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

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A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Molecular and Cellular Neuroscience".

Deadline for manuscript submissions: closed (20 December 2021) | Viewed by 24209

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Special Issue Editors

Dr. James O'Callaghan

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Guest Editor

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

Special Issue Information

Dear Colleagues,

After the success of our first Special Issue on Gulf War Illness, we are pleased to announce a second Special Issue titled, "Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness – Series II ). Gulf War illness (GWI) is a chronic debilitating disorder discovered 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 that veterans experienced during their deployment, including that to nerve agents (sarin/cyclosarin), pesticides, and prophylactic medications, as well as 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 the 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 that particular genetic/epigenetic susceptibility may be present in some GW veterans. This second Special Issue will focus on obtaining cutting edge research submissions related to GWI mechanisms (blood biomarkers, brain imaging, cognitive outcomes, and the gut–brain axis), disease susceptibility, and neurotoxicological outcomes in GW veterans and/or GW-relevant animal models. Genetic markers and biomarkers of exposure and disease as well as treatment development studies are also welcome.

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

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Keywords

Gulf War Illness
Neurotoxicology
Genetic Susceptibility
Neuroinflammation

Published Papers (7 papers)

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Editorial

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2 pages, 173 KiB

Open AccessEditorial

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

by Kimberly Sullivan and James P. O’Callaghan

Brain Sci. 2022, 12(8), 1068; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12081068 - 12 Aug 2022

Viewed by 2032

Abstract

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting as many as 30% of veterans of the 1991 Gulf War [...] Full article

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

Research

Jump to: Editorial

12 pages, 232 KiB

Open AccessArticle

Association of Gulf War Illness-Related Symptoms with Military Exposures among 1990–1991 Gulf War Veterans Evaluated at the War-Related Illness and Injury Study Center (WRIISC)

by Sarah T. Ahmed, Lea Steele, Peter Richardson, Shree Nadkarni, Sandhya Bandi, Mazhgan Rowneki, Kellie J. Sims, Jacqueline Vahey, Elizabeth J. Gifford, Stephen H. Boyle, Theresa H. Nguyen, Alice Nono Djotsa, Donna L. White, Elizabeth R. Hauser, Helena Chandler, Jose-Miguel Yamal and Drew A. Helmer

Brain Sci. 2022, 12(3), 321; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12030321 - 27 Feb 2022

Cited by 6 | Viewed by 2861

Abstract

Veterans with difficult-to-diagnose conditions who receive care in the Department of Veterans Affairs (VA) healthcare system can be referred for evaluation at one of three specialty VA War-Related Illness and Injury Study Centers (WRIISC). Veterans of the 1990–1991 Gulf War have long experienced excess rates of chronic symptoms associated with the condition known as Gulf War Illness (GWI), with hundreds evaluated at the WRIISC. Here we provide the first report from a cohort of 608 Gulf War Veterans seen at the WRIISC who completed questionnaires on chronic symptoms (>6 months) consistent with GWI as well as prominent exposures during Gulf War deployment. These included veterans’ reports of hearing chemical alarms/donning Military-Ordered Protective Posture Level 4 (MOPP4) gear, pesticide use, and use of pyridostigmine bromide (PB) pills as prophylaxis against the effects of nerve agents. Overall, veterans in the cohort were highly symptomatic and reported a high degree of exposures. In multivariable models, these exposures were significantly associated with moderate-to-severe chronic symptoms in neurocognitive/mood, fatigue/sleep, and pain domains. Specifically, exposure to pesticides was associated with problems with concentration and memory, problems sleeping, unrefreshing sleep, and joint pain. Use of MOPP4 was associated with light sensitivity and unrefreshing sleep and use of PB was associated with depression. We also evaluated the association of exposures with symptom summary scores based on veterans’ severity of symptoms in four domains and overall. In multivariable modeling, the pain symptom severity score was significantly associated with pesticide use (Odds ratio (OR): 4.13, 95% confidence intervals (CI): 1.78–9.57) and taking PB pills (OR: 2.28, 95% CI: 1.02–5.09), and overall symptom severity was significantly associated with use of PB pills (OR: 2.41, 95% CI: 1.01–5.75). Conclusion: Decades after deployment, Gulf War veterans referred to a VA tertiary evaluation center report a high burden of chronic symptoms, many of which were associated with reported neurotoxicant exposures during the war. Full article

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

23 pages, 15089 KiB

Open AccessFeature PaperArticle

Gene–Toxicant Interactions in Gulf War Illness: Differential Effects of the PON1 Genotype

by Jacqueline Vahey, Elizabeth J. Gifford, Kellie J. Sims, Blair Chesnut, Stephen H. Boyle, Crystal Stafford, Julie Upchurch, Annjanette Stone, Saiju Pyarajan, Jimmy T. Efird, Christina D. Williams and Elizabeth R. Hauser

Brain Sci. 2021, 11(12), 1558; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11121558 - 25 Nov 2021

