Role of T Cell DNA Methylation in Lupus Syndromes

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Abstract
Current theories postulate that exposure to certain environmental agents will induce lupus in genetically predisposed individuals. However, the mechanisms by which environmental agents interact with the immune system to trigger lupus is unclear. Recent work has shown that some environmental agents associated with lupus, such as procainamide, hydralazine and ultraviolet light, will inhibit T cell DNA methylation, increase LFA-1 expression and induce autoreactivity. In addition, T cells isolated from patients with active lupus have hypomethylated DNA, diminished DNA methyltransferase activity and overexpress LFA-1 on an autoreactive subset of cells which spontaneously lyses autologous macrophages. More recent work has shown that the adoptive transfer of murine T cells made autoreactive with DNA methylation inhibitors is sufficient to cause a lupus-like disease in otherwise healthy syngeneic recipients. Together, these results support a new model of autoimmunity, in which certain environmental agents modify T cells by inhibiting DNA methylation and altering expression of certain genes, thereby inducing autoreactivity. The autoreactive cells then interact with the host to produce a lupus-like disease.