Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome
Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome
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DOI：
10.1016/j.psyneuen.2018.11.032
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发表时间：
2019-02-01
影响因子：
3.7
通讯作者：
Pariante, Carmine M.
中科院分区：
文献类型：
--
作者：
Russell, Alice;Hepgul, Nilay;Pariante, Carmine M.
慢性疲劳综合征（CFS）的发病机制中免疫或感染触发因素的作用尚不完全清楚。在CFS和感染后疲劳模型队列中，在基线（即触发前）获得免疫测量的障碍阻碍了对预先存在的免疫功能障碍和随后对触发的免疫变化的研究。本研究提出干扰素- α (ifn - α)诱导的持续性疲劳作为CFS的模型。ifn - α用于治疗慢性丙型肝炎病毒（HCV）感染，在一些个体中引起持续疲劳，这种疲劳在治疗后不会减轻，也就是说，一旦不再有免疫激活。该模型允许在暴露于免疫触发之前和期间以及在原始触发不再存在之后对患者进行评估。55名接受干扰素α治疗的慢性HCV患者在基线、干扰素α治疗6-12个月期间和治疗后6个月进行了评估。测量疲劳、细胞因子和犬尿氨酸途径代谢产物。54名CFS患者和57名健康志愿者在一次性评估中完成了相同的措施，并将其与HCV患者的治疗后随访措施进行了比较。18名接受ifn - α治疗的患者（33%）随后被定义为“持续性疲劳”（CFS的拟议模型），如果他们的疲劳水平在治疗后6个月高于基线；另外67%被认为是“缓解疲劳”。与未接受ifn - α治疗的患者相比，继续发展为持续性疲劳的患者在ifn - α治疗的前四周内疲劳症状的增加幅度更大(Delta治疗周(TW)-0 vs. TW4；PF: 7.1 +/- 1.5 vs. RF: 4.0 +/- 0.8, p = 0.046)。此外，基线白细胞介素(IL)-6增加，基线IL-10水平显著升高，以及ifn - α治疗后这些细胞因子水平升高的趋势，同时疲劳增加。到治疗周（TW）4时，IL-6和IL-10的水平分别增加到其他患者的两倍以上（p = 0.011和p = 0.001）。治疗6个月后，没有证据表明持续疲劳和外周炎症之间存在关联，我们也没有在CFS队列中观察到外周炎症。虽然犬尿氨酸代谢物在ifn - α的作用下发生了变化，但与持续疲劳没有关联。CFS患者犬尿氨酸与色氨酸和3-羟基犬尿氨酸的比值低于对照组。未来的研究需要阐明，即使免疫触发因素不再存在，免疫系统最初的过度反应背后的机制，以及在缺乏持续的外周免疫激活的情况下，从急性到慢性疲劳的变化。
The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger.This study presents interferon-alpha (IFN-alpha)-induced persistent fatigue as a model of CFS. IFN-alpha, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present.Fifty-five patients undergoing IFN-alpha treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-alpha treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients.Eighteen patients undergoing IFN-alpha treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-alpha, compared with patients who did not (Delta Treatment Week (TW)-0 vs. TW4; PF: 7.1 +/- 1.5 vs. RF: 4.0 +/- 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-alpha treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p = 0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-alpha, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls.Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.