母体变应性鼻炎对子代Foxp3DNA甲基化的影响及干预

Recent researches suggest maternal allergen contact will increase the risk of offspring's allergic diseases in which epigenetics may play an important role.The mechanism of action may be to change the key gene DNA methylation level and to affect its expression, eventually leading to immunoregulatory imbalance. Foxp3 gene as an important transcription factor of Treg cells, its abnormal expression is closely related with allergic diseases.Our preliminary studies found that the Foxp3 gene methylation level of the patients with allergic rhinitis was significantly higher than that of the normal people.This project will observe the effect of materal mice allergic rhinitis on the Foxp3 gene methylation, Treg cell function and allergic inflammation of mice offspring. Further, we will intervene the maternal mice model by using the treatment of immunotherapy, glucocorticoids,DNA methylation transferase inhibitor and observe the preventive effect of maternal intervention on the subsequent allergic disorders in the offspring and the function of Foxp3 gene DNA methylation in this process. This project will help to understand the pathogenetic mechanism of allergic rhinitis from the origin, and to explore the possibiliy of the maternal intervention aiming at preventing the offspring from developing to allergic rhinitis,thus obtaining a new idea for the prevention of allergic rhinitis.

研究提示母体变应原接触会增加子代变应性疾病的风险，表观遗传学在其中可能起重要作用，作用机制可能是改变了关键基因DNA甲基化水平，影响其表达，最终导致免疫调节失衡。Foxp3基因作为Treg细胞的重要转录因子，其表达异常与变应性疾病发生密切相关。我们在前期研究中发现变应性鼻炎患者的Foxp3DNA甲基化水平显著高于正常人群，本项目将以Foxp3基因甲基化状态作为研究靶点，观察母代小鼠变应性鼻炎对子代变应性炎症、Foxp3基因甲基化及Treg细胞功能的影响；进一步采用免疫治疗、糖皮质激素、甲基化转移酶抑制剂等干预变应性鼻炎母代小鼠模型，研究母代干预对子代变应性鼻炎的预防作用以及Foxp3DNA甲基化在此过程中的作用。本项目的完成将有助于从起源上研究子代变应性鼻炎的发生机制，并探讨在母体进行干预从而预防子代发生变应性鼻炎的可行性，为变应性鼻炎的预防提供新思路。

变应性鼻炎（AR）发病近年来持续上升，且呈现低龄化趋势。相关研究证明母代患病导致子代AR易感性增加，但其机制尚不清楚。近来发现，表观遗传学在变应性疾病发生发展中有重要作用。本项目研究从调节性T细胞（Treg细胞）特异性转录因子Foxp3入手，研究Foxp3 DNA甲基化在AR发病、特异性免疫治疗（SIT）AR、AR母子代易感性遗传和AR子代出生后免疫状态改变中的作用及机制。结果显示AR患者Foxp3 DNA甲基化程度明显增加，而SIT可在一定程度上逆转AR患者的Foxp3 DNA高甲基化，从而诱导免疫耐受；AR母代的Foxp3 DNA高甲基化可遗传至子代，导致其子代出生早期即存在免疫异常和对变应性疾病的潜在易感性；但在不受变应原刺激的前提下，随着生长发育，早期存在的免疫状态异常将逐渐恢复，Foxp3在AR子代中早期启动子区高甲基化及成年后可逆性恢复，可能是上述免疫改变的重要原因。本课题研究首次从表观遗传学中DNA甲基化的角度解释AR的母子代易感性遗传，综合考虑基因和环境对AR的影响，为AR的发病机制做了重要完善和补充；同时，DNA甲基化也是一种可逆的改变，本课题首次研究Foxp3 DNA甲基化在AR子代生长发育中的变化，证实Foxp3 DNA甲基化改变可影响AR进程，为应用表观遗传学早期预防和治疗AR提供新思路和作用靶点。