Special Issue "Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness"

A special issue of Brain Sciences (ISSN 2076-3425).

Deadline for manuscript submissions: closed (5 March 2021).

Special Issue Editors

Dr. James O'Callaghan
E-Mail Website
Guest Editor
Centers for Disease Control and Prevention, Morgantown, WV 26505, USA
Interests: glia; neurotoxicity; neuroinflammation
Special Issues and Collections in MDPI journals
Dr. Kimberly Sullivan
E-Mail Website
Guest Editor
Department of Environmental Health, School of Public Health, Boston University, Boston, MA 02118, USA
Interests: gulf War Illness; pesticides; environmental health; neurotoxicology; behavioral neuroscience; neuropsychology
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Gulf War Illness (GWI) is a chronic debilitating disorder found in 1991 Gulf War veterans that is characterized by a constellation of symptoms, including cognitive decrements, debilitating fatigue, chronic pain, and gastrointestinal, respiratory, and skin problems. Research to date suggests that GWI resulted from the many neurotoxicant exposures veterans experienced during their deployment, including to nerve agents (sarin/cyclosarin), pesticides, prophylactic medications, as well as to mild traumatic brain injuries (mTBI) and/or physical stressors. There is mounting evidence that veterans with GWI show neuroinflammatory and oxidative stress markers related to chronic aberrant glial activation loops (microglia and astrocytes) and signaling of proinflammatory cytokines/chemokines in the brain and throughout the affected body systems. What is less clear is why some similarly exposed veterans have suffered with chronic GWI symptoms and others have not. This suggests potential priming from multiple insults to the central nervous system and/or particular genetic/epigenetic susceptibility may be present in some GW veterans. This Special Issue will focus on obtaining submissions related to GWI mechanisms (blood biomarkers, brain imaging, cognitive outcomes, gut–brain axis), disease susceptibility, and neurotoxicological outcomes in GW veterans and/or GW-relevant animal models. Genetic markers, biomarkers of exposure and disease as well as treatment development studies are welcome.

Dr. James O'Callaghan
Dr. Kimberly Sullivan
Guest Editors

Manuscript Submission Information

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Keywords

  • Gulf War Illness
  • Neurotoxicology
  • Genetic Susceptibility
  • Neuroinflammation

Published Papers (6 papers)

