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DNA methylation plays an essential role in maintaining T-cell function. A growing body of literature indicates that failure to maintain DNA methylation levels and patterns in mature T cells can result in T-cell autoreactivity in vitro and autoimmunity in vivo. Defective maintenance of DNA methylation may be caused by drugs such as procainamide or hydralazine, or failure to activate the genes encoding maintenance DNA methyltransferases during mitosis, resulting in the development of a lupus-like disease or perhaps other autoimmune disorders. This paper reviews the evidence supporting a role for abnormal T-cell DNA methylation in causing autoimmunity in an animal model of drug-induced lupus, and discusses some of the mechanisms involved. T cells from patients with active lupus have evidence for most if not all of the same methylation abnormalities, suggesting that abnormal DNA methylation plays a role in idiopathic human lupus as well.

The induction of experimental autoimmune myasthenia gravis (EAMG) has long been shown to result in inefficient function of the acetylcholine receptor (AChR) and concomitant impairment of AChR-dependent neuromuscular communication. As an animal model of human myasthenia gravis, AChR-immunized rats demonstrate symptoms of MG very similar to those observed in human patients resulting from the presence of circulating anti-AChR antibodies which interfere with the normal function of the receptor. In addition to antibody antagonists of neuromuscular function, a variety of drugs have been observed to be associated with possible exacerbations of impaired neuromuscular function leading to myasthenic crisis in some MG patients. One drug, the cardiac anti-arrhythmic agent, procainamide, has been reported to cause both pre-synaptic and post-synaptic electrophysiologic effects at the neuromuscular junction. The study described below extends these observations to include the demonstration of perturbed AChR-dependent contractile muscle function in a rat model of MG.

A number of drugs and chemicals can induce autoimmune disorders. Previous studies suggested the popliteal lymph node (PLN) assay might be a suitable and reliable model to detect such compounds in the mouse. The applicability of this assay has been examined in the Brown-Norway rat using a panel of positive as well as negative reference compounds. Popliteal lymph nodes were excised and weighed seven days after subcutaneous injection of 5 mg of each compound into one footpad. Interestingly, all negative reference compounds produced no significant increase in PLN weight index whereas four positive reference compounds were associated with PLN-weight indices greater than 2.3. However, no increase in PLN weight was noted in procainamide- and isoniazide-treated rats as previously reported in the mouse. This first set of experiments indicates that the PLN assay is applicable to Brown-Norway rats and warrants further investigation.