炎症小体基因多态性在长寿人群免疫衰老中作用的研究

Inflammasomes are a group of multi-protein complexes mainly consisted of nod-like receptor proteins (NLRPs). They play very important roles in innate immune by mediating pro- and anti-inflammatory responses and cellular pyroptosis. Variants on inflammasome genes have been linked to several aged-related disorders, we thus hypothesize that individuals who have successfully aged may be endowed unique polymorphism profiles and different immunosenescence patterns. In the current study, we aim to genotype 41 candidate immune- and aged-related single nucleotide polymorphisms on inflammasome genes with TaqMan technique for a long-lived cohort living in Guangxi Hongshuihe River Basin, to measure the serum levels of pyroptosis-related cytokines including IL-1beta and IL-18 as well as immunological profiles such as IgG and T-cell subsets, then analyze the potential interactions among these parameters and their plausible impacts on immunosenescence. To our knowledge, this is the first study to explore the genetic variants on inflammasome genes and their possible interplay with serum pyroptotic associated cytokines in long-lived individuals who received no vaccinations but naturally and successfully aged, hoping to have more understanding on the evolutionary profiles of innate immune genes and their potential influences on natural immune status for this healthy aging cohort. The results of this study will add important genetic data to human immunosenesence hypothesis.

炎症小体(inflammasome)为nod-样受体蛋白(nod-like receptor proteins, NLRPs)参与组装而成的多聚蛋白复合体，是天然免疫的重要组成部分，介导促炎、抗炎反应及细胞焦亡(pyroptosis)。炎症小体基因多态性与多种老年病密切相关，故我们推测健康长寿人群可能存在不同的多态性格局及免疫衰老模式。本研究拟应用TaqMan技术对广西红水河流域长寿人群41个与免疫及老年病相关的炎症小体基因单核苷酸多态(SNPs)进行分型，并检测血清IL-1b、IL-18等焦亡相关的炎性因子水平及免疫功能状态，分析这些SNPs与炎性因子及免疫指标之间的交互作用及对免疫衰老的影响。本研究首次在缺乏免疫接种的自然长寿人群中检测炎症小体基因变异及血清焦亡相关因子水平，有望了解该人群的固有免疫基因的进化格局及其对天然免疫的影响，研究结果将对人类免疫衰老学说提供重要的遗传学数据。

免疫功能退化与机体衰老互为因果。炎症小体(inflammasome)为nod-样受体蛋白(nod-like receptor proteins, NLRPs)参与组装而成的多聚蛋白复合体，是天然免疫的重要组成部分，介导促炎、抗炎反应及细胞焦亡，涉及众多的病理生理学过程，包括单纯的微生物感染、复杂的自身免疫性疾病及多基因遗传病，如细菌、病毒、疟原虫等感染性疾病及糖尿病、高血压、肿瘤等衰老相关性疾病。因此，炎症小体基因的多态性势必影响免疫衰老进程，进而影响个体的寿限。健康衰老（successful aging）人群之所以高寿，推测可能存在有别于常人的炎症小体基因多态性格局及免疫衰老模式。本项目应用TaqMan和iMLDR技术对广西红水河流域长寿人群41个与免疫及老年病相关的炎症小体基因单核苷酸多态(SNPs)进行分型，并检测血清IL-1β、IL-18、CRP等炎性因子水平及免疫功能状态，分析这些SNPs与炎性因子及免疫指标之间的交互作用及对免疫衰老的影响。目前取得的主要结果如下：（1）长寿组的血清IL-1β、IL-6、CRP、IgG水平明显高于子女组及当地对照组，而子女组的IL-1β、IL-6、CRP低于当地对照组。（2）长寿人群在免疫相关基因CTC1 rs3027247、CD33 rs3865444及CD2AP rs9349407三个位点上，存在与普通人群有明显差异的基因型频率分布，有些基因型对免疫及炎性指标表现为有利的影响。（3）免疫相关基因CD33 rs3865444多态性与血脂水平有一定的关系，并受性别及环境等因素的影响。（4）IGF2R rs9456497多态与长寿群体代谢综合征危险因素有一定的关系，而且这些作用受到性别、不同血脂及BMI状态的影响。（5）血清HBB mRNA表达水平与其启动子的多态性有关，HBB mRNA与代谢指标的相互作用可能影响机体衰老相关性疾病的发生及衰老进程。以上结果提示，长寿老人及其子女携带一些有利的免疫相关基因的变异，进而有效地调控炎症因子水平及免疫功能状态，促进健康衰老。