Source: PlosOne, 8 January 2014
A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and Chronic Fatigue Syndrome
Travis J. A. Craddock(1,2,3,*), Paul Fritsch(4), Mark A. Rice Jr(3), Ryan M. del Rosario(3), Diane B. Miller(5), Mary Ann Fletcher(6), Nancy G. Klimas(3,7), Gordon Broderick(1,3,5,8)
1) Center for Psychological Studies, Nova Southeastern University, Fort Lauderdale, Florida, United States of America
2) Graduate School for Computer and Information Sciences, Nova Southeastern University Fort Lauderdale, Florida, United States of America
3) Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States of America
4) Department of Medicine, Faculty of Dentistry and Medicine, University of Alberta, Edmonton, Alberta, Canada
5) Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia, United States of America
6) Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
7) College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States of America
8) College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida, United States of America
* E-mail firstname.lastname@example.org
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.
From PlosOne, 15 January 2013
Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome
Madlen Loebel(1*), Kristin Strohschein(1,2), Carolin Giannini(1), Uwe Koelsch(3), Sandra Bauer(1), Cornelia Doebis(4), Sybill Thomas(1), Nadine Unterwalder(3), Volker von Baehr(4), Petra Reinke(5,6),
Michael Knops(1), Leif G. Hanitsch(1), Christian Meisel(1,3), Hans-Dieter Volk(1,5), Carmen Scheibenbogen(1,5)
1) Institute for Medical Immunology, Charite ́ University Medicine Berlin, Campus Virchow, Berlin, Germany
2) Julius Wolff Institute, Charite ́ University Medicine Berlin, Campus Virchow, Berlin, Germany
3) Labor Berlin GmbH, Immunology Department, Charite ́ University Medicine Berlin, Campus Virchow, Berlin, Germany
4) Institute for Medical Diagnostics, Berlin, Germany, 5Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charite ́ University Medicine Berlin, Germany, 6Department Nephrology, Charite ́ University Medicine Berlin, Germany
* E-mail: Madlen.email@example.com
Epstein-Barr virus (EBV) has long been discussed as a possible causeor trigger of Chronic Fatigue Syndrome (CFS). In a subset of patients the disease starts with infectious mononucleosis and both enhanced and diminished EBV-specific antibody titers have been reported.
In this study, we comprehensively analyzed the EBV-specific memory B- and T-cell response in patients with CFS. While we observed no difference in viral capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG titers were low or absent in 10% of CFS patients.
Remarkably, when analyzing the EBV-specific memory B-cell reservoir in vitro a diminished or absent number of EBNA-1- and VCA-antibody secreting cells was found in up to 76% of patients. Moreover, the ex vivo EBV-induced secretion of TNF-α and IFN-γ was significantly lower in patients.
Multicolor flow cytometry revealed that the frequencies of EBNA-1-specific triple TNF-α/IFN-γ/IL-2 producing CD4+ and CD8+ T-cell subsets were significantly diminished whereas no difference could be detected for HCMV-specific T-cell responses.
When comparing EBV load in blood immune cells, we found more frequently EBER-DNA but not BZLF-1 RNA in CFS patients compared to healthy controls suggesting more frequent latent replication. Taken together, our findings give evidence for a deficient EBV-specific B- and T-cell memory response in CFS patients and suggest an impaired ability to control early steps of EBV reactivation.
In addition the diminished EBV response might be suitable to develop diagnostic marker in CFS.