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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >PNAS Plus: Distinctive roles of age sex and genetics in shaping transcriptional variation of human immune responses to microbial challenges
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PNAS Plus: Distinctive roles of age sex and genetics in shaping transcriptional variation of human immune responses to microbial challenges

机译：PNAS Plus：年龄性别和遗传学在塑造人类对微生物挑战的免疫反应的转录变异中的独特作用

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The contribution of host genetic and nongenetic factors to immunological differences in humans remains largely undefined. Here, we generated bacterial-, fungal-, and viral-induced immune transcriptional profiles in an age- and sex-balanced cohort of 1,000 healthy individuals and searched for the determinants of immune response variation. We found that age and sex affected the transcriptional response of most immune-related genes, with age effects being more stimulus-specific relative to sex effects, which were largely shared across conditions. Although specific cell populations mediated the effects of age and sex on gene expression, including CD8+ T cells for age and CD4+ T cells and monocytes for sex, we detected a direct effect of these intrinsic factors for the majority of immune genes. The mapping of expression quantitative trait loci (eQTLs) revealed that genetic factors had a stronger effect on immune gene regulation than age and sex, yet they affected a smaller number of genes. Importantly, we identified numerous genetic variants that manifested their regulatory effects exclusively on immune stimulation, including a Candida albicans-specific master regulator at the CR1 locus. These response eQTLs were enriched in disease-associated variants, particularly for autoimmune and inflammatory disorders, indicating that differences in disease risk may result from regulatory variants exerting their effects only in the presence of immune stress. Together, this study quantifies the respective effects of age, sex, genetics, and cellular heterogeneity on the interindividual variability of immune responses and constitutes a valuable resource for further exploration in the context of different infection risks or disease outcomes.
机译：宿主遗传和非遗传因素对人类免疫学差异的贡献在很大程度上尚不确定。在这里，我们在1000名健康个体的年龄和性别平衡的队列中生成了细菌，真菌和病毒诱导的免疫转录谱，并搜索了免疫应答变异的​​决定因素。我们发现年龄和性别会影响大多数免疫相关基因的转录反应，而年龄效应相对于性别效应则更具刺激特异性，而性别效应在不同情况下基本相同。尽管特定的细胞群介导了年龄和性别对基因表达的影响，包括年龄的CD8 + T细胞和性别的CD4 + T细胞和单核细胞，但我们检测到直接这些内在因素对大多数免疫基因的作用。表达定量性状基因座（eQTL）的图谱显示，遗传因素对免疫基因调控的影响大于年龄和性别，但它们影响的基因数目较少。重要的是，我们鉴定了许多遗传变异，这些变异仅对免疫刺激具有调节作用，其中包括CR1位点的白色念珠菌特异性主调节剂。这些应答eQTL富含疾病相关变体，尤其是自身免疫和炎性疾病，表明疾病风险的差异可能是由于调节变体仅在存在免疫应激时发挥作用而引起的。总之，这项研究量化了年龄，性别，遗传学和细胞异质性对免疫应答个体间变异性的各自影响，并构成了在不同感染风险或疾病结果的情况下进一步探索的宝贵资源。

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