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

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A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neural Engineering, Neuroergonomics and Neurorobotics".

Deadline for manuscript submissions: closed (5 March 2021) | Viewed by 42331

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Dr. James O'Callaghan

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Centers for Disease Control and Prevention, Morgantown, WV 26505, USA
Interests: glia; neurotoxicity; neuroinflammation
Special Issues, Collections and Topics in MDPI journals

Dr. Kimberly Sullivan

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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, Collections and Topics in MDPI journals

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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

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Keywords

Gulf War Illness
Neurotoxicology
Genetic Susceptibility
Neuroinflammation

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Published Papers (7 papers)

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16 pages, 1583 KiB

Open AccessArticle

RETRACTED: Sex-Based Differences in Plasma Autoantibodies to Central Nervous System Proteins in Gulf War Veterans versus Healthy and Symptomatic Controls

by Mohamed B. Abou-Donia, Maxine H. Krengel, Elizabeth S. Lapadula, Clara G. Zundel, Jessica LeClair, Joseph Massaro, Emily Quinn, Lisa A. Conboy, Efi Kokkotou, Daniel D. Nguyen, Maria Abreu, Nancy G. Klimas and Kimberly Sullivan

Brain Sci. 2021, 11(2), 148; https://doi.org/10.3390/brainsci11020148 - 23 Jan 2021

Cited by 7 | Viewed by 6456 | Retraction

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 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

(This article belongs to the Special Issue Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness)

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13 pages, 1352 KiB

Open AccessFeature PaperArticle

Neuroimaging Markers for Studying Gulf-War Illness: Single-Subject Level Analytical Method Based on Machine Learning

by Yi Guan, Chia-Hsin Cheng, Weifan Chen, Yingqi Zhang, Sophia Koo, Maxine Krengel, Patricia Janulewicz, Rosemary Toomey, Ehwa Yang, Rafeeque Bhadelia, Lea Steele, Jae-Hun Kim, Kimberly Sullivan and Bang-Bon Koo

Brain Sci. 2020, 10(11), 884; https://doi.org/10.3390/brainsci10110884 - 20 Nov 2020

Cited by 7 | Viewed by 5560

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 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

(This article belongs to the Special Issue Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness)

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15 pages, 2258 KiB

Open AccessArticle

RETRACTED: Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls

by Mohamed B. Abou-Donia, Elizabeth S. Lapadula, Maxine H. Krengel, Emily Quinn, Jessica LeClair, Joseph Massaro, Lisa A. Conboy, Efi Kokkotou, Maria Abreu, Nancy G. Klimas, Daniel D. Nguyen and Kimberly Sullivan

Brain Sci. 2020, 10(9), 610; https://doi.org/10.3390/brainsci10090610 - 5 Sep 2020

Cited by 18 | Viewed by 11205 | Retraction

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 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

(This article belongs to the Special Issue Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness)

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22 pages, 6330 KiB

Open AccessArticle

TLR Antagonism by Sparstolonin B Alters Microbial Signature and Modulates Gastrointestinal and Neuronal Inflammation in Gulf War Illness Preclinical Model

by Dipro Bose, Ayan Mondal, Punnag Saha, Diana Kimono, Sutapa Sarkar, Ratanesh K. Seth, Patricia Janulewicz, Kimberly Sullivan, Ronnie Horner, Nancy Klimas, Mitzi Nagarkatti, Prakash Nagarkatti and Saurabh Chatterjee

Brain Sci. 2020, 10(8), 532; https://doi.org/10.3390/brainsci10080532 - 8 Aug 2020

Cited by 16 | Viewed by 5919

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 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

(This article belongs to the Special Issue Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness)

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18 pages, 4946 KiB

Open AccessArticle

Logistic Regression Algorithm Differentiates Gulf War Illness (GWI) Functional Magnetic Resonance Imaging (fMRI) Data from a Sedentary Control

by Destie Provenzano, Stuart D. Washington, Yuan J. Rao, Murray Loew and James N. Baraniuk

Brain Sci. 2020, 10(5), 319; https://doi.org/10.3390/brainsci10050319 - 25 May 2020

Cited by 5 | Viewed by 4673

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) 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

(This article belongs to the Special Issue Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness)

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14 pages, 4531 KiB

Open AccessFeature PaperArticle

Modeling the Genetic Basis of Individual Differences in Susceptibility to Gulf War Illness

by Byron C. Jones, Diane B. Miller, Lu Lu, Wenyuan Zhao, David G. Ashbrook, Fuyi Xu, Megan K. Mulligan, Robert W. Williams, Daming Zhuang, Carolina Torres-Rojas and James P. O’Callaghan

Brain Sci. 2020, 10(3), 143; https://doi.org/10.3390/brainsci10030143 - 2 Mar 2020

Cited by 7 | Viewed by 3298

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 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

(This article belongs to the Special Issue Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness)

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13 pages, 491 KiB

Open AccessStudy Protocol

Genomics of Gulf War Illness in U.S. Veterans Who Served during the 1990–1991 Persian Gulf War: Methods and Rationale for Veterans Affairs Cooperative Study #2006

by Krishnan Radhakrishnan, Elizabeth R. Hauser, Renato Polimanti, Drew A. Helmer, Dawn Provenzale, Rebecca B. McNeil, Alysia Maffucci, Rachel Quaden, Hongyu Zhao, Stacey B. Whitbourne, Kelly M. Harrington, Jacqueline Vahey, Joel Gelernter, Daniel F. Levey, Grant D. Huang, John Michael Gaziano, John Concato and Mihaela Aslan

Brain Sci. 2021, 11(7), 845; https://doi.org/10.3390/brainsci11070845 - 25 Jun 2021

Cited by 8 | Viewed by 3949

Abstract

Background: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990–1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs). Methods: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene–gene and gene–environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored. Conclusions: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses. Full article

(This article belongs to the Special Issue Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness)

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