阳江高本底地区居民IL-2R多态性影响免疫功能增强的NF-κB调控机制

The molecular biology effect of high dose of ionizing radiation（HDIR） had been relatively well-studied. However, the effect of low dose of ionizing radiation (LDIR) is still controversial. There were two kinds of different theories on physiological effect of LDIR. Namely, one was Linear No Threshold Theory (LNT), and the other was Adaptive Response (AR) or Linear threshold theory (LTT). Epidemiologic studies of LDIR on human health had been lasted for more than forty years in residents living in the high background radiation area (HBRA) of Yangjiang, Guangdong. The average annual effective dose received by the residents in the HBRA was determined to be 4mSv/a higher than the residents in the control area (CA), which was equal to occupational exposed level. Epidemiologic studies showed the beneficial effects of LDIR on human health. LDIR enhanced the immune function and therefore played the protective roles in carcinogenesis, pathogen infection. However, the mechanism is still unclear. More cellular and molecular studies were needed to clarify the mechanism of immunity enhancement and identify the scope of LTT..High dose of radiation (HDR) has been reported to upregulate the expression of IL-2 gene. IL-2 was a well-studied cytokine on the immunity function and ironing radiation, and played a important role in regulating the proliferation and differatiation of T lymphocytes, the expression of many other cytokines, immune response and the development of tumor. The mechanism of IL-2 on immunity enhancement has been well-studied. A few studies have been shown that there is an opposite relationship between the level of serum IL-2R (sIL-2R) and IL-2. And some polymorphisms have been reported to be associated with a certain immune diseases but without function confirmation. NF-κB is an important transcription factor in the immune system, and the NF--κB activity contributes to proliferation, apoptosis, autoimmunity and malignant diseases. Enhanced NF--κB activity resulted in IL-2 gene expression. The role of IL-2R promoter polymorphisms in immune function and the interaction with NF-kappaB signaling pathway of LDIR is still unknown. The epidemiologic study aims to validate the mechanism of the polymorphisms of IL-2R genes promoter play a role in the NF-κB signaling regualted immunity enhancement induced by low dose of ionizing radiation, by the personal radiation exposure surveillence, immunity function, polymorphisms and genetic analysis methods. These results were expected to provide a new insight for further investigate on the molecular mechanism of LDIR-induced immunity enhancement and development tumor immunity as well as the supplement the content of LTT.

目前低剂量电离辐射对人体健康存在无阈和有阈两种理论。阳江高本底辐射地区（与职业暴露剂量相当）持续近40年研究表明，低剂量电离辐射具免疫功能增强作用，支持有阈理论，但分子机制未完全阐明。IL-2在T细胞增殖、分化、细胞免疫应答类型调控、肿瘤抑制等方面发挥重要作用，已发现IL-2R基因多态性与影响免疫调节的自身免疫性疾病易感性相关。NF-κB是一种可诱导的转录因子，在增殖、凋亡、免疫调控和成瘤过程中起重要作用，NF-κB信号和IL-2之间存在调控关系。本研究应用分子流行病学研究方法，开展天然高本底地区人群低剂量电离辐射暴露人群的研究，通过外暴露剂量监测、免疫功能检测、IL-2R各亚基基因多态性分析等研究手段，在人群中验证IL-2R多态性和高本底电离辐射致免疫增强的NF-κB调控机制，阐述低剂量电离辐射暴露-基因交互作用，为探明高本底电离辐射诱导免疫功能增强的分子学机制以及开展肿瘤免疫学研究提供基础资料。

流行病学研究表明，低剂量电离辐射可诱导机体产生诱导性反应，促进免疫功能增强。本研究通过开展天然高本底地区人群低剂量电离辐射暴露人群免疫功能的分子流行病学研究，分析低剂量电离辐射暴露与IL-2等免疫功能指标的关系，筛选并确定IL-2R各亚基基因(IL2RA、IL2RB、IL2RG)启动子区多态性位点，分析高本底地区人群中目的基因潜在功能性多态性位点与机体免疫功能关联性，为探讨高本底电离辐射诱导机体免疫功能改变的分子机制提供流行病学依据。我们发现高本底地区健康居民血浆IL-2的浓度略高于对照地区；IL-4、IL-5、sIL-2R、TGF-β的浓度略低于对照地区居民，其中IL-5、TGF-β的统计结果在两地区之间差异有统计学意义。调整相关因素后，发现家庭燃料类型、收入、饮食习惯对上述指标表达水平有影响。对IL-2及IL2R各亚基基因表达水平进行协方差分析分析，结果显示地区、年龄对IL2RG的表达，年龄、职业对IL2RA的表达影响有统计学意义。Sequenom MassArray结果提示IL2RG上rs76206423（A/G）在两地区间有差异，但与基因表达结果、机体免疫水平无明显相关一致性。高本底地区人群中，与多种疾病有关的多态性位点rs7072793（T>C）和 rs3118470（T>C）相对保守，可能具有较高遗传变异型。本研究提示，天然放射性高本底地区居民的免疫功能略强于对照地区，提示长期慢性低剂量电离辐射有增强机体免疫的趋势，有待进一步探索。

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