Abstract
BackgroundThough 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).MethodsSubjects 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.ResultsClassification 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.ConclusionsThough 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.
Highlights
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
We still have no clear understanding of Gulf War Syndrome (GWS), called Gulf War Illness (GWI), evidence is mounting of immunological dysfunction in this population that may be potentiated by response to stress
Results presented in Additional file 1: Table S2 show significant differences in cytokine expression across sexes, namely elevated IL-23 in healthy female subjects at all time points (p ≤ 0.01) as well as elevated IL-12 expression post-exercise (p = 0.03)
Summary
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. Female adolescent CFS patients (n = 67 females; age 15 ± 1.4 years) showed a distinct immune profile when compared to acutely fatigued or non-fatigued participants, including increased production of anti-inflammatory cytokines IL-10, decreased IFNγ /IL-10 ratio and reduced production of pro-inflammatory cytokines IL-6, and TNFα in response to lipopolysaccaride (LPS) challenge in vitro [12]. Suggesting an anti-inflammatory polarity in CFS, Skowera et al (2004) [13] reported relatively high levels of intracellular IL-4 and IL-10 following in vitro polyclonal stimulation of whole blood from a mixed population of males and females (n = 13 males and 22 females; age 39 ± 2.1 years [19–62 years]). Carlo-Stella et al (2006) [19] investigated cytokine gene polymorphisms and found significant differences in TNFα and IFNγ genotypes in CFS subjects suggesting that they might be genetically predisposed to differences in inflammatory response
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