Search Results (59)

Gulf War Illness (GWI) is a multi-symptom disorder affecting 1990–1991 Persian Gulf War veterans and is characterized by post-exertional malaise, neurological symptoms, immune deregulation, and exhaustion. Causation is not understood, and effective diagnostics and therapies have not yet been developed. In this work, we analyzed stress-related, sex-specific transcriptomic shifts in GWI subjects and healthy controls through RNA sequencing of peripheral blood mononuclear cells (PBMCs). Blood samples at baseline (T0), at maximal exertion (T1), and four hours post-exertion (T2) were analyzed. In female subjects with GWI, pathways associated with pro-inflammatory processes were found to be deregulated, and in male GWI subjects, pathways related to IL-12 signaling and lymphocytic activation were deregulated at T1 compared to T0. During recovery from stress, pathways corresponding to immune responses and microglial cell activation were altered in female GWI subjects, and apoptotic signaling changed in males with GWI. Documented sex-specific immune deregulation leads to finding better biomarkers. Targeting sex-specific transcriptomic markers of the disease could lead to new therapies for GWI. Full article

Background: Anthrax is a serious disease caused by Bacillus anthracis (B. anthracis) with a very high mortality when the spores of B. anthracis are inhaled (inhalational anthrax). Aerosolized B. anthracis spores can be used as a deadly bioweapon. Vaccination against anthrax is the only effective preventive measure and, hence, the anthrax vaccine was administered to United States (and other) troops during the 1990–91 Gulf War. However, the anthrax vaccine is not harmless, and the anthrax vaccination has been linked to the occurrence and severity of Gulf War Illness (GWI), a debilitating Chronic Multisymptom Illness (CMI). We hypothesized that this is partly due to the combination of two factors, namely (a) the cytotoxicity of the antigen (anthrax Protective Antigen, PA) contained in the vaccine, and (b) the Human Leukocyte Antigen (HLA) genotype of susceptible vaccinees, reducing their ability to make antibodies against the cytotoxic PA. Method: Here, we tested this hypothesis by determining the association between severity of GWI symptoms in 458 GW veterans and the overall strength of the binding affinity of the PA epitopes to the specific six Human Leukocyte Antigen (HLA) Class II alleles carried by each individual (two of each of the HLA-II genes: DPB1, DQB1, DRB1), responsible for initiating the process of antibody production in otherwise immunocompetent individuals, estimated in silico. Results: We found that the severity of GWI symptomatology was negatively and significantly correlated with the strength of the predicted binding affinity of PA peptides to HLA-II molecules ($r=-0.356, p<0.001)$; the stronger the overall binding affinity, the weaker the symptoms. Since the binding of a peptide to an HLA-II molecule is the first and necessary step in initiating the production of antibodies, the findings above support our hypothesis that the severity of GWI symptomatology is partly due to a lack of HLA-II protection. Conclusions: Reduced HLA protection against the toxic anthrax vaccine may underlie GWI. Full article

Gulf War Illness (GWI) is a debilitating condition marked by chronic fatigue, cognitive problems, pain, and gastrointestinal (GI) complaints in veterans who were deployed to the 1990–1991 Gulf War. Fatigue, GI complaints, and other chronic symptoms continue to persist more than 30 years post-deployment. Several potential mechanisms for the persistent illness have been identified and our prior pilot study linked an altered gut microbiome with the disorder. This study further validates and builds on our prior preliminary findings of host gut microbiome dysbiosis in veterans with GWI. Using stool samples and Multidimensional Fatigue Inventory (MFI) data from 89 GW veteran participants (63 GWI cases and 26 controls) from the Boston biorepository, recruitment, and integrative network (BBRAIN) for Gulf War Illness, we found that the host gut bacterial signature of veterans with GWI showed significantly different Bray–Curtis beta diversity than control veterans. Specifically, a higher Firmicutes to Bacteroidetes ratio, decrease in Akkermansia sp., Bacteroides thetaiotamicron, Bacteroides fragilis, and Lachnospiraceae genera and increase in Blautia, Streptococcus, Klebsiella, and Clostridium genera, that are associated with gut, immune, and brain health, were shown. Further, using MaAsLin and Boruta algorithms, Coprococcus and Eisenbergiella were identified as important predictors of GWI with an area under the curve ROC predictive value of 74.8%. Higher self-reported MFI scores in veterans with GWI were also significantly associated with an altered gut bacterial diversity and species abundance of Lachnospiraceae and Blautia. These results suggest potential therapeutic targets for veterans with GWI that target the gut microbiome and specific symptoms of the illness. Full article

