Gulf War Illness: Is there lasting damage to the endocrine-immune circuitry?

Abstract

We reported previously that the persistence of complex immune, endocrine and neurological symptoms that afflict up to one third of veterans from the 1990-91 Gulf War might be supported by a misdirected regulatory drive. Here we use a detailed model of immune signaling in concert with an overarching circuit model of known sex and stress hormone co-regulation to explore how the failure of regulatory elements may further establish a self-perpetuating imbalance that closely resembles Gulf War Illness (GWI). Defects to the model were imparted iteratively and the stable regulatory modes supported by these altered immune-endocrine circuits were identified using repeated simulation experiments. In each case the predicted homeostatic regimes were compared to experimental data collected in male GWI (n=20 ) and matched healthy veterans (n=22 ). We found that alignment of GWI with a new homeostatic regime improved significantly when cortisol's normal anti-inflammatory activity was interrupted. Alignment improved further when this cortisol insensitivity was compounded by the loss of the normal antagonistic effects of Th1 cytokines on Th2 lymphocyte activation. Together these simulation results suggest altered glucocorticoid gene regulation compounded by possible changes in IGF-1 regulation of Th1:Th2 immune balance may be key underlying features of GWI.

Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness

“…This hypothesis is supported by the relief of chronic pain symptoms following the application of testosterone gel [83]. Therefore, while our modeling efforts indicate the potential for low testosterone in GWI [38,39,66,84], which is supported by trends in our data, there is a lack of conclusive findings in this area; thus, a more formal analysis of endocrine dysfunction in GWI accounting for confounding factors, such as age and BMI, is needed.…”

“…Following [38], to check the validity of our model, we compared stable states predicted by the latter to gene expression profiles measured experimentally in the mouse model of Gulf War Illness [51] in both brain and blood, and to blood measures using the cohort of male veterans. Brown's theoretical approximation [100] of Fisher's statistics was used as a measure of similarity between a given model-predicted state and the expression profile measured in a subset of genes corresponding to the cellular and molecular entities used in our model, as done in our previous work [38,39,66,84]. Fisher's statistics provide a meta-analysis technique to combine probabilities and obtain the overall significance of a set of p-values corresponding to independent tests of the same null hypothesis.…”

A Logic Model of Neuronal-Glial Interaction Suggests Altered Homeostatic Regulation in the Perpetuation of Neuroinflammation

“…As we expect that the continued presence of an aggravating factor (biological, chemical or physical), would result in new patterns of regulation, capturing such changes would also involve structural modifications to the computational model. While we have studied such effects in a broader model of sex hormone, stress hormone, and immune regulatory physiology (Rice et al, 2014 ) in Gulf War Illness one of the objectives here was to demonstrate that indeed no such changes to the signaling circuitry are required to support a persistent departure from normal neuro-immune regulation.…”

“…In an effort to check the validity of our model, we compared stable states predicted by the latter to gene expression profiles measured experimentally in a mouse model of Gulf War Illness (O'Callaghan et al, 2015 ). Brown's theoretical approximation (Brown, 1975 ) of Fisher's statistics was used as a measure of similarity between a given model predicted state and the expression profile measured in a subset of genes corresponding to the cellular and molecular entities used in our model, as done in our previous work (Craddock et al, 2014 , 2015 ; Fritsch et al, 2014 ; Rice et al, 2014 ). Fisher's statistics provide a meta-analysis technique to combine probabilities and obtain the overall significance of a set of p -values corresponding to independent tests of the same null hypothesis.…”

Leveraging Prior Knowledge to Recover Characteristic Immune Regulatory Motifs in Gulf War Illness

“…Affecting several of the body's principal regulatory systems (Unwin et al, 1999;Bourdette et al, 2001;Kang et al, 2003) GWI is now thought to involve a neuroinflammatory pathology arising from exposures to a range of organophosphates including pyridostigmine, DEET and sarin exacerbated by environmental stressors in theater (Amourette et al, 2009;Barbier et al, 2009;O'Callaghan and Miller, 2019). Among these, our work and the work of others suggest alterations to the hypothalamic-pituitary-adrenal (HPA) response to challenge (Golier et al, 2006(Golier et al, , 2007Rice et al, 2016;Craddock et al, 2014) and that such alterations may become persistent and stable dysregulations (Rice et al, 2016). Exercise has been used as a minimally invasive means of interrogating HPA axis response (Duclos and Tabarin, 2016), one that is especially appropriate given that a chief presenting symptom of GWI is debilitating fatigue.…”