Elwenspoek Martha M C, Sias Krystel, Hengesch Xenia, Schaan Violetta K, Leenen Fleur A D, Adams Philipp, Mériaux Sophie B, Schmitz Stephanie, Bonnemberger Fanny, Ewen Anouk, Schächinger Hartmut, Vögele Claus, Muller Claude P, Turner Jonathan D
Department of Infection and Immunity, Luxembourg Institute of Health, Luxembourg City, Luxembourg.
Department of Immunology, Research Institute of Psychobiology, University of Trier, Trier, Germany.
Front Immunol. 2017 Oct 17;8:1263. doi: 10.3389/fimmu.2017.01263. eCollection 2017.
Early life adversity (ELA) increases the risk for multiple age-related diseases, such as diabetes type 2 and cardiovascular disease. As prevalence is high, ELA poses a major and global public health problem. Immunosenescence, or aging of the immune system, has been proposed to underlie the association between ELA and long-term health consequences. However, it is unclear what drives ELA-associated immunosenescence and which cells are primarily affected. We investigated different biomarkers of immunosenescence in a healthy subset of the EpiPath cohort. Participants were either parent-reared (Ctrl, = 59) or had experienced separation from their parents in early childhood and were subsequently adopted (ELA, = 18). No difference was observed in telomere length or in methylation levels of age-related CpGs in whole blood, containing a heterogeneous mixture of immune cells. However, when specifically investigating T cells, we found a higher expression of senescence markers (CD57) in ELA. In addition, senescent T cells (CD57) in ELA had an increased cytolytic potential compared to senescent cells in controls. With a mediation analysis we demonstrated that cytomegalovirus (CMV) infection, which is an important driving force of immunosenescence, largely accounted for elevated CD57 expression observed in ELA. Leukocyte telomere length may obscure cell-specific immunosenescence; here, we demonstrated that the use of cell surface markers of senescence can be more informative. Our data suggest that ELA may increase the risk of CMV infection in early childhood, thereby mediating the effect of ELA on T cell-specific immunosenescence. Thus, future studies should include CMV as a confounder or selectively investigate CMV seronegative cohorts.
早年生活逆境（ELA）会增加患多种与年龄相关疾病的风险，如2型糖尿病和心血管疾病。由于其患病率很高，ELA构成了一个重大的全球性公共卫生问题。免疫衰老，即免疫系统的老化，被认为是ELA与长期健康后果之间关联的基础。然而，尚不清楚是什么驱动了与ELA相关的免疫衰老，以及哪些细胞受到的影响最为主要。我们在EpiPath队列的一个健康子集中研究了免疫衰老的不同生物标志物。参与者要么是由父母抚养长大（对照组，n = 59），要么在幼儿期与父母分离，随后被收养（ELA组，n = 18）。在包含异质免疫细胞混合物的全血中，端粒长度或与年龄相关的CpG甲基化水平未观察到差异。然而，当专门研究T细胞时，我们发现ELA组中衰老标志物（CD57）的表达更高。此外，与对照组的衰老细胞相比，ELA组中的衰老T细胞（CD57）具有更高的细胞溶解潜能。通过中介分析，我们证明巨细胞病毒（CMV）感染作为免疫衰老的一个重要驱动力，在很大程度上解释了ELA组中观察到的CD57表达升高。白细胞端粒长度可能掩盖细胞特异性免疫衰老；在这里，我们证明使用衰老的细胞表面标志物可能更具信息性。我们的数据表明，ELA可能会增加儿童早期CMV感染的风险，从而介导ELA对T细胞特异性免疫衰老的影响。因此，未来的研究应将CMV作为一个混杂因素纳入，或选择性地研究CMV血清阴性队列。