Background: Deployment-related neurotoxicant exposures are implicated in the etiology of Gulf War illness (GWI), the multisymptom condition associated with military service in the 1990–1991 Gulf War (GW). A Q/R polymorphism at position 192 of the paraoxonase (PON)-1 enzyme produce PON1₁₉₂ variants with different capacities for neutralizing specific chemicals, including certain acetylcholinesterase inhibitors. Methods: We evaluated PON1₁₉₂ status and GW exposures in 295 GWI cases and 103 GW veteran controls. Multivariable logistic regression determined independent associations of GWI with GW exposures overall and in PON1₁₉₂ subgroups. Exact logistic regression explored effects of exposure combinations in PON1₁₉₂ subgroups. Results: Hearing chemical alarms (proxy for possible nerve agent exposure) was associated with GWI only among RR status veterans (OR = 8.60, p = 0.014). Deployment-related skin pesticide use was associated with GWI only among QQ (OR = 3.30, p = 0.010) and QR (OR = 4.22, p < 0.001) status veterans. Exploratory assessments indicated that chemical alarms were associated with GWI in the subgroup of RR status veterans who took pyridostigmine bromide (PB) (exact OR = 19.02, p = 0.009) but not RR veterans who did not take PB (exact OR = 0.97, p = 1.00). Similarly, skin pesticide use was associated with GWI among QQ status veterans who took PB (exact OR = 6.34, p = 0.001) but not QQ veterans who did not take PB (exact OR = 0.59, p = 0.782). Conclusion: Study results suggest a complex pattern of PON1₁₉₂ exposures and exposure–exposure interactions in the development of GWI. Full article

Gulf War Illness (GWI) is a chronic multi-symptom neurological disorder affecting veterans of the Gulf War that is commonly comorbid with depression. A secondary data analysis was conducted to examine serum homocysteine and inflammatory cytokines (IFN-γ, IL-6, IL-1β, TNF-α) as potential biomarkers of depression improvement among veterans with GWI after a one-month dietary intervention aimed at reducing excitotoxicity and increasing micronutrients. Analyses, including multiple linear and logistic regression, were conducted in R studio. Dietary adherence was estimated using a specialized excitotoxin food frequency questionnaire (FFQ), and depression was measured using the Center for Epidemiologic Studies Depression (CES-D) scale. After one month on the diet, 52% of participants reported a significant decrease in depression (p < 0.01). Greater dietary adherence (FFQ) was associated with increased likelihood of depression improvement; OR (95% CI) = 1.06 (1.01, 1.11), (p = 0.02). Reduced homocysteine was associated with depression improvement after adjusting for FFQ change (β = 2.58, p = 0.04), and serum folate and vitamin B12 were not mediators of this association. Reduction in IFN-γ was marginally associated with likelihood of depression improvement (OR (95% CI) = 1.11 (0.00, 1.42), (p = 0.06)), after adjustment for potential confounders. Findings suggest that homocysteine, and possibly IFN-γ, may serve as biomarkers for depression improvement in GWI. Larger trials are needed to replicate this work. Full article

We report on a highly significant, positive association between anthrax vaccination and occurrence of Gulf War Illness (GWI) in 111 Gulf War veterans (42 with GWI and 69 controls). GWI was diagnosed in 47.1% of vaccinated veterans but only in 17.2% of non-vaccinated veterans (Pearson χ² = 7.08, p = 0.008; odds ratio = 3.947; relative risk = 2.617), with 1.6x higher GWI symptom severity in vaccinated veterans (p = 0.007, F-test in analysis of covariance). Next, we tested the hypothesis that the susceptibility to GWI following anthrax vaccination could be due to inability to make antibodies against the anthrax protective antigen (PA), the key protein contained in the vaccine. Since the first step in initiating antibody production would be the binding of PA peptide fragments (typically 15-amino acid long [15-mer]) to peptide-binding motifs of human leukocyte antigen (HLA) Class II molecules, we assessed the binding-motif affinities of such HLA specific molecules to all linear 15-mer peptide fragments of the anthrax PA. We identified a total of 58 HLA Class II alleles carried by the veterans in our sample and found that, of those, 18 (31%) were present in the vaccinated group that did not develop GWI but were absent from the vaccinated group who developed GWI. Remarkably, in silico analyses revealed very high binding affinities of peptide-binding motifs of those 18 HLA alleles with fragments of anthrax vaccine PA, leading to the successful production of anti-PA antibodies. Conversely, the absence of these protective HLA alleles points to a reduced ability to develop antibodies against PA, thus resulting in harmful PA persistence and development of GWI. Full article

