-Decreased T cell DNA methyltransferase (MTase) activity has been causally linked to human lupus. The principal investigator's group has reported that inhibiting DNA MTase in dividing T cells results in DNA hypomethylation, LFA-1 overexpression, and autoreactivity, and that adoptive transfer of the autoreactive cells is sufficient to cause a lupus-like disease. They have also shown that some agent which induce lupus, including procainamide, hydralazine, and UV light, inhibit T cell DNA methylation, increase LFA-1 expression, and induce autoreactivity, and they have used the adoptive transfer model to demonstrate a mechanism by which these agents can trigger a lupus-like disease. They and others have shown that T cells from patients with active lupus have diminished levels of DNA MTase, hypomethylated DNA, and overexpress LFA-1 on an autoreactive T cell subset, indicating that a similar mechanism could contribute to idiopathic SLE Together, these results suggest that abnormally decreased T cell DNA MTase enzyme activity may directly contribute to the development of drug- induced and idiopathic lupus by modifying T cell gene expression. The mechanisms regulating human DNA MTase are unknown. This group has established that levels of DNA MTase normally increase following T cell stimulation. They have also obtained evidence that human DNA MTase levels may be regulated through the ras-MAPK signaling pathway. In other studies the principal investigator found that the mitogen-stimulated increase in DNA MTase is impaired in T cells from patients with active lupus, and the Ha-ras mRNA levels and ras-MAPK signaling are diminished in these T cells, suggesting a mechanism for the decreased DNA MTas response. Finally, the principal investigator has evidence for multiple isoforms of human DNA MTase, the function and expression of which are unknown. The principal investigator hypothesizes that decreases in the levels of DNA MTase, due to decreased Ha-ras expression, may contribute to the development of lupus. The principal investigator also hypothesizes that the different isoform of DNA MTase serve distinct roles within the cell.
The specific aims are to: 1 Determine the role of the ras-MAPK signaling pathway in the regulation and function of human T cell DNA MTase; 2) determine the pathologic significance of decreased Ha-ras pathway signaling using a novel model of drug-induced lupus; 3) determine the significance of the decreased Ha-ras levels observed in T cells from patients with active lupus, and 4) characterize expression of DNA MTase isoforms. The principal investigator anticipates that these studies will clarify mechanisms contributing to the development of human lupus.
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