Environment, Epigenetics and Autoimmunity

Bruce Richardson
Department of Medicine; University of Michigan

Drugs such as procainamide and hydralazine cause lupus in genetically predisposed individuals, suggesting that idiopathic lupus may also be caused by environmental elements through similar mechanisms. We have shown that procainamide and hydralazine inhibit human and murine T cell DNA methylation, altering gene expression and inducing autoreactivity, and that T cells demethylated with these drugs, or with 5-azacytidine, cause a lupus-like disease in mice. T cells from patients with active lupus have hypomethylated DNA, are similarly autoreactive, overexpress the same genes affected by DNA methylation inhibitors, and the same regulatory regions of the affected genes are demethylated in lupus as in T cells demethylated in vitro. We have also shown that DNA methyltransferase levels are regulated in part by the ERK pathway, that hydralazine inhibits ERK pathway signaling, and that ERK pathway signaling and DNA methyltransferase levels are diminished in lupus T cells. Further, murine T cells treated with ERK pathway inhibitors become autoreactive and cause a lupus-like disease similar to that caused by direct DNA methyltransferase inhibitors and hydralazine. More recently we have reported that the same regulatory elements are demethylated in human lupus and in T cells treated with DNA methyltransferase or ERK pathway inhibitors. This suggests a model in which DNA hypomethylation, caused by environmental agents including ERK pathway inhibitors, contribute to the development of autoimmunity by modifying DNA methylation patterns and altering gene expression. This mechanism could contribute to idiopathic and drug induced lupus [1, 2].

REFERENCES:

  1. Richardson, B., DNA methylation and autoimmune disease. Clin Immunol, 2003. 109(1): p. 72-9.

  2. Oelke, K. and B. Richardson, Decreased T cell ERK pathway signaling may contribute to the development of lupus through effects on DNA methylation and gene expression. Int Rev Immunol, 2004. 23(3-4): p. 315-31.