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Whole Blood Gene Expression in Adolescent Chronic Fatigue Syndrome

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Whole Blood Gene Expression in Adolescent Chronic Fatigue Syndrome Nguyen et al. J Transl Med (2017) 15:102 DOI 10.1186/s12967-017-1201-0 Journal of Translational Medicine RESEARCH Open Access Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross‑sectional study suggesting altered B cell diferentiation and survival Chinh Bkrong Nguyen1,2, Lene Alsøe3, Jessica M. Lindvall4, Dag Sulheim5, Even Fagermoen6, Anette Winger7, Mari Kaarbø8, Hilde Nilsen3 and Vegard Bruun Wyller1,2* Abstract Background: Chronic fatigue syndrome (CFS) is a prevalent and disabling condition afecting adolescents. The pathophysiology is poorly understood, but immune alterations might be an important component. This study compared whole blood gene expression in adolescent CFS patients and healthy controls, and explored associations between gene expression and neuroendocrine markers, immune markers and clinical markers within the CFS group. Methods: CFS patients (12–18 years old) were recruited nation-wide to a single referral center as part of the Nor- CAPITAL project. A broad case defnition of CFS was applied, requiring 3 months of unexplained, disabling chronic/ relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls having comparable distribution of gender and age were recruited from local schools. Whole blood samples were subjected to RNA sequencing. Immune markers were blood leukocyte counts, plasma cytokines, serum C-reactive protein and immunoglobulins. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, infammation, fatigue, depression and trait anxiety, as well as activity recordings. Results: A total of 29 CFS patients and 18 healthy controls were included. We identifed 176 genes as diferentially expressed in patients compared to controls, adjusting for age and gender factors. Gene set enrichment analyses suggested impairment of B cell diferentiation and survival, as well as enhancement of innate antiviral responses and infammation in the CFS group. A pattern of co-expression could be identifed, and this pattern, as well as single gene transcripts, was signifcantly associated with indices of autonomic nervous activity, plasma cortisol, and blood mono- cyte and eosinophil counts. Also, an association with symptoms of post-exertional malaise was demonstrated. Conclusion: Adolescent CFS is characterized by diferential gene expression pattern in whole blood suggestive of impaired B cell diferentiation and survival, and enhanced innate antiviral responses and infammation. This expres- sion pattern is associated with neuroendocrine markers of altered HPA axis and autonomic nervous activity, and with symptoms of post-exertional malaise. Trial registration Clinical Trials NCT01040429 Keywords: Chronic fatigue syndrome, Adolescent, Gene expression, Infammation, B cell diferentiation, B cell survival *Correspondence: [email protected] 1 Department of Paediatrics and Adolescent Health, Akershus University Hospital, 1478 Lørenskog, Norway Full list of author information is available at the end of the article © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nguyen et al. J Transl Med (2017) 15:102 Page 2 of 21 Background Te reasons for these discrepancies may partly be due Chronic fatigue syndrome (CFS) is a long-lasting and dis- to the multifactorial nature of CFS, which may obscure abling condition characterized by disproportional fatigue direct correlations with molecular observations. Te after exertions, musculoskeletal pain, headaches, cogni- complex regulation of transcription, post transcriptional tive impairments, and other symptoms [1, 2]. Adolescent control and RNA metabolism may also prompt variability CFS prevalence is estimated at 0.1–1.0% [3–5], and CFS in gene expression studies; hence mRNA measurements may have detrimental efects on psychosocial and aca- are not always linearly correlated with targeted functional demic development [6], as well as family functioning [7]. proteins in biological samples at varying time-points. Te disease mechanisms of CFS remain poorly under- In addition to immune changes, some studies have stood, but some studies indicate modest immunological found that CFS disease mechanisms are characterized alterations, such as low-grade systemic infammation by neuroendocrine alterations including enhanced sym- and attenuation of NK cell function [8–10]. Furthermore, pathetic and attenuated