eur J Immunol. 1982 Feb;12(2):152–159. doi: 10.1002/eji.1830120210. [DOI] [PubMed] [Google Scholar]
  5. Kaye J., Porcelli S., Tite J., Jones B., Janeway C. A., Jr Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen-presenting cells in the activation of T cells. J Exp Med. 1983 Sep 1;158(3):836–856. doi: 10.1084/jem.158.3.836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Krieg A. M., Yi A. K., Matson S., Waldschmidt T. J., Bishop G. A., Teasdale R., Koretzky G. A., Klinman D. M. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature. 1995 Apr 6;374(6522):546–549. doi: 10.1038/374546a0. [DOI] [PubMed] [Google Scholar]
  7. Pals S. T., Radaszkiewicz T., Roozendaal L., Gleichmann E. Chronic progressive polyarthritis and other symptoms of collagen vascular disease induced by graft-vs-host reaction. J Immunol. 1985 Mar;134(3):1475–1482. [PubMed] [Google Scholar]
  8. Quddus J., Johnson K. J., Gavalchin J., Amento E. P., Chrisp C. E., Yung R. L., Richardson B. C. Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. J Clin Invest. 1993 Jul;92(1):38–53. doi: 10.1172/JCI116576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Regnier-Vigouroux A., Blanc D., Pont S., Marchetto S., Pierres M. Accessory molecules and T cell activation. I. Antigen receptor avidity differentially influences T cell sensitivity to inhibition by monoclonal antibodies to LFA-1 and L3T4. Eur J Immunol. 1986 Nov;16(11):1385–1390. doi: 10.1002/eji.1830161112. [DOI] [PubMed] [Google Scholar]
  10. Richardson B. C., Buckmaster T., Keren D. F., Johnson K. J. Evidence that macrophages are programmed to die after activating autologous, cloned, antigen-specific, CD4+ T cells. Eur J Immunol. 1993 Jul;23(7):1450–1455. doi: 10.1002/eji.1830230708. [DOI] [PubMed] [Google Scholar]
  11. Richardson B. C., Strahler J. R., Pivirotto T. S., Quddus J., Bayliss G. E., Gross L. A., O'Rourke K. S., Powers D., Hanash S. M., Johnson M. A. Phenotypic and functional similarities between 5-azacytidine-treated T cells and a T cell subset in patients with active systemic lupus erythematosus. Arthritis Rheum. 1992 Jun;35(6):647–662. doi: 10.1002/art.1780350608. [DOI] [PubMed] [Google Scholar]
  12. Richardson B. Effect of an inhibitor of DNA methylation on T cells. II. 5-Azacytidine induces self-reactivity in antigen-specific T4+ cells. Hum Immunol. 1986 Dec;17(4):456–470. doi: 10.1016/0198-8859(86)90304-6. [DOI] [PubMed] [Google Scholar]
  13. Richardson B., Powers D., Hooper F., Yung R. L., O'Rourke K. Lymphocyte function-associated antigen 1 overexpression and T cell autoreactivity. Arthritis Rheum. 1994 Sep;37(9):1363–1372. doi: 10.1002/art.1780370915. [DOI] [PubMed] [Google Scholar]
  14. Richardson B., Scheinbart L., Strahler J., Gross L., Hanash S., Johnson M. Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 1990 Nov;33(11):1665–1673. doi: 10.1002/art.1780331109. [DOI] [PubMed] [Google Scholar]
  15. Saizawa M. K., Hug E., Haque S., Portoles P., Suzuki S., Eichmann K. Autoreactivity of low but not of high CD4 variants of an antigen-specific, I-A-restricted mouse T cell clone. J Immunol. 1992 Feb 1;148(3):702–709. [PubMed] [Google Scholar]
  16. Steinberg A. D., Gourley M. F., Klinman D. M., Tsokos G. C., Scott D. E., Krieg A. M. NIH conference. Systemic lupus erythematosus. Ann Intern Med. 1991 Oct 1;115(7):548–559. doi: 10.7326/0003-4819-115-7-548. [DOI] [PubMed] [Google Scholar]
  17. Takeuchi T., Amano K., Sekine H., Koide J., Abe T. Upregulated expression and function of integrin adhesive receptors in systemic lupus erythematosus patients with vasculitis. J Clin Invest. 1993 Dec;92(6):3008–3016. doi: 10.1172/JCI116924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Wacholtz M. C., Patel S. S., Lipsky P. E. Leukocyte function-associated antigen 1 is an activation molecule for human T cells. J Exp Med. 1989 Aug 1;170(2):431–448. doi: 10.1084/jem.170.2.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Yung R. L., Quddus J., Chrisp C. E., Johnson K. J., Richardson B. C. Mechanism of drug-induced lupus. I. Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo. J Immunol. 1995 Mar 15;154(6):3025–3035. [PubMed] [Google Scholar]
  20. Yung R. L., Richardson B. C. Drug-induced lupus. Rheum Dis Clin North Am. 1994 Feb;20(1):61–86. [PubMed] [Google Scholar]

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

RESOURCES