A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome - PubMed (original) (raw)

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

Anne Liese Smylie et al. BMC Immunol. 2013.

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

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Figures

Figure 1

Figure 1

Gender differences in immune signatures among healthy controls. Immune cytokine expression of male and female healthy controls was compared using a step-wise method across all time points (rest, peak activity, and recovery). Red arrows indicate a negative contribution of a particular cytokine in female healthy controls compared to males and vice versa for black arrows. Arrow line thickness is proportional to the magnitude of the standardized canonical coefficients. Changes in IL-23 were a dominant factor at all time points, in particular when cast against concurrent levels of IL-2 and IL-5 expression under challenge.

Figure 2

Figure 2

Cytokine signatures separating illness groups in male subjects. Immune cytokine expression patterns separating of male GWI, CFS and healthy control subjects identified using a step-wise selection method across all time points (rest, peak activity, and recovery). Red arrows indicate a negative contribution, vice versa for black arrows. Arrow line thickness is proportional to the magnitude of standardized canonical coefficients. NK cell promoters (IL-12 or 15) are observed in both illnesses, as are IL-10 and 23. Stronger IL-2 expression was characteristic of CFS while stronger IL-13 contribution was indicative of GWI (Table 2 and Additional file 2: Table S5).

Figure 3

Figure 3

Cytokine signatures separating illness groups in female subjects. Immune cytokine expression patterns separating of female GWI, CFS and healthy control subjects identified using a step-wise selection method across all time points (rest, peak activity, and recovery). Red arrows indicate a negative contribution, vice versa for black arrows. Arrow line thickness is proportional to the magnitude of standardized canonical coefficients. While decreased IL-23 expression in the context of increased IL-5 levels provided strong separation of GWI from healthy controls the signal for CFS was much weaker and required relaxation of the constraints on cross-correlation between cytokines.

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