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A Formal Analysis of Cytokine Networks in Chronic Fatigue Syndrome


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.



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.