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Research

Open AccessArticle
Sex-Based Differences in Plasma Autoantibodies to Central Nervous System Proteins in Gulf War Veterans versus Healthy and Symptomatic Controls
Brain Sci. 2021, 11(2), 148; https://doi.org/10.3390/brainsci11020148 - 23 Jan 2021
Viewed by 1114
Abstract
Veterans from the 1991 Gulf War (GW) have suffered from Gulf War illness (GWI) for nearly 30 years. This illness encompasses multiple body systems, including the central nervous system (CNS). Diagnosis and treatment of GWI is difficult because there has not been an [...] Read more.
Veterans from the 1991 Gulf War (GW) have suffered from Gulf War illness (GWI) for nearly 30 years. This illness encompasses multiple body systems, including the central nervous system (CNS). Diagnosis and treatment of GWI is difficult because there has not been an objective diagnostic biomarker. Recently, we reported on a newly developed blood biomarker that discriminates GWI from GW healthy controls, and symptomatic controls with irritable bowel syndrome (IBS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The present study was designed to compare levels of these biomarkers between men and women with GWI, as well as sex-specific effects in comparison to healthy GW veterans and symptomatic controls (IBS, ME/CFS). The results showed that men and women with GWI differ in 2 of 10 plasma autoantibodies, with men showing significantly elevated levels. Men and women with GWI showed significantly different levels of autoantibodies in 8 of 10 biomarkers to neuronal and glial proteins in plasma relative to controls. In summary, the present study addressed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among both men and women veterans with GWI and other healthy and symptomatic control groups. Full article
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Open AccessFeature PaperArticle
Neuroimaging Markers for Studying Gulf-War Illness: Single-Subject Level Analytical Method Based on Machine Learning
Brain Sci. 2020, 10(11), 884; https://doi.org/10.3390/brainsci10110884 - 20 Nov 2020
Viewed by 1460
Abstract
Gulf War illness (GWI) refers to the multitude of chronic health symptoms, spanning from fatigue, musculoskeletal pain, and neurological complaints to respiratory, gastrointestinal, and dermatologic symptoms experienced by about 250,000 GW veterans who served in the 1991 Gulf War (GW). Longitudinal studies showed [...] Read more.
Gulf War illness (GWI) refers to the multitude of chronic health symptoms, spanning from fatigue, musculoskeletal pain, and neurological complaints to respiratory, gastrointestinal, and dermatologic symptoms experienced by about 250,000 GW veterans who served in the 1991 Gulf War (GW). Longitudinal studies showed that the severity of these symptoms often remain unchanged even years after the GW, and these veterans with GWI continue to have poorer general health and increased chronic medical conditions than their non-deployed counterparts. For better management and treatment of this condition, there is an urgent need for developing objective biomarkers that can help with simple and accurate diagnosis of GWI. In this study, we applied multiple neuroimaging techniques, including T1-weighted magnetic resonance imaging (T1W-MRI), diffusion tensor imaging (DTI), and novel neurite density imaging (NDI) to perform both a group-level statistical comparison and a single-subject level machine learning (ML) analysis to identify diagnostic imaging features of GWI. Our results supported NDI as the most sensitive in defining GWI characteristics. In particular, our classifier trained with white matter NDI features achieved an accuracy of 90% and F-score of 0.941 for classifying GWI cases from controls after the cross-validation. These results are consistent with our previous study which suggests that NDI measures are sensitive to the microstructural and macrostructural changes in the brain of veterans with GWI, which can be valuable for designing better diagnosis method and treatment efficacy studies. Full article
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Open AccessFeature PaperArticle
Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls
Brain Sci. 2020, 10(9), 610; https://doi.org/10.3390/brainsci10090610 - 05 Sep 2020
Cited by 1 | Viewed by 2908
Abstract
For the past 30 years, there has been a lack of objective tools for diagnosing Gulf War Illness (GWI), which is largely characterized by central nervous system (CNS) symptoms emerging from 1991 Gulf War (GW) veterans. In a recent preliminary study, we reported [...] Read more.
For the past 30 years, there has been a lack of objective tools for diagnosing Gulf War Illness (GWI), which is largely characterized by central nervous system (CNS) symptoms emerging from 1991 Gulf War (GW) veterans. In a recent preliminary study, we reported the presence of autoantibodies against CNS proteins in the blood of veterans with GWI, suggesting a potential objective biomarker for the disorder. Now, we report the results of a larger, confirmatory study of these objective biomarkers in 171 veterans with GWI compared to 60 healthy GW veteran controls and 85 symptomatic civilian controls (n = 50 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and n = 35 irritable bowel syndrome (IBS)). Specifically, we compared plasma markers of CNS autoantibodies for diagnostic characteristics of the four groups (GWI, GW controls, ME/CFS, IBS). For veterans with GWI, the results showed statistically increased levels of nine of the ten autoantibodies against neuronal “tubulin, neurofilament protein (NFP), Microtubule Associated Protein-2 (MAP-2), Microtubule Associated Protein-Tau (Tau), alpha synuclein (α-syn), calcium calmodulin kinase II (CaMKII)” and glial proteins “Glial Fibrillary Acidic Protein (GFAP), Myelin Associated Glycoprotein (MAG), Myelin Basic Protein (MBP), S100B” compared to healthy GW controls as well as civilians with ME/CFS and IBS. Next, we summed all of the means of the CNS autoantibodies for each group into a new index score called the Neurodegeneration Index (NDI). The NDI was calculated for each tested group and showed veterans with GWI had statistically significantly higher NDI values than all three control groups. The present study confirmed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among veterans with GWI and other healthy and symptomatic control groups. Full article
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Open AccessArticle
TLR Antagonism by Sparstolonin B Alters Microbial Signature and Modulates Gastrointestinal and Neuronal Inflammation in Gulf War Illness Preclinical Model
Brain Sci. 2020, 10(8), 532; https://doi.org/10.3390/brainsci10080532 - 08 Aug 2020
Cited by 1 | Viewed by 1428
Abstract
The 1991 Persian Gulf War veterans presented a myriad of symptoms that ranged from chronic pain, fatigue, gastrointestinal disturbances, and cognitive deficits. Currently, no therapeutic regimen exists to treat the plethora of chronic symptoms though newer pharmacological targets such as microbiome have been [...] Read more.
