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

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Abstract

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.

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The danger model: a renewed sense of self.

Polly Matzinger (2002)

For over 50 years immunologists have based their thoughts, experiments, and clinical treatments on the idea that the immune system functions by making a distinction between self and nonself. Although this paradigm has often served us well, years of detailed examination have revealed a number of inherent problems. This Viewpoint outlines a model of immunity based on the idea that the immune system is more concerned with entities that do damage than with those that are foreign.

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Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities

Diego Lozano, Gabriel S Gonzales-Portillo, Sandra Acosta … (2015)

Traumatic brain injury (TBI) is a serious public health problem accounting for 1.4 million emergency room visits by US citizens each year. Although TBI has been traditionally considered an acute injury, chronic symptoms reminiscent of neurodegenerative disorders have now been recognized. These progressive neurodegenerative-like symptoms manifest as impaired motor and cognitive skills, as well as stress, anxiety, and mood affective behavioral alterations. TBI, characterized by external bumps or blows to the head exceeding the brain’s protective capacity, causes physical damage to the central nervous system with accompanying neurological dysfunctions. The primary impact results in direct neural cell loss predominantly exhibiting necrotic death, which is then followed by a wave of secondary injury cascades including excitotoxicity, oxidative stress, mitochondrial dysfunction, blood–brain barrier disruption, and inflammation. All these processes exacerbate the damage, worsen the clinical outcomes, and persist as an evolving pathological hallmark of what we now describe as chronic TBI. Neuroinflammation in the acute stage of TBI mobilizes immune cells, astrocytes, cytokines, and chemokines toward the site of injury to mount an antiinflammatory response against brain damage; however, in the chronic stage, excess activation of these inflammatory elements contributes to an “inflamed” brain microenvironment that principally contributes to secondary cell death in TBI. Modulating these inflammatory cells by changing their phenotype from proinflammatory to antiinflammatory would likely promote therapeutic effects on TBI. Because neuroinflammation occurs at acute and chronic stages after the primary insult in TBI, a treatment targeting neuroinflammation may have a wider therapeutic window for TBI. To this end, a better understanding of TBI etiology and clinical manifestations, especially the pathological presentation of chronic TBI with neuroinflammation as a major component, will advance our knowledge on inflammation-based disease mechanisms and treatments.

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Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Frances Corrigan, Kimberley Mander, Anna Leonard … (2016)

Background The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.

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Author and article information

Journal

Journal ID (nlm-ta): Brain Sci

Journal ID (iso-abbrev): Brain Sci

Journal ID (publisher-id): brainsci

Title: Brain Sciences

Publisher: MDPI

ISSN (Electronic): 2076-3425

Publication date (Electronic): 13 November 2018

Publication date Collection: November 2018

Volume: 8

Issue: 11

Electronic Location Identifier: 198

Affiliations

[1 ]Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA; ajamajoy@ 123456bu.edu (J.A.); tty@ 123456bu.edu (K.S.)

[2 ]Research Service, VA Boston Healthcare System, Boston, MA 02130, USA; mhk@ 123456bu.edu

[3 ]Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA

[4 ]Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA 02118, USA; eq@ 123456bu.edu

[5 ]Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; tch@ 123456bu.edu

[6 ]Department of Psychological and Brain Sciences, Boston University, Boston, MA 02215, USA; toomey@ 123456bu.edu

[7 ]Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA; killiany@ 123456bu.edu

[8 ]Department of Behavioral Neuroscience, Boston University School of Medicine, Boston, MA 02118, USA; cgzundel@ 123456bu.edu

[9 ]Centers for Disease Control and Prevention-NIOSH, Morgantown, WV 26505, USA; jdo5@ 123456cdc.gov

[10 ]Department of Psychiatry and Behavioral Sciences, Division of Neuropsychiatry, Baylor College of Medicine, Houston, TX 77030, USA; Lea.Steele@ 123456bcm.edu

[11 ]Department of Medicine, Miami VA Healthcare System, Miami, FL 33125, USA; nklimas@ 123456nova.edu

[12 ]Department of Clinical Immunology, Nova Southeastern University, Miami, FL 33314, USA

Author notes

[* ]Correspondence: paj@ 123456bu.edu ; Tel.: +1-617-638-4620

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Kimberly Sullivan https://orcid.org/0000-0001-7940-6123

Article

Publisher ID: brainsci-08-00198

DOI: 10.3390/brainsci8110198

PMC ID: 6266762

PubMed ID: 30428552

SO-VID: cc7f1114-4580-4f6a-81c9-ed3943762d8c

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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

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Most cited references 30

The danger model: a renewed sense of self.

Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities

Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

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