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

Francisco J Carrera Arias,Lindsay T Michalovicz,Maria Abreu,Travis J A Craddock,James P O’Callaghan,Kimberly A Kelly,Nancy Klimas,Mary A Holschbach,Kristina Aenlle

doi:10.3390/ijms22168546

Abstract

Gulf War Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain communicate through several signaling pathways, including the hypothalamic–pituitary–adrenal (HPA) axis, it underlies many of the behavioral and physiological responses to stressors via blood-borne mediators, such as cytokines, chemokines, and hormones. Signaling by these molecules is mediated by the semipermeable blood–brain barrier (BBB) made up of a monocellular layer forming an integral part of the neuroimmune axis. BBB permeability can be altered and even diminished by both external factors (e.g., chemical agents) and internal conditions (e.g., acute or chronic stress, or cross-signaling from the hypothalamic–pituitary–gonadal (HPG) axis). Such a complex network of regulatory interactions that possess feed-forward and feedback connections can have multiple response dynamics that may include several stable homeostatic states beyond normal health. Here we compare immune and hormone measures in the blood of human clinical samples and mouse models of Gulf War Illness (GWI) subtyped by exposure to traumatic stress for subtyping this complex illness. We do this via constructing a detailed logic model of HPA–HPG–Immune regulatory behavior that also considers signaling pathways across the BBB to neuronal–glial interactions within the brain. We apply conditional interactions to model the effects of changes in BBB permeability. Several stable states are identified in the system beyond typical health. Following alignment of the human and mouse blood profiles in the context of the model, mouse brain sample measures were used to infer the neuroinflammatory state in human GWI and perform treatment simulations using a genetic algorithm to optimize the Monte Carlo simulations of the putative treatment strategies aimed at returning the ill system back to health. We identify several ideal multi-intervention strategies and potential drug candidates that may be used to treat chronic neuroinflammation in GWI.

Highlights

Gulf War Illness (GWI) is a chronic disorder that affects up to one-third of the700,000 veterans of the Persian Gulf War of 1991
As there is a substantial overlap of post-traumatic stress disorder (PTSD) symptoms with the symptoms defining GWI [20], with both PTSD [21,22,23,24] and GWI [6,25,26] exhibiting immunological dysfunction and abnormal neural synchrony [14], this suggests that GWI and PTSD share several core pathophysiological processes and that these processes may be altered in the context of co-morbidity
We propose to build on our ongoing research directed at mapping complex inflammatory mechanisms in GWI to improve our understanding of the immunologic underpinnings of GWI, the compounding effects of co-morbidity with PTSD, and the potential of this comorbidity to define a unique subtype of GWI

Summary

Introduction

Gulf War Illness (GWI) is a chronic disorder that affects up to one-third of the700,000 veterans of the Persian Gulf War of 1991. Gulf War Illness (GWI) is a chronic disorder that affects up to one-third of the. Many symptoms of GWI, including fatigue, musculoskeletal pain, cognitive, and neurological problems [1], are indicative of a neuroinflammatory disorder, and abnormal regulation of the hypothalamic–pituitary–. Possible explanations for the cause of GWI include exposure to mild traumatic brain injury and chemical/biological weapons [7] as well as the involvement of a neuroinflammatory signaling cascade triggered by exposure to a neurotoxin (e.g., the organophosphate sarin) and exposure to a combat environment [8,9,10]. Veterans suffering from GWI are often diagnosed with post-traumatic stress disorder (PTSD) [16,17]. A population-based study estimates that 35% of veterans with GWI suffer from PTSD [18], which exacerbates all the overall clinical symptoms of GWI [19]. The presence or absence of PTSD in GWI provides one mean to subtype this illness

Methods

Discussion

Conclusion