Open Access Highly Accessed Research article

A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome

Anne Liese Smylie1, Gordon Broderick14*, Henrique Fernandes1, Shirin Razdan2, Zachary Barnes2, Fanny Collado3, Connie Sol34, Mary Ann Fletcher2 and Nancy Klimas34

Author affiliations

1 Department of Medicine, University of Alberta, Edmonton, AB, Canada

2 Department of Medicine, University of Miami, Miami, FL, USA

3 Department of Clinical Immunology, Miami Veterans Affairs Medical Center, Miami, FL, USA

4 Institute for Neuro-immune Medicine, Nova South eastern University, Suite 3440 University Park Plaza, 3424 South University Drive, Fort Lauderdale, 33328, FL, USA

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Citation and License

BMC Immunology 2013, 14:29  doi:10.1186/1471-2172-14-29

Published: 25 June 2013



Though potentially linked to the basic physiology of stress response we still have no clear understanding of Gulf War Illness (GWI), a debilitating condition presenting complex immune, endocrine and neurological symptoms. Here we compared male (n = 20) and female (n = 10) veterans with GWI separately against their healthy counterparts (n = 21 male, n = 9 female) as well as subjects with chronic fatigue syndrome/ myalgic encephalomyelitis (CFS/ME) (n = 12 male, n = 10 female).


Subjects were assessed using a Graded eXercise Test (GXT) with blood drawn prior to exercise, at peak effort (VO2 max) and 4-hours post exercise. Using chemiluminescent imaging we measured the concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12 (p70), 13, 15, 17 and 23, IFNγ, TNFα and TNFβ in plasma samples from each phase of exercise. Linear classification models were constructed using stepwise variable selection to identify cytokine co-expression patterns characteristic of each subject group.


Classification accuracies in excess of 80% were obtained using between 2 and 5 cytokine markers. Common to both GWI and CFS, IL-10 and IL-23 expression contributed in an illness and time-dependent manner, accompanied in male subjects by NK and Th1 markers IL-12, IL-15, IL-2 and IFNγ. In female GWI and CFS subjects IL-10 was again identified as a delineator but this time in the context of IL-17 and Th2 markers IL-4 and IL-5. Exercise response also differed between sexes: male GWI subjects presented characteristic cytokine signatures at rest but not at peak effort whereas the opposite was true for female subjects.


Though individual markers varied, results collectively supported involvement of the IL-23/Th17/IL-17 axis in the delineation of GWI and CFS in a sex-specific way.

Cytokines; Chronic fatigue; Gulf war illness; Exercise challenge; Immune signaling; Classification model