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.
References
[1]
Groeneweg FL, Karst H, de Kloet ER, Jo？ls M (2011) Rapid non-genomic effects of corticosteroids and their role in the central stress response. J Endocrinol 209: 153–167.
[2]
Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10: 434–445.
[3]
Mikics é, Kruk MR, Haller J (2004) Genomic and non-genomic effects of glucocorticoids on aggressive behavior in male rats. Psychoneuroendocrino 29: 618–635.
[4]
Pariante CM, Lightman SL (2008) The HPA axis in major depression: classical theories and new developments. Trend Neurosci 31: 464–468.
[5]
Gerritsen L, Comijs HC, van der Graaf Y, Knoops AJ, Penninx BW, et al. (2011) Depression, hypothalamic pituitary adrenal axis, and hippocampal and entorhinal cortex volumes—the SMART Medea study. Biol Psychiatry 70: 373–380.
[6]
Mehta D, Binder EB (2012) Gene × environment vulnerability factors for PTSD: The HPA-axis. Neuropharmacol 62: 654–662.
[7]
Yehuda R (2009) HPA alterations in PTSD. In: Fink G, editor. Stress Consequences: Mental, Neuropsychological and Socioeconomic. San Diego: Academic Press. pp. 125–130.
[8]
Young EA (2009) PTSD and HPA axis: same hormones, different disorders. In: Pariante CM, editor. Understanding Depression: A Translational Approach. New York: Oxford University Press. pp. 193–212.
[9]
Gil-Bea FJ, Aisa B, Solomon A, Solas M, del Carmen Mugueta M, et al. (2010) HPA axis dysregulation associated to apolipoprotein E4 genotype in Alzheimer's disease. J Alzheimers Dis. 22: 829–838.
[10]
Golier JA, Schmeidler J, Legge J, Yehuda R (2006) Enhanced cortisol suppression to dexamethasone associated with Gulf War deployment. Psychoneuroendocrinology 31(10): 1181–1189.
[11]
Golier JA, Schmeidler J, Legge J, Yehuda R (2007) Twenty-four hour plasma cortisol and adrenocorticotropic hormone in Gulf War Veterans: relationships to posttraumatic stress disorder and health symptoms. Biol Psychiatry 62(10): 1175–1178.
[12]
Golier JA, Schmeidler J, Yehuda R (2009) Pituitary response to metyrapone in Gulf War veterans: relationship to deployment, PTSD and unexplained health symptoms. Psychoneuroendocrinology 34(9): 1338–1345.
[13]
Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ (2007) Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. Neuropsychobiol 55: 112–120.
[14]
Crofford LJ, Young EA, Engleberg NC, Korszun A, Brucksch CB, et al. (2004) Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav Immun 18: 314–325.
[15]
Aschbacher K, Adam EK, Crofford LJ, Kemeny ME, Demitrack MA, et al. (2012) Linking disease symptoms and subtypes with personalized systems-based phenotypes: A proof of concept study. Brain Behav Immun. 26(7): 1047–1056.
[16]
Ben-Zvi A, Vernon SD, Broderick G (2009) Model-Based Therapeutic Correction of Hypothalamic-Pituitary-Adrenal Axis Dysfunction. PLoS Comp Biol 5: e1000273.
[17]
Alon U (2007) Network motifs: theory and experimental approaches. Nat Rev Genet 8(6): 450–461.
[18]
Vinther F, Andersen M, Ottesen JT (2011) The minimal model of the hypothalamic–pituitary–adrenal axis. J Math Biol 63(4): 663–690.
[19]
Rankin J, Walker JJ, Windle R, Lightman SL, Terry JR (2012) Characterizing dynamic interactions between ultradian glucocorticoid rhythmicity and acute stress using the phase response curve. PLoS One 7(2): e30978.
[20]
Walker JJ, Terry JR, Lightman SL (2010) Origin of ultradian pulsatility in the hypothalamic–pituitary–adrenal axis. Proc R Soc B 277(1688): 1627–1633.
[21]
Walker JJ, Spiga F, Waite E, Zhao Z, Kershaw Y, et al. (2012) The Origin of Glucocorticoid Hormone Oscillations. PLoS Biol 10(6): e1001341.
[22]
Gupta S, Aslakson E, Gurbaxani BM, Vernon SD (2007) Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability. Theor Biol Med Model 4: 8.
[23]
Thomas R, Thieffry D, Kaufman M (1995) Dynamical behaviour of biological regulatory networks—I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state. Bull Math Biol. 57: 247–276.