Cited by 5 | Viewed by 2512

Abstract

About 25–35% of United States veterans who fought in the 1990–1991 Gulf War report several moderate or severe chronic systemic symptoms, defined as Gulf War illness (GWI). Thirty years later, there is little consensus on the causes or biological underpinnings of GWI. The Gulf War Era Cohort and Biorepository (GWECB) was designed to investigate genetic and environmental associations with GWI and consists of 1343 veterans. We investigate candidate gene–toxicant interactions that may be associated with GWI based on prior associations found in human and animal model studies, focusing on SNPs in or near ACHE, BCHE, and PON1 genes to replicate results from prior studies. SOD1 was also considered as a candidate gene. CDC Severe GWI, the primary outcome, was observed in 26% of the 810 deployed veterans included in this study. The interaction between the candidate SNP rs662 and pyridostigmine bromide (PB) pills was found to be associated with CDC Severe GWI. Interactions between PB pill exposure and rs3917545, rs3917550, and rs2299255, all in high linkage disequilibrium in PON1, were also associated with respiratory symptoms. These SNPs could point toward biological pathways through which GWI may develop, which could lead to biomarkers to detect GWI or to better treatment options for veterans with GWI. Full article

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

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7 pages, 408 KiB

Open AccessCommunication

Associations of Immune Genetic Variability with Gulf War Illness in 1990–1991 Gulf War Veterans from the Gulf War Illness Consortium (GWIC) Multisite Case-Control Study

by Janet K. Coller, Jonathan Tuke, Taylor J. Wain, Emily Quinn, Lea Steele, Maria Abreu, Kristina Aenlle, Nancy Klimas and Kimberly Sullivan

Brain Sci. 2021, 11(11), 1410; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11111410 - 26 Oct 2021

Cited by 3 | Viewed by 2371

Abstract

Gulf War illness (GWI) encompasses a constellation of persistent debilitating symptoms associated with significant changes in central nervous system (CNS) and immune functioning. Currently, there is no validated biomarker for GWI risk susceptibility. Given the impact of immune responses linked to GWI symptomology, genetic variability that causes persistent inflammatory/immune alterations may be key. This Boston University-based Gulf War Illness Consortium (GWIC) study investigated the impact of single nucleotide polymorphisms (SNPs) in variants of immune and pain genetic markers IL1B, IL2, IL6, IL6R, IL10, TNF, TGF, TLR2, TLR4, MD2, MYD88, BDNF, CRP, ICE, COMT and OPRM1 on GWI occurrence in a Caucasian subset of Gulf War (GW) veterans with (cases, n = 170) and without (controls, n = 34) GWI. Logistic regression modeling created a prediction model of GWI risk that associated genetic variability in TGF (rs1800469, p = 0.009), IL6R (rs8192284, p = 0.004) and TLR4 (rs4986791, p = 0.013) with GWI occurrence. This prediction model was specific and sensitive, with a receiver operator characteristic area under the curve of 71.4%. This is the first report of immune genetic variability being predictive of GWI and warrants validation in larger independent cohorts. Future reports will present interactions of these genetic risk factors with other characteristics of GW service. Full article

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

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13 pages, 495 KiB

Open AccessArticle

The Department of Veterans Affairs Gulf War Veterans’ Illnesses Biorepository: Supporting Research on Gulf War Veterans’ Illnesses

by Christopher B. Brady, Ian Robey, Thor D. Stein, Bertrand R. Huber, Jessica Riley, Nazifa Abdul Rauf, Keith R. Spencer, Gabriel Walt, Latease Adams, James G. Averill, Sean Walker, Ann C. McKee, Stephen P. Thomson and Neil W. Kowall

Brain Sci. 2021, 11(10), 1349; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11101349 - 14 Oct 2021

Cited by 2 | Viewed by 2612

Abstract

Aims: To introduce a resource supporting research on Gulf War illness (GWI) and related disorders, the Gulf War Veterans’ Illnesses Biorepository (GWVIB). Methods: Gulf War era veterans (GWVs) are recruited nationally and enrolled via telephone and email/postal mail. Enrolled veterans receive annual telephone and mail follow-up to collect health data until their passing. A postmortem neuropathological examination is performed, and fixed and frozen brain and spinal cord samples are banked to support research. Investigators studying GWI and related disorders may request tissue and data from the GWVIB. Results: As of September 2021, 127 GWVs from 39 states were enrolled; 60 met the criteria for GWI, and 14 met the criteria for chronic multisymptom illness (CMI). Enrollees have been followed up to six years. Postmortem tissue recoveries were performed on 14 GWVs. The most commonly found neuropathologies included amyotrophic lateral sclerosis, chronic traumatic encephalopathy, and Lewy body disease. Tissue was of good quality with an average RNA integrity number of 5.8 (SD = 1.0) and ≥4.8 in all of the cases. Discussion: The availability of health data and high-quality CNS tissue from this well-characterized GWV cohort will support research on GWI and related disorders affecting GWVs. Enrollment is ongoing. Full article

