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.
R Yung, D Powers, K Johnson, E Amento, D Carr, T Laing, J Yang, S Chang, N Hemati, B Richardson
Title and authors | Publication | Year |
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Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling
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Arthritis & Rheumatism | 2003 |
Defective activity of ERK-1 and ERK-2 mitogen-activated protein kinases in peripheral blood T lymphocytes from patients with systemic lupus erythematosus: potential role of altered coupling of Ras guanine nucleotide exchange factor hSos to adapter protein Grb2 in lupus T cells☆☆Supported by Grant S1-200000440 from Fondo Nacional de Ciencia, Innovación y Tecnologia (FONACIT), Ministerio de Ciencia y Tecnologia
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T cell integrin overexpression as a model of murine autoimmunity
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Biological Procedures Online | 2003 |
DNA methylation and autoimmune disease
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Clinical Immunology | 2003 |
Impact of aging on DNA methylation
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Ageing Research Reviews | 2003 |
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Current Opinion in Allergy and Clinical Immunology | 2003 |
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S Xiao, SJ Sung, SM Fu, ST Ju |
The Journal of biological chemistry | 2003 |
DNA methylation in systemic lupus erythematosus
I Sekigawa, M Okada, H Ogasawara, H Kaneko, T Hishikawa, H Hashimoto |
Lupus | 2003 |
CD49d Overexpression and T Cell Autoimmunity
RR Mo, JK Eisenbraun, J Sonstein, RA Craig, JL Curtis, LM Stoolman, J Chen, RL Yung |
Journal of immunology (Baltimore, Md. : 1950) | 2003 |