Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. Brain Behav Immun. 2010 May 3. [Epub ahead of print] Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. http://www.ncbi.nlm.nih.gov/pubmed/20447453 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 IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12, 13, 15, 17 and 23, IFN-gamma, lymphotoxin-alpha (LT-alpha) and TNF-alpha 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 esponses in CFS. High Th2 marker expression but weak interaction atterns pointed to an established Th2 inflammatory milieu. Similarly, altered associations in CFS provided indirect evidence of diminished NK cell responsiveness to IL-12 and LTalpha 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 sub-networks such as IL-2:IFNgamma:TNFalpha that might be targeted in restoring normal immune function. Copyright 2010. Published by Elsevier Inc.