[24]
Thomas R (1991) Regulatory Networks Seen as Asynchronous Automata: A Logical Description. J Theor Biol 153: 1–23.
[25]
Mendoza L, Xenarios I (2006) A method for the generation of standardized qualitative dynamical systems of regulatory networks . Theor Biol Med Model 3: 13.
Viau V (2002) Functional Cross-Talk Between the Hypothalamic-Pituitary-Gonadal and -Adrenal Axes. J Neuroendocrinol 14: 506–513.
[28]
Dallman MF, Viau V, Bhatnagar S, Laugero K, Gomez F, et al.. (2002) Corticotropin-releasing factor (CRF), corticosteroids and stress, energy balance, the brain and behavior. In: Pfaff DW, editor. Hormones, Brain and Behavior. New York: Academic Press. Pp. 571–632.
[29]
Tilbrook AJ, Turner AI, Clarke IJ (2000) Effects of stress on reproduction in non-rodent mammals: the role of glucocorticoids and sex differences. Rev Reprod 5: 105–113.
[30]
Torpy DJ, Chrousos GR (1996) The three-way interactions between the hypothalamic-pituitary-adrenal and gonadal axes and the immune system. Baillires Clin Rheumatol 10: 181–198.
[31]
Rivier C, Rivest S (1991) Effect of stress on the activity of the hypothalamic pituitary-gonadal axis: peripheral and central mechanisms. Biol Reprod 45: 523–532.
[32]
Pi？ón R (2001) Biology of human reproduction. Sausalito: University Science Books. 535 p.
[33]
Hiller-Sturmh？fel S, Bartke A (1998) The endocrine system: an overview. Alcohol Health Res World 22: 153–164.
[34]
Folcik VA, Broderick G, Mohan S, Block B, Ekbote C, et al. (2011) Using an agent-based model to analyze the dynamic communication network of the immune response. Theor Biol Med Model 8: 1.
[35]
Silverman MN, Pearce BD, Biron CA, Miller AH (2005) Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol 18: 41–78.
[36]
Cutolo M (2004) Immune System, Hormonal Effects on. In: Martini L, editor. Encyclopedia of Endocrine Diseases, Volume 2. Elsevier Academic Press. pp. 755–760.
[37]
Berczi I, Szentivanyi A (2003) Autoimmune disease. In: Berczi I, Szentivanyi A, editors. Neuroimmmune Biology: Vol. 3: The Immune-Neuroendocrine Circuitry. History and Progress. Amsterdam: Elsevier Science BV. pp. 495–536
[38]
Bush KA, Krukowski K, Eddy JL, Janusek LW, Mathews HL (2012) Glucocorticoid receptor mediated suppression of natural killer cell activity: Identification of associated deacetylase and corepressor molecules. Cell Immunol 275: 80–89.
[39]
Zen M, Canova M, Campana C, Bettio S, Nalotta L, et al. (2011) The kaleidoscope of glucocorticoid effects on immune system. Autoimmun Rev 10: 305–310.
[40]
Liberman AC, Druker J, Refojo D, Holsboer F, Arzt E (2009) Glucocorticoids inhibit GATA-3 phosphorylation and activity in T cells. FASEB J 23: 1558–1571.
[41]
Elenkov IJ (2004) Glucocorticoids and the Th1/Th2 balance. Ann NY Acad Sci 1024: 138–146.
[42]
González D, Díaz B, Pérez M, Hernández A, Chico B, et al. (2010) Sex hormones and autoimmunity. Immunol Lett 133: 6–13.
[43]
Lélu K, Laffont S, Delpy L, Paulet PE, Périnat T, et al. (2011) Estrogen Receptor α Signaling in T Lymphocytes Is Required for Estradiol-Mediated Inhibition of Th1 and Th17 Cell Differentiation and Protection against Experimental Autoimmune Encephalomyelitis. J Immunol 187: 2386–2393.
[44]
Foster S, Daniels C, Bourdette D, Bebo BF (2003) Dysregulation of the hypothalamic pituitary-gonadal axis in experimental autoimmune encephalomyelitis and multiple sclerosis. J Neuroimmunol 140: 78–87.
[45]
Watanobe H, Hayakawa Y (2003) Hypothalamic interleukin-1 beta and tumor necrosis factor-alpha, but not interleukin-6, mediate the endotoxin-induced suppression of the reproductive axis in rats. Endocrinology 144: 4868–4875.
