A role for homeostatic drive in the perpetuation of complex chronic illness: gulf War illness and chronic fatigue syndrome
Open accessAbstract
A key component in the body's stress response, the hypothalamic-pituitary-adrenal (HPA) axis orchestrates changes across a broad range of major biological systems. Its dysfunction has been associated with numerous chronic diseases including Gulf War Illness (GWI) and chronic fatigue syndrome (CFS). Though tightly coupled with other components of endocrine and immune function, few models of HPA function account for these interactions. Here we extend conventional models of HPA function by including feed-forward and feedback interaction with sex hormone regulation and immune response. We use this multi-axis model to explore the role of homeostatic regulation in perpetuating chronic conditions, specifically GWI and CFS. An important obstacle in building these models across regulatory systems remains the scarcity of detailed human in vivo kinetic data as its collection can present significant health risks to subjects. We circumvented this using a discrete logic representation based solely on literature of physiological and biochemical connectivity to provide a qualitative description of system behavior. This connectivity model linked molecular variables across the HPA axis, hypothalamic-pituitary-gonadal (HPG) axis in men and women, as well as a simple immune network. Inclusion of these interactions produced multiple alternate homeostatic states and sexually dimorphic responses. Experimental data for endocrine-immune markers measured in male GWI subjects showed the greatest alignment with predictions of a naturally occurring alternate steady state presenting with hypercortisolism, low testosterone and a shift towards a Th1 immune response. In female CFS subjects, expression of these markers aligned with an alternate homeostatic state displaying hypocortisolism, high estradiol, and a shift towards an anti-inflammatory Th2 activation. These results support a role for homeostatic drive in perpetuating dysfunctional cortisol levels through persistent interaction with the immune system and HPG axis. Though coarse, these models may nonetheless support the design of robust treatments that might exploit these regulatory regimes.
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The authors found that even their coarse-grained model could support multiple steady states, two of which were proximal to immune marker profiles exhibited by ME/CFS subjects.
“We found that even this coarse-grained model could support multiple steady states, two of which were proximal to immune marker profiles exhibited by ME/CFS subjects26,27.”
From Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically-relevant Phenotyping of Women with Chronic Fatigue Syndrome (2019) · cites this paper as [27]
The finding is consistent with earlier work by our group using a coarser-grained representation and resting state data only.
“This finding, which is here supported by longitudinal exercise-response data applied to a much more detailed model of endocrine-immune function, remains consistent with earlier work by our group using a much coarser grained representation and resting state data only27.”
From Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically-relevant Phenotyping of Women with Chronic Fatigue Syndrome (2019) · cites this paper as [27]
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- Authors
- Craddock, T. J. A., Fritsch, P., Rice, M. A., del Rosario, R. M., Miller, D. B., Fletcher, M. A., Klimas, N. G., & Broderick, G.
- Affiliations
- Nova Southeastern University (US)
- University of Alberta (CA)
- Centers for Disease Control and Prevention (US)
- University of Miami (US)
- Corresponding author
- Craddock, Travis J. A.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-01-08
- Volume
- 9
- Issue
- 1
- Pages
- e84839
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3885655
- OpenAlex
- W2009478129
- Cited by
- 75
- References
- 97
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 12 · 2020: 5 · 2019: 11 · 2018: 8 · 2017: 2 · 2016: 9 · 2015: 5 · 2014: 4 · 2013: 2
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Update notices
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- NSUWorks (Nova Southeastern University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Defense (GW093042)
- University of Miami
- Compute Canada
- Western Canada Research Grid
- National Institutes of Health
- U.S. Public Health Service (RES0008852)
- Congressionally Directed Medical Research Programs (GW093042)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- Gulf War illness, chronic fatigue syndrome, hypothalamic-pituitary-adrenal axis, homeostatic regulation, hypothalamic-pituitary-gonadal axis, endocrine-immune interaction, cortisol, sex differences, Th1/Th2 immune response, hypercortisolism, adrenal insufficiency, testosterone, estradiol
- MeSH terms
- Adult, Female, Gonads, Homeostasis, Humans, Hypothalamus, Male, Pituitary-Adrenal System, Veterans, Fatigue Syndrome, Chronic
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