Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; Interdepartmental Center "L. Galvani", University of Bologna, Bologna, Italy; IRCCS Institute of Neurological Sciences, Bologna, Italy.
Exp Gerontol. 2018 May;105:94-100. doi: 10.1016/j.exger.2018.01.019. Epub 2018 Jan 31.
Several evidences indicate that aging negatively affects the effectiveness of influenza vaccination. Although it is well established that immunosenescence has an important role in vaccination response, the molecular pathways underlying this process are largely unknown. Given the importance of epigenetic remodeling in aging, here we analyzed the relationship between responsiveness to influenza vaccination and DNA methylation profiles in healthy subjects of different ages. Peripheral blood mononuclear cells were collected from 44 subjects (age range: 19-90 years old) immediately before influenza vaccination. Subjects were subsequently classified as responders or non-responders according to hemagglutination inhibition assay 4-6 weeks after the vaccination. Baseline whole genome DNA methylation in peripheral blood mononuclear cells was analyzed using the Illumina® Infinium 450 k microarray. Differential methylation analysis between the two groups (responders and non-responders) was performed through an analysis of variance, correcting for age, sex and batch. We identified 83 CpG sites having a nominal p-value <.001 and absolute difference in DNA methylation of at least 0.05 between the two groups. For some CpG sites, we observed age-dependent decrease or increase in methylation, which in some cases was specific for the responders and non-responders groups. Finally, we divided the cohort in two subgroups including younger (age < 50) and older (age ≥ 50) subjects and compared DNA methylation between responders and non-responders, correcting for sex and batch in each subgroup. We identified 142 differentially methylated CpG sites in the young subgroup and 305 in the old subgroup, suggesting a larger epigenetic remodeling at older ages. Interestingly, some of the differentially methylated probes mapped in genes involved in immunosenescence (CD40) and in innate immunity responses (CXCL16, ULK1, BCL11B, BTC). In conclusion, the analysis of epigenetic landscape can shed light on the biological basis of vaccine responsiveness during aging, possibly providing new appropriate biomarkers of this process.
有几项证据表明，衰老会降低流感疫苗的有效性。虽然免疫衰老在疫苗反应中起着重要作用已得到充分证实，但这一过程背后的分子途径在很大程度上仍是未知的。鉴于表观遗传重塑在衰老中的重要性，我们在此分析了不同年龄健康受试者对流感疫苗的反应性与 DNA 甲基化谱之间的关系。从 44 名受试者（年龄范围：19-90 岁）中采集外周血单核细胞，在流感疫苗接种前立即采集。根据接种后 4-6 周的血凝抑制试验，将受试者随后分为有反应者和无反应者。使用 Illumina® Infinium 450k 微阵列分析外周血单核细胞中的全基因组 DNA 甲基化。通过方差分析对两组（有反应者和无反应者）进行差异甲基化分析，校正年龄、性别和批次。我们鉴定了 83 个 CpG 位点，其名义 p 值<.001，两组之间的 DNA 甲基化差异至少为 0.05。对于一些 CpG 位点，我们观察到随着年龄的增长，甲基化程度降低或升高，在某些情况下，这种降低或升高仅存在于有反应者和无反应者组中。最后，我们将队列分为包括较年轻（年龄<50 岁）和较年长（年龄≥50 岁）的两个亚组，并在每个亚组中校正性别和批次后，比较有反应者和无反应者之间的 DNA 甲基化。我们在年轻亚组中鉴定了 142 个差异甲基化 CpG 位点，在老年亚组中鉴定了 305 个差异甲基化 CpG 位点，这表明随着年龄的增长，表观遗传重塑更大。有趣的是，一些差异甲基化探针映射到参与免疫衰老（CD40）和固有免疫反应（CXCL16、ULK1、BCL11B、BTC）的基因中。总之，对表观遗传景观的分析可以揭示衰老过程中疫苗反应性的生物学基础，可能为这一过程提供新的适当的生物标志物。
