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

Smylie, Anne Liese; Broderick, Gordon; Fernandes, Henrique; Razdan, Shirin; Barnes, Zachary; Collado, Fanny; Sol, Connie; Fletcher, Mary Ann; Klimas, Nancy

doi:10.1186/1471-2172-14-29

Cited by 73Fibromyalgia and Chronic Fatigue Syndrome ResearchLong-Term Effects of COVID-19Stress Responses and Cortisol

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

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Smylie, Anne Liese, Broderick, Gordon, Fernandes, Henrique, Razdan, Shirin, Barnes, Zachary, Collado, Fanny, Sol, Connie, Fletcher, Mary Ann +1 more·2013·BMC Immunology

DOI 10.1186/1471-2172-14-29PMC PMC3698072

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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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Female sex hormones play an important role in the onset, persistence, and symptom burden of ME/CFS.
“Since women are at higher risk of ME/CFS than men5,18, it is thought that female sex hormones play an important role in the onset, persistence, and symptom burden of this illness19.”
From Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically-relevant Phenotyping of Women with Chronic Fatigue Syndrome (2019) · cites this paper as [19]
The Discussion suggests that sex hormones may modulate immune responses in CFS, and the Conclusions support a role for endocrine modulation of immunity. Neither section addresses whether female sex hormones affect ME/CFS onset, persistence, or symptom burden; those specific parts of the claim are unsupported. (LLM, conf=0.86)
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Additional file 1 of Disentangling the effects of PTSD from Gulf War Illness in male veterans via a systems-wide analysis of immune cell, cytokine, and symptom measures
Sultana, E., Shastry, N., Kasarla, R., Hardy, J., Collado, F., Aenlle, K. K., Abreu, M. M., Sisson, E., Sullivan, K. A., Klimas, N., et al. (2024) · Figshare · doi:10.6084/m9.figshare.24934447
Self-citation
Additional file 3 of Disentangling the effects of PTSD from Gulf War Illness in male veterans via a systems-wide analysis of immune cell, cytokine, and symptom measures
Sultana, E., Shastry, N., Kasarla, R., Hardy, J., Collado, F., Aenlle, K. K., Abreu, M. M., Sisson, E., Sullivan, K. A., Klimas, N., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26658358
Self-citation
Additional file 2 of Disentangling the effects of PTSD from Gulf War Illness in male veterans via a systems-wide analysis of immune cell, cytokine, and symptom measures
Sultana, E., Shastry, N., Kasarla, R., Hardy, J., Collado, F., Aenlle, K. K., Abreu, M. M., Sisson, E., Sullivan, K. A., Klimas, N., et al. (2024) · Figshare · doi:10.6084/m9.figshare.24934559
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Tryptophan Metabolism and Aryl‐Hydrocarbon Receptor Agonists in the Gut Microbiome of People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Esteban, D. J., Conrad, B., Cullinan, A., Luong, S., Albaum, J. A., & WILK, V. (2026) · MicrobiologyOpen · doi:10.1002/mbo3.70333

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Identifying Immune Drivers of Gulf War Illness Using Novel Daily Sampling Approach
Younger, J. (2013) · Defense Technical Information Center (DTIC) · doi:10.21236/ada590164
Gulf War Illness Induced Sex-Specific Transcriptional Differences Under Stressful Conditions
Frank, J., Tehrani, L., Gamer, J., Booven, D. J. V., Ballarin, S., Rossman, R., Edelstein, A., Uppalati, S., Reuthebuck, A., Collado, F., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26083610 · Cited by 3 · see citing works
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Evidence for abnormal cytokine expression in Gulf War Illness: A preliminary analysis of daily immune monitoring data
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Authors: Smylie, A. L., Broderick, G., Fernandes, H., Razdan, S., Barnes, Z., Collado, F., Sol, C., Fletcher, M. A., & Klimas, N.
Affiliations: University of Alberta (CA)
University of Miami (US)
Miami VA Healthcare System (US)
Nova Southeastern University (US)
Corresponding author: Broderick, Gordon
ORCID: Broderick, Gordon
Razdan, Shirin
Klimas, Nancy
Venue: BMC Immunology
Publisher: Springer Science and Business Media LLC
Published: 2013-06-25
Volume: 14
Issue: 1
Pages: 29-29
ISSN: 1471-2172 (ISSN-L)
DOI: 10.1186/1471-2172-14-29
PMC: PMC3698072
OpenAlex: W2115959705
Cited by: 71
References: 61
Citations by year: 2026: 1 · 2025: 1 · 2024: 6 · 2023: 1 · 2022: 2 · 2021: 7 · 2020: 8 · 2019: 14 · 2018: 4 · 2017: 8 · 2016: 9 · 2015: 5 · 2014: 3 · 2013: 2
FWCI: 4.50
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: BMC Immunology (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
NSUWorks (Nova Southeastern University) (submittedVersion)
Funders: U.S. Department of Defense
U.S. Department of Veterans Affairs
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: Gulf War illness, chronic fatigue syndrome, sex differences, cytokine signature, IL-10, IL-17, Th1/Th2 immune response, exercise response, veterans, plasma cytokines
MeSH terms: Adult, Female, Humans, Male, Middle Aged, Sex Characteristics, Cohort Studies, Fatigue Syndrome, Chronic, Case-Control Studies, Cytokines, Persian Gulf Syndrome, Gulf War

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

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