Falkenberg Virginia R, Whistler Toni, Murray Janna R, Unger Elizabeth R, Rajeevan Mangalathu S
Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Genet Epigenet. 2013 Jan 28;5:1-9. doi: 10.4137/GEG.S10944. eCollection 2013.
Perforin (PRF1) is essential for immune surveillance and studies report decreased perforin in chronic fatigue syndrome (CFS), an illness potentially associated with stress and/or infection. We hypothesize that stress can influence regulation of PRF1 expression, and that this regulation will differ between CFS and non-fatigued (NF) controls. We used the Trier Social Stress Test (TSST) as a standardized acute psychosocial stress, and evaluated its effect on PRF1 expression and methylation in CFS (n = 34) compared with NF (n = 47) participants. During the TSST, natural killer (NK) cells increased significantly in both CFS (P = <0.0001) and NF subjects (P = <0.0001). Unlike previous reports, there was no significant difference in PRF1 expression at baseline or during TSST between CFS and NF. However, whole blood PRF1 expression increased 1.6 fold during the TSST in both CFS (P = 0.0003) and NF (P = <0.0001). Further, the peak response immediately following the TSST was lower in CFS compared with NF (P = 0.04). In addition, at 1.5 hours post TSST, PRF1 expression was elevated in CFS compared with NF (whole blood, P = 0.06; PBMC, P = 0.02). Methylation of seven CpG sites in the methylation sensitive region of the PRF1 promoter ranged from 38%-79% with no significant differences between CFS and NF. Although, the average baseline methylation of all seven CpG sites did not differ between CFS and NF groups, it showed a significant negative correlation with PRF1 expression at all TSST time points in both CFS (r = -0.56, P = <0.0001) and NF (r = -0.38, P = <0.0001). Among participants with high average methylation (≥65%), PRF1 expression was significantly lower in CFS than NF subjects immediately following TSST. These findings suggest methylation could be an important epigenetic determinant of inter-individual differences in PRF1 expression and that the differences in PRF1 expression and methylation between CFS and NF in the acute stress response require further investigation.
穿孔素（PRF1）对于免疫监视至关重要，且有研究报告称慢性疲劳综合征（CFS）患者体内的穿孔素水平降低，CFS是一种可能与压力和/或感染相关的疾病。我们假设压力会影响PRF1表达的调节，并且这种调节在CFS患者和非疲劳（NF）对照者之间会有所不同。我们使用特里尔社会应激测试（TSST）作为标准化的急性心理社会应激源，并评估其对CFS患者（n = 34）与NF对照者（n = 47）的PRF1表达及甲基化的影响。在TSST过程中，CFS患者（P = <0.0001）和NF对照者（P = <0.0001）的自然杀伤（NK）细胞均显著增加。与先前报道不同的是，CFS患者和NF对照者在基线时或TSST过程中的PRF1表达并无显著差异。然而，在TSST过程中，CFS患者（P = 0.0003）和NF对照者（P = <0.0001）的全血PRF1表达均增加了1.6倍。此外，TSST后立即出现的峰值反应在CFS患者中低于NF对照者（P = 0.04）。另外，在TSST后1.5小时，与NF对照者相比，CFS患者的PRF1表达升高（全血，P = 0.06；外周血单核细胞，P = 0.02）。PRF1启动子甲基化敏感区域中7个CpG位点的甲基化水平在38%至79%之间，CFS患者和NF对照者之间无显著差异。虽然，CFS组和NF组中所有7个CpG位点的平均基线甲基化水平并无差异，但在CFS患者（r = -0.56，P = <0.0001）和NF对照者（r = -0.38，P = <0.0001）的所有TSST时间点，其均与PRF1表达呈显著负相关。在平均甲基化水平较高（≥65%）的参与者中，TSST后立即出现的CFS患者的PRF1表达显著低于NF对照者。这些发现表明甲基化可能是PRF1表达个体差异的重要表观遗传决定因素，并且CFS患者和NF对照者在急性应激反应中PRF1表达和甲基化的差异需要进一步研究。
