Oxidative Damage and Transmethylation Micronutrient Effects on the T Cell Epigenome in Systemic Lupus Erythematosus.

Abstract

Systemic lupus erythematosus is a potentially fatal autoimmune disease that predominantly affects women. Genetic and environmental factors both contribute to disease development, but how environmental factors cause epigenetic changes leading to pathogenesis is unclear. CD4+ T cell DNA demethylation results in overexpression of several immune-relevant methylation-sensitive genes, leading to functional consequences in lupus. Multiple environmental factors affect the methylation cycle, including micronutrients and oxidation of cellular components. This dissertation aims to address the relationship between micronutrients, redox changes, and the expression of methylation-sensitive T cell genes in lupus. The first objective of this dissertation assessed levels of 8 micronutrients that are involved in methylation, in the serum of lupus patients. We found zinc, vitamin B6, and methionine to be decreased and homocysteine to be increased in our cohort of lupus patients compared to the normal population. In the second objective, we investigated whether altered levels of the same 8 micronutrients could alter expression of methylation-sensitive T cell genes in vitro. We did this by developing a custom media in which the transmethylation micronutrient levels were adjusted to physiologic levels. Our findings suggest that micronutrient levels alter the expression of methylation-sensitive T cell genes and may have implications in lupus. We then examined the relationship between micronutrients and peroxynitrite, a potent pro-oxidant, in the third objective. By treating T cells with peroxynitrite and culturing them in media with altered concentrations of folate and methionine, we determined that oxidant and micronutrient effects are additive in promoting increased gene expression. Finally, we compared the effects of altered methionine on CD4+ T cells from lupus patients and age- and gender- matched controls, in the fourth and final objective of this dissertation. The results suggest that T cells from lupus patients may be more sensitive to micronutrient alterations potentially due to increased levels of pro-oxidants. Overall, these studies strongly suggest a potential role for micronutrient modulation of T cells in lupus and establish a link between redox status and micronutrient effects on methylation-sensitive gene expression. These findings provide a basis for future research on therapeutic benefits of dietary modification in autoimmunity.