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A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome.

Authors
Craddock-TJA; Fritsch-P; Rice-MA Jr.; del Rosario-RM; Miller-DB; Fletcher-MA; Klimas-NG; Broderick-G
Source
PLoS One 2014 Jan; 9(1):e84839
NIOSHTIC No.
20043758
Abstract
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.
Keywords
Military-personnel; Physiological-stress; Diseases; Biological-systems; Brain-function; Adrenal-cortex; Pituitary-glands; Fatigue; Biological-function; Hormone-activity; Hormones; Immune-reaction; Chronic-inflammation; Analytical-models; Physiological-response; Biochemical-indicators; Sex-factors; Molecular-structure; Endocrine-function; Biomarkers; Immune-system; Autoimmunity; Stress; Cellular-reactions
Contact
Travis J. A. Craddock, Center for Psychological Studies, Nova Southeastern University, Fort Lauderdale, FL, USA
CODEN
POLNCL
Publication Date
20140108
Document Type
Journal Article
Email Address
tcraddock@nova.edu
Fiscal Year
2014
NTIS Accession No.
NTIS Price
Identifying No.
M022014
Issue of Publication
1
ISSN
1932-6203
NIOSH Division
HELD
Priority Area
Construction; Manufacturing
Source Name
Public Library of Science One
State
FL; WV
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