title: A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome.
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.
authors.affiliation: Center for Psychological Studies, Nova Southeastern University, Fort Lauderdale, Florida, United States of America ; Graduate School for Computer and Information Sciences, Nova Southeastern University, Fort Lauderdale, Florida, United States of America ; Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States of America.
authors.forename: Travis J A
authors.initials: TJ
authors.lastname: Craddock
authors.affiliation: Department of Medicine, Faculty of Dentistry and Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Fritsch
authors.affiliation: Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rice
authors.affiliation: Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States of America.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: del Rosario
authors.affiliation: Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia, United States of America.
authors.forename: Diane B
authors.initials: DB
authors.lastname: Miller
authors.affiliation: Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Fletcher
authors.affiliation: Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States of America ; College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States of America.
authors.forename: Nancy G
authors.initials: NG
authors.lastname: Klimas
authors.affiliation: Center for Psychological Studies, Nova Southeastern University, Fort Lauderdale, Florida, United States of America ; Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States of America ; Department of Medicine, Faculty of Dentistry and Medicine, University of Alberta, Edmonton, Alberta, Canada ; College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida, United States of America.
authors.forename: Gordon
authors.initials: G
authors.lastname: Broderick
mesh_terms: D000328:Adult; D015673:Fatigue Syndrome, Chronic / Q000276:immunology / Q000503:physiopathology* / Q000628:therapy; D005260:Female; D006066:Gonads / Q000503:physiopathology; D006706:Homeostasis; D006801:Humans; D007031:Hypothalamus / Q000503:physiopathology*; D008297:Male; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D014728:Veterans