Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice.
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.
Yung
R
R
Department of Internal Medicine, University of Michigan, Ann Arbor 48109, USA.
Powers
D
D
Johnson
K
K
Amento
E
E
Carr
D
D
Laing
T
T
Yang
J
J
Chang
S
S
Hemati
N
N
Richardson
B
B
D000818:Animals; D015551:Autoimmunity; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D005260:Female; D008177:Lupus Vulgaris / Q000139:chemically induced* / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000502:physiology*; D008745:Methylation; D051379:Mice; D008806:Mice, Inbred AKR; D008811:Mice, Inbred DBA; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
D016169:Lymphocyte Function-Associated Antigen-1; D004247:DNA