Diet influences expression of autoimmune-associated genes and disease severity by epigenetic mechanisms in a transgenic mouse model of lupus.

摘要: Objective Lupus flares occur when genetically predisposed individuals encounter appropriate environmental agents. Current evidence indicates that the environment contributes by inhibiting T cell DNA methylation, causing overexpression of normally silenced genes. methylation depends on both dietary transmethylation micronutrients and ERK-regulated methyltransferase 1 (DNMT-1) levels. We used transgenic mice to study effect interactions between diet, DNMT-1 levels, genetic predisposition development severity lupus. Methods A doxycycline-inducible ERK defect was bred into lupus-resistant (C57BL/6) lupus-susceptible (C57BL/6 × SJL) mouse strains. Doxycycline-treated were fed a standard commercial diet for 18 weeks then switched micronutrient–supplemented (MS) or –restricted (MR) diet. Disease assessed examining anti–double-stranded (anti-dsDNA) antibody presence proteinuria hematuria, histopathologic analysis kidney tissues. Pyrosequencing determine micronutrient effects methylation. Results Doxycycline induced modest levels anti-dsDNA antibodies in C57BL/6 higher SJL mice. developed hematuria glomerulonephritis MR diets but not MS In contrast, disease only Decreasing signaling methyl donors also caused demethylation CD40lg gene female mice, consistent with second X chromosome. Both donor content duration treatment influenced expression gene. Conclusion Dietary affect can exacerbate ameliorate this murine lupus model, contribute susceptibility through genetic–epigenetic interactions.