Supporting a Neuroimmune Basis of Gulf War Illness

O’Callaghan, James P.; Michalovicz, Lindsay T.; Kelly, Kimberly A.

doi:10.1016/j.ebiom.2016.10.037

Cited by 24 publications

(20 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the current study cannot confirm the etiology for GWI symptoms, several studies suggest that the neurotoxicant exposures experienced in war can lead to an increased immune response, not only in the brain, but throughout the body [ 33 , 34 , 35 , 36 ]. Likewise, TBIs can also lead to an increased neuroinflammatory state by priming the immune cells of the brain—microglia and astrocytes—to respond longer and stronger after each additional encounter with foreign or “danger” associated molecular patterns (DAMPS) from damaged or apoptotic neural cells [ 37 , 38 , 39 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 69%

The Multiple Hit Hypothesis for Gulf War Illness: Self-Reported Chemical/Biological Weapons Exposure and Mild Traumatic Brain Injury

et al. 2018

View full text Add to dashboard Cite

The Gulf War Illness Consortium (GWIC) was designed to identify objective biomarkers of Gulf War Illness (GWI) in 1991 Gulf War veterans. The symptoms of GWI include fatigue, pain, cognitive problems, gastrointestinal, respiratory, and skin problems. Neurotoxicant exposures during deployment, such as pesticides, sarin, and pyridostigmine bromide pills have been identified as contributors to GWI. We have also found an association between mild traumatic brain injury (mTBI) and increased rates of GWI. However, the combined impact of these physical and chemical exposures has not yet been explored in GWI. The objective of this study was to examine both self-reported mTBI and exposure to chemical/biological weapons (CBW) as a multiple or two hit model for increased risk of GWI and other chronic health conditions. The study population included 125 Gulf War (GW) veterans from the Boston GWIC. Exposure to CBW was reported in 47.2% of the study population, and 35.2% reported sustaining a mTBI during the war. Results confirmed that those with both exposures (mTBI and CBW) had higher rates of comorbid chronic health conditions while rates of GWI were equivalent for mTBI and CBW or mTBI alone. The timing of exposure to mTBI was found to be strikingly different between those with GWI and those without it. Correspondingly, 42.3% of GWI cases reported experiencing a mTBI during military service while none of the controls did (p = 0.0002). Rates of mTBI before and after the war did not differ between the cases and controls. In addition, 54% of cases compared to 14.3% of controls (p = <0.001) reported being exposed to CBW during military service. The current study examined the relation of the separate and combined effects of exposure to mTBI and CBW in 1991 GW veterans. The findings from this study suggest that both exposure to mTBI and CBW are associated with the development of GWI and multiple chronic health conditions and that combined exposure appears to lead to higher risk of chronic health effects.

show abstract

Section: Discussionmentioning

confidence: 69%

The Multiple Hit Hypothesis for Gulf War Illness: Self-Reported Chemical/Biological Weapons Exposure and Mild Traumatic Brain Injury

et al. 2018

View full text Add to dashboard Cite

show abstract

“…While research into the underlying cause of GWI has largely indicated it to be a neuroimmune-based disorder (for example, see Craddock et al, 2015; Georgopoulous et al, 2017; O’Callaghan et al, 2016), exposure to nerve agents, pesticides, and other chemicals in theater would have been experienced through a variety of routes (e.g., inhalation, dermal, ophthalmic, etc.) that would have resulted in a systemic exposure to these chemicals.…”

Section: Introductionmentioning

confidence: 99%

Corticosterone and pyridostigmine/DEET exposure attenuate peripheral cytokine expression: Supporting a dominant role for neuroinflammation in a mouse model of Gulf War Illness

et al. 2019

Self Cite

View full text Add to dashboard Cite

Gulf War Illness (GWI) is a chronic multi-symptom disorder experienced by as many as a third of the veterans of the 1991 Gulf War; the constellation of “sickness behavior” symptoms observed in ill veterans is suggestive of a neuroimmune involvement. Various chemical exposures and conditions in theater have been implicated in the etiology of the illness. Previously, we found that GW-related organophosphates (OPs), such as the sarin surrogate, DFP, and chlorpyrifos, cause neuroinflammation. The combination of these exposures with exogenous corticosterone (CORT), mimicking high physiological stress, exacerbates the observed neuroinflammation. The potential relationship between the effects of OPs and CORT on the brain versus inflammation in the periphery has not been explored. Here, using our established GWI mouse model, we investigated the effects of CORT and DFP exposure, with or without a chronic application of pyridostigmine bromide (PB) and N, N -diethyl-meta-toluamide (DEET), on cytokines in the liver and serum. While CORT primed DFP-induced neuroinflammation, this effect was largely absent in the periphery. Moreover, the changes found in the peripheral tissues do not correlate with the previously reported neuroinflammation. These results not only support GWI as a neuroimmune disorder, but also highlight the separation between central and peripheral effects of these exposures.

show abstract

“…As described by Dantzer and colleagues [3], sickness behaviors are likely linked to activation of macrophages and microglia, and subsequent neuroinflammation via production of proinflammatory cytokines such as Tnfa, IL1β, and IL6. GWI thus has the features of a neuroimmune disorder [4][5][6][7]; but causes are otherwise poorly understood. The leading suspected causes are chemicals to which the personnel were exposed.…”

Section: Introductionmentioning

confidence: 99%

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

Jones

Miller

et al. 2020

Brain Sciences

View full text Add to dashboard Cite

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.

show abstract

Supporting a Neuroimmune Basis of Gulf War Illness

Cited by 24 publications

References 9 publications

The Multiple Hit Hypothesis for Gulf War Illness: Self-Reported Chemical/Biological Weapons Exposure and Mild Traumatic Brain Injury

The Multiple Hit Hypothesis for Gulf War Illness: Self-Reported Chemical/Biological Weapons Exposure and Mild Traumatic Brain Injury

Corticosterone and pyridostigmine/DEET exposure attenuate peripheral cytokine expression: Supporting a dominant role for neuroinflammation in a mouse model of Gulf War Illness

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

Contact Info

Product

Resources

About