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

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17 pages, 290 KiB

Open AccessArticle

Brain–Immune Interactions as the Basis of Gulf War Illness: Clinical Assessment and Deployment Profile of 1990–1991 Gulf War Veterans in the Gulf War Illness Consortium (GWIC) Multisite Case-Control Study

by Lea Steele, Nancy Klimas, Maxine Krengel, Emily Quinn, Rosemary Toomey, Deborah Little, Maria Abreu, Kristina Aenlle, Ronald Killiany, Bang-Bon Koo, Patricia Janulewicz, Timothy Heeren, Allison N. Clark, Joy Ajama, Joanna Cirillo, Gerardo Buentello, Vanesa Lerma, Janet K. Coller and Kimberly Sullivan

Brain Sci. 2021, 11(9), 1132; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11091132 - 26 Aug 2021

Cited by 15 | Viewed by 5565

Abstract

The Boston University-based Gulf War Illness Consortium (GWIC) is a multidisciplinary initiative developed to provide detailed understanding of brain and immune alterations that underlie Gulf War illness (GWI), the persistent multisymptom disorder associated with military service in the 1990–1991 Gulf War. The core GWIC case-control clinical study conducted in-depth brain and immune evaluation of 269 Gulf War veterans (223 GWI cases, 46 controls) at three U.S. sites that included clinical assessments, brain imaging, neuropsychological testing, and analyses of a broad range of immune and immunogenetic parameters. GWI cases were similar to controls on most demographic, military, and deployment characteristics although on average were two years younger, with a higher proportion of enlisted personnel vs. officers. Results of physical evaluation and routine clinical lab tests were largely normal, with few differences between GWI cases and healthy controls. However, veterans with GWI scored significantly worse than controls on standardized assessments of general health, pain, fatigue, and sleep quality and had higher rates of diagnosed conditions that included hypertension, respiratory and sinus conditions, gastrointestinal conditions, and current or lifetime depression and post-traumatic stress disorder. Among multiple deployment experiences/exposures reported by veterans, multivariable logistic regression identified just two significant GWI risk factors: extended use of skin pesticides in theater (adjusted OR = 3.25, p = 0.005) and experiencing mild traumatic brain injury during deployment (OR = 7.39, p = 0.009). Gulf War experiences associated with intense stress or trauma (e.g., participation in ground combat) were not associated with GWI. Data and samples from the GWIC project are now stored in a repository for use by GWI researchers. Future reports will present detailed findings on brain structure and function, immune function, and association of neuroimmune measures with characteristics of GWI and Gulf War service. Full article

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

28 pages, 5151 KiB

Open AccessArticle

Andrographolide Attenuates Gut-Brain-Axis Associated Pathology in Gulf War Illness by Modulating Bacteriome-Virome Associated Inflammation and Microglia-Neuron Proinflammatory Crosstalk

by Punnag Saha, Peter T. Skidmore, LaRinda A. Holland, Ayan Mondal, Dipro Bose, Ratanesh K. Seth, Kimberly Sullivan, Patricia A. Janulewicz, Ronnie Horner, Nancy Klimas, Mitzi Nagarkatti, Prakash Nagarkatti, Efrem S. Lim and Saurabh Chatterjee

Brain Sci. 2021, 11(7), 905; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11070905 - 09 Jul 2021

Cited by 12 | Viewed by 4752

Abstract

Gulf War Illness (GWI) is a chronic multi-symptomatic illness that is associated with fatigue, pain, cognitive deficits, and gastrointestinal disturbances and presents a significant challenge to treat in clinics. Our previous studies show a role of an altered Gut–Brain axis pathology in disease development and symptom persistence in GWI. The present study utilizes a mouse model of GWI to study the role of a labdane diterpenoid andrographolide (AG) to attenuate the Gut–Brain axis-linked pathology. Results showed that AG treatment in mice (100 mg/kg) via oral gavage restored bacteriome alterations, significantly increased probiotic bacteria Akkermansia, Lachnospiraceae, and Bifidobacterium, the genera that are known to aid in preserving gut and immune health. AG also corrected an altered virome with significant decreases in virome families Siphoviridae and Myoviridae known to be associated with gastrointestinal pathology. AG treatment significantly restored tight junction proteins that correlated well with decreased intestinal proinflammatory mediators IL-1β and IL-6 release. AG treatment could restore Claudin-5 levels, crucial for maintaining the BBB integrity. Notably, AG could decrease microglial activation and increase neurotrophic factor BDNF, the key to neurogenesis. Mechanistically, microglial conditioned medium generated from IL-6 stimulation with or without AG in a concentration similar to circulating levels found in the GWI mouse model and co-incubated with neuronal cells in vitro, decreased Tau phosphorylation and neuronal apoptosis. In conclusion, we show that AG treatment mitigated the Gut–Brain-Axis associated pathology in GWI and may be considered as a potential therapeutic avenue for the much-needed bench to bedside strategies in GWI. Full article

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

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