parasympathetic cardiovascular the reported benefcial efect of treatment with the anti- nervous activity [26–29] and attenuation of the hypo- CD20 antibody rituximab might suggest a role for B cells thalamus–pituitary–adrenal axis (HPA axis) [30–32]. in the pathophysiology [11]. Studies of plasma cytokine Tese phenomena might be causally related. Te com- levels have been inconclusive; fndings include increased plex immune infuence exerted by glucocorticoids has levels of interleukin (IL)-1 and tumor necrosis factor been recognized for decades [33]; more recently, ample (TNF) [12], increased levels of IL-1α and IL-1β but nor- evidence suggests that both parasympathetic and sym- mal levels of TNF [13], and no diferences between CFS pathetic nervous activity promotes immunomodulation patients and healthy controls [14, 15]. [34–36]. Accordingly, the “sustained arousal” model of Immune cell gene expression has been addressed by CFS suggests that the observed immune alterations are several studies over the last decade. However, the fnd- secondary to the neuroendocrine alterations [37]. Tis ings do not give a consistent picture: Kerr and co-work- hypothesis received some support from the observation ers reported diferential expression of 88 genes in whole that treatment of adolescent CFS patients with low-dose blood samples from CFS patients and healthy controls clonidine, which attenuates sympathetic and enhanced [16]. A similar pattern of gene expression was later found parasympathetic nervous activity through central mecha- in two other CFS patient cohorts by the same research nisms [38], caused a signifcant reduction in serum levels group [17]. From leukocyte samples, Light and co-work- of C-reactive protein (CRP) [39]. ers reported an increase in expression of genes that are To the best of our knowledge, no previous study has related to sensory, adrenergic and immune system as a addressed whole blood gene expression in adolescent response to physical exercise in CFS patients but not in CFS patients, who are less burdened by comorbidity and healthy controls [18]. A recent review concluded that aging processes and presumably more homogeneous there is a larger post-exercise increase in IL-10 and Toll- than adult patients. Nor do we know of any study using like receptor 4 (TLR4) gene transcripts in CFS as com- high throughput sequencing (HTS) for gene expression pared to healthy controls [19]. Restricting the analyses to analyses in CFS. Furthermore, no previous study has gene expression from peripheral blood mononuclear cells explored associations between neuroendocrine mark- (PBMC) correlated with multidimensional fatigue inven- ers and gene expression in CFS. Tus, the aim of this tory and depression scales, Fang and co-workers identi- exploratory study was twofold: (a) To map whole blood fed cytokine–cytokine receptor interaction as one of diferential gene expression in adolescent CFS patients the most signifcant pathways [20]. Also studying PBMC, and healthy controls, and (b) To explore the associations Gow and co-workers identifed that the top upregulated between gene expression and neuroendocrine markers, genes are related to immunological processes [21]. On the immune markers and clinical markers within the CFS other hand, a study of monozygotic twins discordant for group. CFS did not reveal any diferences in whole blood gene expression [22], and it has been maintained that previ- Methods ously reported diferences in gene expression were study- CFS patients specifc and not useful for CFS diagnostic purposes [23]. Tis study is part of the NorCAPITAL-project (Te Also, attempts of relating gene expression profles to clini- Norwegian Study of Chronic Fatigue Syndrome in Ado- cal symptoms of CFS have had limited success [24]. For lescents: Pathophysiology and Intervention Trial; Clini- instance, Galbraith and co-workers investigated whole calTrials ID: NCT01040429). Details of the recruitment blood gene expression in three post-infective cohorts; 63 procedure and inclusion/exclusion criteria are described genes were identifed as diferentially expressed, but there elsewhere [39]. Briefy, all hospital paediatric depart- were no consistent associations to clinical symptoms [25]. ments in Norway (n = 20), as well as primary care Nguyen et al. J Transl Med (2017) 15:102 Page 3 of 21 paediatricians and general practitioners, were invited according to manufacturer’s manual with the exception to refer CFS patients aged 12–18
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