[46]
Broderick G, Katz BZ, Fernandes H, Fletcher MA, Klimas NG, et al. (2012) Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue. J Transl Med 10(1): 191.
[47]
Aspler AL, Bolshin C, Vernon SD, Broderick G (2008) Evidence of inflammatory immune signaling in chronic fatigue syndrome: A pilot study of gene expression in peripheral blood. Behav Brain Funct 4: 44.
[48]
Broderick G, Kreitz A, Fuite J, Fletcher MA, Vernon SD, et al. (2011) A pilot study of immune network remodeling under challenge in Gulf War Illness. Brain Behav Immun 25: 302–313.
[49]
Fukuda K, Nisenbaum R, Stewart G, Thompson WW, Robin L, et al. (1998) Chronic multisymptom illness affecting Air Force veterans of the Gulf War. J Am Med Assoc 280: 981–998.
[50]
Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, et al. (1994) The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 12: 953–959.
[51]
Collins JF, Donta ST, Engel CC, Baseman JB, Dever LL, et al. (2002) The antibiotic treatment trial of Gulf War Veterans' Illnesses: issues, design, screening, and baseline characteristics. Control Clin Trials 23: 333–353.
[52]
Vernon SD, Reeves WC (2006) The challenge of integrating disparate high-content data: epidemiological, clinical and laboratory data collected during an in-hospital study of chronic fatigue syndrome. Pharmacogenomics 7: 345–354.
[53]
Fuite J, Vernon SD, Broderick G (2008) Neuroendocrine and immune network re-modeling in chronic fatigue syndrome: An exploratory analysis. Genomics 92: 393–399.
[54]
Broderick G, Craddock RC, Whistler T, Taylor R, Klimas N, et al. (2006) Identifying illness parameters in fatiguing syndromes using classical projection methods. Pharmacogenomics 7: 407–419.
[55]
Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, et al. (2010) A formal analysis of cytokine networks in Chronic Fatigue Syndrome. Brain Behav Immun 24: 1209–1217.
[56]
Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, et al. (2003) Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res 3: 25.
[57]
Brown M (1975) A method for combining non-independent, one-sided tests of significance. Biometrics 31: 987–992.
[58]
Beacher FDCC, Gray MA, Mathias CJ, Crichlek HD (2009) Vulnerability to simple faints is predicted by regional differences in brain anatomy,. NeuroImage 47: 937–945.
[59]
Queen KJ, Shi M, Zhang F, Cvek U, Scott RS (2013) Epstein-Barr virus-induced epigenetic alterations following transient infection. Int J Cancer 132(9): 2076–2086.
[60]
Hernando H, Shannon-Lowe C, Islam AB, Al-Shahrour F, Rodríguez-Ubreva J, et al. (2013) The B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion. Genome Biol. 14(1): R3.
[61]
Wolfram M, Bellingrath S, Kudielka BM (2011) The cortisol awakening response (CAR) across the female menstrual cycle. Psychoneuroendocrinol 36: 905–912.
[62]
Chrousos GP (2010) Stress and Sex Versus Immunity and Inflammation. Sci Signal 3: pe36.
[63]
Young EA, Korszun A, Figueiredo HF, Banks-Solomon M, Herman JP (2007) Sex Differences in HPA axis regulation, In: Becker JB, Berkley KJ, Geary N, Hampson E, Herman JP, et al., editors. Sex Differences in the Brain: From Genes to Behavior. New York, USA: Oxford University Press. pp. 95–105.
[64]
Tarín JJ, Hamatani T, Cano A (2010) Acute stress may induce ovulation in women. Reprod Biol Endocrinol 8: 53.
[65]
Skowera A, Hotopf M, Sawicka E, Varela-Calvino R, Unwin C, et al. (2004) Cellular Immune Activation in Gulf War Veterans. J Clin Immunol 24: 66–73.
[66]
Whistler T, Fletcher MA, Lonergan W, Zeng XR, Lin JM, et al. (2009) Impaired immune function in Gulf War Illness. BMC Medical Genomics 2: 12.
[67]
Doyle P, Maconochie N, Ryan M (2006) Reproductive health of Gulf War veterans. Philos Trans R Soc Lond B Biol Sci 361: 571–584.
[68]
Papadopoulos AS, Cleare AJ (2012) Hypothalamic–pituitary–adrenal axis dysfunction in chronic fatigue syndrome. Nat Rev Endocrinol 8: 22–32.
[69]
Jerjes WK, Peters TJ, Taylor NF, Wood PJ, Wessely S, et al. (2006) Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome. Psychosom Res 60: 145–153.
