Environmental effects on lupus T cell DNA methylation and gene expression

描述（由申请人提供）： 异常过表达甲基化敏感基因CD 11 a、IFN-γ、perform和CD 70的低甲基化T细胞与人类狼疮的发病机制有关。最近的研究表明，与急性冠状动脉综合征（不稳定型心绞痛和心肌梗死）有关的KIR基因也是甲基化敏感的，并且在狼疮T细胞上过表达。初步研究表明，甲基化敏感性T细胞基因表达可以通过限制叶酸或Met，或通过直接/特异性抑制剂，信号传导抑制剂或SAH降低DNA甲基转移酶（DNMT）酶活性来增加，并且这些作用是累加的。此外，补充Met或叶酸减少或防止这些抑制剂对甲基化敏感基因的过表达。这些结果表明，由于环境外源性物质影响转移酶水平或功能，加上饮食影响，DNMT表达减少，是影响甲基化敏感基因表达的附加因素，最终导致狼疮及其并发症的发生。这些结果还表明，膳食补充一种或多种与DNA甲基化有关的营养素可能具有保护作用。将通过比较以下因素的影响来检验这些假设：1）营养限制/补充和DNA甲基化抑制剂单独和组合对T细胞CD 11 a、CD 70、IFN-γ、穿孔素和KIR的表达和甲基化的影响，并确定对巨噬细胞和内皮细胞的细胞毒性的后果，2）体外营养限制和补充对来自狼疮受试者和正常对照的T细胞中甲基化敏感基因的表达和甲基化的影响，和3）对照，甲基供体缺乏和甲基丰富的饮食对甲基化敏感的T细胞基因的表达和狼疮的严重程度在小鼠与自身免疫引起的诱导ERK途径信号转导缺陷。饮食调整可以改善体外异常基因表达和小鼠模型中疾病严重程度的证据将导致研究将这些结果扩展到狼疮患者。

DESCRIPTION (provided by applicant): Hypomethylated T cells aberrantly overexpressing the methylation sensitive genes CD11a, IFN-gamma, perform and CD70 have been implicated in the pathogenesis of human lupus. Recent studies from this group demonstrate that KIR genes, implicated in acute coronary syndromes (unstable angina and myocardial infarctions), are also methylation sensitive and overexpressed on lupus T cells. Preliminary studies suggest that methylation sensitive T cell gene expression can be increased by restricting either folate or Met, or by decreasing DNA methyl transferase (DNMT) enzyme activity with direct/specific inhibitors, signaling inhibitors, or SAH, and that these effects are additive. Further, supplementation with either Met or folate decreases or prevents overexpression of the methylation sensitive genes by these inhibitors. These results suggest that decreases in DNMT expression due to environmental xenobiotics affecting transferase levels or function, together with dietary influences, are additive in affecting methylation sensitive gene expression, and ultimately causal in the development of lupus and its complications. These results also suggest that dietary supplementation of one or more nutrients involved in DNA methylation may be protective. These hypotheses will be tested by comparing the effects of: 1) nutrient restriction/supplementation and DNA methylation inhibitors alone and in combination on the expression and methylation of T cell CD11a, CD70, IFN-gamma, perforin and KIR and determining the consequences on cytotoxicity for macrophages and endothelial cells, 2) nutrient restriction and supplementation in vitro on the expression and methylation of methylation sensitive genes in T cells from subjects with lupus and normal controls, and 3) control, methyl-donor deficient, and methyl-rich diet on the expression of methylation sensitive T cell genes and lupus severity in mice with autoimmunity caused by an inducible ERK pathway signaling defect. Evidence that dietary modification can ameliorate aberrant gene expression in vitro and disease severity in the murine model will lead to studies extending these results to lupus patients.