Developmental programming of TCE induced autoimmune disease

描述(申请人提供)：自身免疫性疾病是一个普遍存在的人类健康问题。由于我们对自身免疫性疾病病因学的了解有限，目前预防这些不治之症是不可能的。有证据表明，暴露于某些环境污染物，如溶剂三氯乙烯(TCE)，可引发特发性自身免疫性疾病。我们已经证明，暴露于低水平TCE的成年MRL+/+小鼠会发生自身免疫性疾病，并伴有与DNA甲基化相关的CD4+T细胞功能的“可遗传”变化。尽管只有成年人接触三氯乙烯会引发自身免疫性疾病，但有证据表明，发育中的免疫系统比成人免疫系统对化学毒性更敏感。因此，发育过程中接触三氯乙烯可能会增强成人接触的自身免疫促进作用。预计这一效应将通过改变CD4+T细胞中特定效应基因的DNA甲基化来实现。如果这些预测得到证实，它将支持这样的概念，即发育过程中暴露于以前认为安全的化学物质可以促进成人自身免疫性疾病的发展。这些预测和相关的作用机制将在这里的三个目标中得到检验。目的1.确定发育期三氯乙烯暴露对成人自身免疫性疾病的影响。我们将测试如果TCE暴露于妊娠期而不是成年后，自身免疫性疾病的病理和相关的CD4+T细胞变化是否更强劲。目的2.明确三氯乙烯诱导的CD4+T细胞表观遗传学改变。新的基因组规模的DNA甲基化图谱将识别TCE处理小鼠的CD4+T细胞中依赖时间和浓度的基因变化。目的3.研究TCE处理小鼠外周血中CD4+T细胞的自身反应性。来自TCE治疗的MRL+/+小鼠的CD4+T细胞将在过继转移到淋巴细胞缺陷(RAG基因敲除)MRL+/+小鼠后，测试它们产生自身免疫性疾病的能力。这项过继转移实验将比较供体TCE暴露的两个窗口(仅限发育期和成人)产生的CD4+T细胞的自身反应。

DESCRIPTION (provided by applicant): Autoimmune diseases are a widespread human health problem. Preventing these incurable disorders is currently impossible due to our limited knowledge of autoimmune disease etiology. There is evidence that idiopathic autoimmune disease can be triggered by exposure to certain environmental pollutants such as the solvent trichloroethylene (TCE). We have shown that adult MRL+/+ mice exposed to low-level TCE developed autoimmune disease along with "heritable" alterations in CD4+ T cell function associated with DNA methylation. Although adult-only exposure to TCE triggered autoimmune disease, there is evidence that the developing immune system is even more sensitive than the adult immune system to chemical toxicity. Thus, developmental exposure to TCE is likely to augment the autoimmune-promoting effects of adult exposure. It is expected that this effect will be mediated by changes in the DNA methylation of specific effector genes in CD4+ T cells. If these predictions are confirmed it would support the concept that developmental exposure to chemicals at levels previously thought safe can promote autoimmune disease development in adults. These predictions and associated mechanism of action will be tested here in 3 Aims. Aim 1. Determine impact of developmental TCE exposure on adult autoimmune disease. We will test whether autoimmune disease pathology and associated CD4+ T cell alterations are more robust if TCE exposure begins at gestation rather than as an adult. Aim 2. Define TCE-induced epigenetic alterations in CD4+ T cells. Novel genome-scale DNA methylation profiles will identify time- and concentration-dependent gene alterations in CD4+ T cells from the TCE-treated mice. Aim 3. Characterize autoreactivity of CD4+ T cells from TCE-treated mice. CD4+ T cells from TCE-treated MRL+/+ mice will be tested for their ability to generate autoimmune disease following adoptive transfer into lymphocyte-deficient (Rag knockout) MRL+/+ mice. This adoptive transfer experiment will compare the autoreactivity of CD4+ T cells generated from two windows of donor TCE exposure (developmental and adult- only).