[70]
Cleare AJ (2003) The neuroendocrinology of chronic fatigue syndrome. Endocr Rev 24: 236–252.
[71]
Brenu EW, van Driel ML, Staines DR, Ashton KJ, Ramos SB, et al. (2011) Immunological abnormalities as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med 9: 81.
[72]
Nakamura T, Schwander SK, Donnelly R, Ortega F, Togo F, et al. (2010) Cytokines across the night in chronic fatigue syndrome with and without fibromyalgia. Clin Vacc Immunol 17(4): 582–587.
[73]
Natelson BH, Weaver SA, Tseng CL, Ottenweller JE (2005) Spinal fluid abnormalities in patients with chronic fatigue syndrome. Clin Diagnost Lab Immunol 12(1): 52–55.
[74]
Nacul LC, Lacerda EM, Pheby D, Campion P, Molokhia M, et al. (2011) Prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in primary care. BMC Med 9: 91.
[75]
Evengard B, Jacks A, Pedersen N, Sullivan PF (2005) The epidemiology of chronic fatigue in the Swedish Twin Registry. Psych Med 35: 1317–1326.
[76]
Gallagher AM, Thomas JM, Hamilton WT, White PD (2004) Incidence of fatigue symptoms and diagnoses presenting in UK family care from 1990 to 2001. J Roy Soc Med 97: 571–575.
[77]
Reyes M, Nisenbaum R, Hoaglin D, Unger ER, Emmons C, et al. (2003) Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med 163: 1530–1536.
[78]
Lindal E, Stefansson JG, Bergmann S (2002) The prevalence of chronic fatigue syndrome in Iceland—a national comparison by gender drawing on four different criteria . Nord J Psychiatry 56: 273-277. Erratum in: Lindal E, Stefansson JG, Bergmann S (2006) Nord J Psychiatry. 60: 183.
[79]
Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, et al. (1999) A community-based study of chronic fatigue syndrome. Arch Intern Med 159: 2129–2137.
[80]
Boneva RS, Maloney EM, Lin JM, Jones JF, Wieser F, et al. (2011) Gynecological History in Chronic Fatigue Syndrome: A Population-Based Case-Control Study. J Womens Health 20: 21–28.
[81]
Schacterle RS, Komaroff AL (2004) A comparison of pregnancies that occur before and after the onset of chronic fatigue syndrome. Arch Intern Med 164: 401–404.
[82]
Gangestad SW, Caldwell Hooper AE, Eaton MA (2012) On the function of placental corticotropin-releasing hormone: a role in maternal-fetal conflicts over blood glucose concentrations. Biol Rev Camb Philos Soc 87: 856–873.
[83]
Torpy DJ, Ho JT (2007) Corticosteroid-binding globulin gene polymorphisms: clinical implications and links to idiopathic chronic fatigue disorders. Clin Endocrinol (Oxf) 67: 161–167.
[84]
Gagliardi L, Ho JT, Torpy DJ (2010) Corticosteroid-binding globulin: the clinical significance of altered levels and heritable mutations. Mol Cell Endocrinol 316: 24–34.
[85]
Frankenstein Z, Alon U, Cohen IR (2006) The immune-body cytokine network defines a social architecture of cell interactions. Biol Direct 1: 32.
[86]
Kin NW, Sanders VM (2006) It takes nerve to tell T and B cells what to do. J Leukocy Biol 79: 1093–1104.
[87]
Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (2000) The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System. Pharmacol Rev 52: 595–638.
[88]
Kawashima K, Fujii T (2003) The lymphocytic cholinergic system and its contribution to the regulation of immune activity. Life Sci 74: 675–696.
[89]
Wheway J, Mackay CR, Newton RA, Sainsbury A, Boey D, et al. (2005) A fundamental bimodal role for neuropeptide Y1 receptor in the immune system. J Exp Med 202: 1527–1538.
[90]
Fletcher MA, Rosenthal M, Antoni M, Ironson G, Zeng XR, et al. (2010) Plasma neuropeptide Y: a biomarker for symptom severity in chronic fatigue syndrome. Behav Brain Funct. 6: 76.
[91]
Broderick G, Fletcher MA, Gallgher M, Barnes Z, Vernon SD, et al.. (2012) Exploring the Predictive Potential of Immune Response to Exercise in Gulf War Illness. In: Yan Q. (Ed.), Psychoneuroimmunology: Methods and Protocols (Methods in Molecular Biology), Springer, New York, NY, In Press.