The 1991 Persian Gulf War veterans presented a myriad of symptoms that ranged from chronic pain, fatigue, gastrointestinal disturbances, and cognitive deficits. Currently, no therapeutic regimen exists to treat the plethora of chronic symptoms though newer pharmacological targets such as microbiome have been identified recently. Toll-like receptor 4 (TLR4) antagonism in systemic inflammatory diseases have been tried before with limited success, but strategies with broad-spectrum TLR4 antagonists and their ability to modulate the host-microbiome have been elusive. Using a mouse model of Gulf War Illness, we show that a nutraceutical, derived from a Chinese herb Sparstolonin B (SsnB) presented a unique microbiome signature with an increased abundance of butyrogenic bacteria. SsnB administration restored a normal tight junction protein profile with an increase in Occludin and a parallel decrease in Claudin 2 and inflammatory mediators high mobility group box 1 (HMGB1), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the distal intestine. SsnB also decreased neuronal inflammation by decreasing IL-1β and HMGB1, while increasing brain-derived neurotrophic factor (BDNF), with a parallel decrease in astrocyte activation in vitro. Mechanistically, SsnB inhibited the binding of HMGB1 and myeloid differentiation primary response protein (MyD88) to TLR4 in the intestine, thus attenuating TLR4 downstream signaling. Studies also showed that SsnB was effective in suppressing TLR4-induced nod-like receptor protein 3 (NLRP3) inflammasome activation, a prominent inflammatory disease pathway. SsnB significantly decreased astrocyte activation by decreasing colocalization of glial fibrillary acid protein (GFAP) and S100 calcium-binding protein B (S100B), a crucial event in neuronal inflammation. Inactivation of SsnB by treating the parent molecule by acetate reversed the deactivation of NLRP3 inflammasome and astrocytes in vitro, suggesting that SsnB molecular motifs may be responsible for its anti-inflammatory activity. Full article
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Open AccessArticle
Logistic Regression Algorithm Differentiates Gulf War Illness (GWI) Functional Magnetic Resonance Imaging (fMRI) Data from a Sedentary Control
Brain Sci. 2020, 10(5), 319; https://doi.org/10.3390/brainsci10050319 - 25 May 2020
Cited by 2 | Viewed by 1686
Abstract
Gulf War Illness (GWI) is a debilitating condition characterized by dysfunction of cognition, pain, fatigue, sleep, and diverse somatic symptoms with no known underlying pathology. As such, uncovering objective biomarkers such as differential regions of activity within a Functional Magnetic Resonance Imaging (fMRI) [...] Read more.
Gulf War Illness (GWI) is a debilitating condition characterized by dysfunction of cognition, pain, fatigue, sleep, and diverse somatic symptoms with no known underlying pathology. As such, uncovering objective biomarkers such as differential regions of activity within a Functional Magnetic Resonance Imaging (fMRI) scan is important to enhance validity of the criteria for diagnosis. Symptoms are exacerbated by mild activity, and exertional exhaustion is a key complaint amongst sufferers. We modeled this exertional exhaustion by having GWI (n = 80) and sedentary control (n = 31) subjects perform submaximal exercise stress tests on two consecutive days. Cognitive differences were assessed by comparing fMRI scans performed during 2-Back working memory tasks before and after the exercise. Machine learning algorithms were used to identify differences in brain activation patterns between the two groups on Day 1 (before exercise) and Day 2 (after exercise). The numbers of voxels with t > 3.17 (corresponding to p < 0.001 uncorrected) were determined for brain regions defined by the Automated Anatomical Labeling (AAL) atlas. Data were divided 70:30 into training and test sets. Recursive feature selection identified twenty-nine regions of interest (ROIs) that significantly distinguished GWI from control on Day 1 and 28 ROIs on Day 2. Ten regions were present in both models between the two days, including right anterior insula, orbital frontal cortex, thalamus, bilateral temporal poles, and left supramarginal gyrus and cerebellar Crus 1. The models had 70% accuracy before exercise on Day 1 and 85% accuracy after exercise on Day 2, indicating the logistic regression model significantly differentiated subjects with GWI from the sedentary control group. Exercise caused changes in these patterns that may indicate the cognitive differences caused by exertional exhaustion. A second set of predictive models was able to classify previously identified GWI exercise subgroups START, STOPP, and POTS for both Days 1 and Days 2 with 67% and 69% accuracy respectively. This study was the first of its kind to differentiate GWI and the three sub-phenotypes START, STOPP, and POTS from a sedentary control using a logistic regression estimation method. Full article
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Open AccessFeature PaperArticle
Modeling the Genetic Basis of Individual Differences in Susceptibility to Gulf War Illness
Brain Sci. 2020, 10(3), 143; https://doi.org/10.3390/brainsci10030143 - 02 Mar 2020
Cited by 2 | Viewed by 1175
Abstract
Between 25% and 30% of the nearly one million military personnel who participated in the 1991 Persian Gulf War became ill with chronic symptoms ranging from gastrointestinal to nervous system dysfunction. This disorder is now referred to as Gulf War Illness (GWI) and [...] Read more.
Between 25% and 30% of the nearly one million military personnel who participated in the 1991 Persian Gulf War became ill with chronic symptoms ranging from gastrointestinal to nervous system dysfunction. This disorder is now referred to as Gulf War Illness (GWI) and the underlying pathophysiology has been linked to exposure-based neuroinflammation caused by organophosphorous (OP) compounds coupled with high circulating glucocorticoids. In a mouse model of GWI we developed, corticosterone was shown to act synergistically with an OP (diisopropylflurophosphate) to dramatically increase proinflammatory cytokine gene expression in the brain. Because not all Gulf War participants became sick, the question arises as to whether differential genetic constitution might underlie individual differences in susceptibility. To address this question of genetic liability, we tested the impact of OP and glucocorticoid exposure in a genetic reference population of 30 inbred mouse strains. We also studied both sexes. The results showed wide differences among strains and overall that females were less sensitive to the combined treatment than males. Furthermore, we identified one OP-glucocorticoid locus and nominated a candidate gene—Spon1—that may underlie the marked differences in response. Full article
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