Unraveling the multisymptomatic Gulf War Illness (GWI) pathology and finding an effective cure have eluded researchers for decades. The chronic symptom persistence and limitations for studying the etiologies in mouse models that differ significantly from those in humans pose challenges for drug discovery and finding effective therapeutic regimens. The GWI exposome differs significantly in the study cohorts, and the above makes it difficult to recreate a model closely resembling the GWI symptom pathology. We have used a double engraftment strategy for reconstituting a human immune system coupled with human microbiome transfer to create a humanized-mouse model for GWI. Using whole-genome shotgun sequencing and blood immune cytokine enzyme linked immunosorbent assay (ELISA), we show that our double humanized mice treated with Gulf War (GW) chemicals show significantly altered gut microbiomes, similar to those reported in a Veteran cohort of GWI. The results also showed similar cytokine profiles, such as increased levels of IL-1β, IL-6, and TNF R-1, in the double humanized model, as found previously in a human cohort. Further, a novel GWI Veteran fecal microbiota transfer was used to create a second alternative model that closely resembled the microbiome and immune-system-associated pathology of a GWI Veteran. A GWI Veteran microbiota transplant in humanized mice showed a human microbiome reconstitution and a systemic inflammatory pathology, as reflected by increases in interleukins 1β, 6, 8 (IL-1β, IL-6, IL-8), tumor necrosis factor receptor 1 (TNF R-1), and endotoxemia. In conclusion, though preliminary, we report a novel in vivo model with a human microbiome reconstitution and an engrafted human immune phenotype that may help to better understand gut–immune interactions in GWI. Full article

Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood–brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders. Full article

Vaccination against Bacillus anthracis is the best preventive measure against the development of deadly anthrax disease in the event of exposure to anthrax either as a bioweapon or in its naturally occurring form. Anthrax vaccines, however, have historically been plagued with controversy, particularly related to their safety. Fortunately, recent improvements in anthrax vaccines have been shown to confer protection with reduced short-term safety concerns, although questions about long-term safety remain. Here, we (a) review recent and ongoing advances in anthrax vaccine development, (b) emphasize the need for thorough characterization of current (and future) vaccines, (c) bring to focus the importance of host immunogenetics as the ultimate determinant of successful antibody production and protection, and (d) discuss the need for the systematic, active, and targeted monitoring of vaccine recipients for possible Chronic Multisymptom Illness (CMI). Full article

To address gaps in understanding the pathophysiology of Gulf War Illness (GWI), the VA Million Veteran Program (MVP) developed and implemented a survey to MVP enrollees who served in the U.S. military during the 1990–1991 Persian Gulf War (GW). Eligible Veterans were invited via mail to complete a survey assessing health conditions as well as GW-specific deployment characteristics and exposures. We evaluated the representativeness of this GW-era cohort relative to the broader population by comparing demographic, military, and health characteristics between respondents and non-respondents, as well as with all GW-era Veterans who have used Veterans Health Administration (VHA) services and the full population of U.S. GW-deployed Veterans. A total of 109,976 MVP GW-era Veterans were invited to participate and 45,270 (41%) returned a completed survey. Respondents were 84% male, 72% White, 8% Hispanic, with a mean age of 61.6 years (SD = 8.5). Respondents were more likely to be older, White, married, better educated, slightly healthier, and have higher socioeconomic status than non-respondents, but reported similar medical conditions and comparable health status. Although generally similar to all GW-era Veterans using VHA services and the full population of U.S. GW Veterans, respondents included higher proportions of women and military officers, and were slightly older. In conclusion, sample characteristics of the MVP GW-era cohort can be considered generally representative of the broader GW-era Veteran population. The sample represents the largest research cohort of GW-era Veterans established to date and provides a uniquely valuable resource for conducting in-depth studies to evaluate health conditions affecting 1990–1991 GW-era Veterans. Full article

Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling. Full article

To examine associations between the pyridostigmine bromide (PB) pill and/or pesticide exposure during the 1990–1991 Gulf War (GW) and eye findings years after deployment. A cross-sectional study of South Florida veterans who were deployed on active duty during the GW Era (GWE). Information on GW exposures and ocular surface symptoms were collected via standardized questionnaires and an ocular surface examination was performed. Participants underwent spectral domain–ocular coherence tomography (SD-OCT) imaging that included retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and macular maps. We examined for differences in eye findings between individuals exposed versus not exposed to PB pills or pesticides during service. A total of 40.7% (n = 44) of individuals reported exposure to PB pills and 41.7% (n = 45) to pesticides; additionally, 24 reported exposure to both in the GW arena. Demographics were comparable across groups. Individuals exposed to PB pills reported higher dry eye (DE) symptoms scores (the 5-Item Dry Eye Questionnaire, DEQ-5: 9.3 ± 5.3 vs. 7.3 ± 4.7, p = 0.04) and more intense ocular pain (average over the last week: 2.4 ± 2.6 vs. 1.5 ± 1.8, p = 0.03; Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-E): 18.2 ± 20.0 vs. 10.8 ± 13.8, p = 0.03) compared to their non-exposed counterparts. DE signs were comparable between the groups. Individuals exposed to PB pills also had thicker OCT measurements, with the largest difference in the outer temporal segment of the macula (268.5 ± 22.2 μm vs. 260.6 ± 14.5 μm, p = 0.03) compared to non-exposed individuals. These differences remained significant when examined in multivariable models that included demographics and deployment history. Individuals exposed to pesticides had higher neuropathic ocular pain scores (NPSI-E: 17.1 ± 21.1 vs. 11.6 ± 12.9, p = 0.049), but this difference did not remain significant in a multivariable model. Individuals exposed to PB pills during the GWE reported more severe ocular surface symptoms and had thicker OCT measures years after deployment compared to their non-exposed counterparts. Full article

The pathophysiology of Gulf War Illness (GWI) remains elusive even after three decades. The persistence of multiple complex symptoms along with metabolic disorders such as obesity worsens the health of present Gulf War (GW) Veterans often by the interactions of the host gut microbiome and inflammatory mediators. In this study, we hypothesized that the administration of a Western diet might alter the host metabolomic profile, which is likely associated with the altered bacterial species. Using a five-month symptom persistence GWI model in mice and whole-genome sequencing, we characterized the species-level dysbiosis and global metabolomics, along with heterogenous co-occurrence network analysis, to study the bacteriome–metabolomic association. Microbial analysis at the species level showed a significant alteration of beneficial bacterial species. The beta diversity of the global metabolomic profile showed distinct clustering due to the Western diet, along with the alteration of metabolites associated with lipid, amino acid, nucleotide, vitamin, and xenobiotic metabolism pathways. Network analysis showed novel associations of gut bacterial species with metabolites and biochemical pathways that could be used as biomarkers or therapeutic targets to ameliorate symptom persistence in GW Veterans. Full article

Gulf War Illness (GWI), a chronic multisymptom illness with a complex and uncertain etiology and pathophysiology, is highly prevalent among veterans deployed to the 1990–1991 GW. We examined how GWI phenotypes varied by demographic and military characteristics among GW-era veterans. Data were from the VA’s Cooperative Studies Program 2006/Million Veteran Program (MVP) 029 cohort, Genomics of GWI. From June 2018 to March 2019, 109,976 MVP enrollees (out of a total of over 676,000) were contacted to participate in the 1990–1991 GW-era Survey. Of 109,976 eligible participants, 45,169 (41.1%) responded to the 2018–2019 survey, 35,902 respondents met study inclusion criteria, 13,107 deployed to the GW theater. GWI phenotypes were derived from Kansas (KS) and Centers for Disease Control and Prevention (CDC) GWI definitions: (a) KS Symptoms (KS Sym+), (b) KS GWI (met symptom criteria and without exclusionary health conditions) [KS GWI: Sym+/Dx−], (c) CDC GWI and (d) CDC GWI Severe. The prevalence of each phenotype was 67.1% KS Sym+, 21.5% KS Sym+/Dx−, 81.1% CDC GWI, and 18.6% CDC GWI severe. These findings affirm the persistent presence of GWI among GW veterans providing a foundation for further exploration of biological and environmental underpinnings of this condition. Full article