A formal analysis of cytokine networks in Chronic Fatigue Syndrome

Abstract

Chronic Fatigue Syndrome (CFS) is a complex illness affecting 4 million Americans for which no characteristic lesion has been identified. Instead of searching for a deficiency in any single marker, we propose that CFS is associated with a profound imbalance in the regulation of immune function forcing a departure from standard preprogrammed responses. To identify these imbalances we apply network analysis to the co-expression of 16 cytokines in CFS subjects and healthy controls. Concentrations of 1b,2,4,5,6,8,10,12,13,15, 17 and 23, and TNF-α were measured in the plasma of 40 female CFS and 59 case-matched controls. Cytokine co-expression networks were constructed from the pair-wise mutual information (MI) patterns found within each subject group. These networks differed in topology significantly more than expected by chance with the CFS network being more hub-like in design. Analysis of local modularity isolated statistically distinct cytokine communities recognizable as pre-programmed immune functional components. These showed highly attenuated Th1 and Th17 immune responses in CFS. High Th2 marker expression but weak interaction patterns pointed to an established Th2 inflammatory milieu. Similarly, altered associations in CFS provided indirect evidence of diminished NK cell responsiveness to IL-12 and LTα stimulus. These observations are consistent with several processes active in latent viral infection and would not have been uncovered by assessing marker expression alone. Furthermore this analysis identifies key subnetworks such as IL-2:IFNγ:TNFα that might be targeted in restoring normal immune function. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptBrain Behav Immun. Author manuscript; available in PMC 2011 October 1. BackgroundChronic Fatigue Syndrome (CFS) is characterized by persistent and unexplained fatigue resulting in severe impairment in daily function and is defined by symptoms, disability, and exclusion of medical and psychiatric conditions that could explain the fatigue (Fukuda et al., 1994;Reeves et al., 2003;Prins et al., 2006). The US Centers for Disease Control and Prevention (CDC) estimates that as many as 4 million people are affected with CFS in the US alone (Reeves et al. 2007;Chandler et al., 2008). Costs to the US economy are estimated at $9.1 billion in lost productivity (Reynolds et al., 2004) and up to $24 billion dollars in health care expenditures annually (Jason et al., 2008). Furthermore complications and co-morbidity can be severe. For example, CFS is associated with chronic and episodic car...

Inflammatory and Cell-Mediated Immune Biomarkers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Depression: Inflammatory Markers Are Higher in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome than in Depression

“…While there is some evidence that depression is accompanied by an increased production of IFN-γ and a Th1-like response [1,2], most papers show a more prominent Th2 response in ME/CFS [32,33,34,35]. For example, Broderick et al [36] observed suppressed Th1 but increased Th2 responses in ME/CFS, while Nakamura et al [37] found increased IL-10 levels, a Th2-like, anti-inflammatory cytokine, in ME/CFS. The increased neopterin levels established in some ME/CFS patients [16,17,18] and patients suffering from fatigue during chronic Epstein-Barr infections [38] suggest that IFN-γ-induced pathways are activated.…”

Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins

“…The elevated ROS production in CFS patients is sometimes associated with altered innate immunity and an accentuated inflammatory response to exercise [29][30][31][32][33][34][35][36]. However, no clear evidence of a link between abnormal immunity and CFS has been established [1,10].…”

Exercise and Sleep Deprivation Do Not Change Cytokine Expression Levels in Patients with Chronic Fatigue Syndrome

“…Negative studies are always problematic because of the possibility of our having found more dramatic effects had we waited longer to sample and prolonged the period of sleep deprivation for another 24 h. Moreover, looking for individual cytokine abnormalities may not reveal discrete abnormalities compared to what using a more integrated network analysis can show (31). However, we designed this study based on the current state of knowledge on the topic by using a maximum exercise demand and overnight sleep deprivation, both of which can make worsen symptoms in CFS patients.…”