Altered Immune Pathway Activity under Exercise Challenge in Gulf War Illness: An Exploratory Analysis.

Department of Medicine, University of Alberta, Edmonton, Canada. Electronic address: .
Brain Behavior and Immunity (Impact Factor: 5.89). 11/2012; 28. DOI: 10.1016/j.bbi.2012.11.007
Source: PubMed


Though potentially linked to the basic physiology of stress response we still have no clear understanding of Gulf War Illness (GWI), a debilitating illness presenting with a complex constellation of immune, endocrine and neurological symptoms. Here we compared male GWI (n=20) with healthy veterans (n=22) and subjects with chronic fatigue syndrome/ myalgic encephalomyelitis (CFS/ME) (n=7). Blood was drawn during a Graded eXercise Test (GXT) prior to exercise, at peak effort (VO2 max) and 4-hours post exercise. Affymetrix HG U133 plus 2.0 microarray gene expression profiling in peripheral blood mononuclear cells (PBMCs) was used to estimate activation of over 500 documented pathways. This was cast against ELISA-based measurement of 16 cytokines in plasma and flow cytometric assessment of lymphocyte populations and cytotoxicity. A 2-way ANOVA corrected for multiple comparisons (q statistic <0.05) indicated significant increases in neuroendocrine-immune signaling and inflammatory activity in GWI, with decreased apoptotic signaling. Conversely, cell cycle progression and immune signaling were broadly subdued in CFS. Partial correlation networks linking pathways with symptom severity via changes in immune cell abundance, function and signaling were constructed. Central to these were changes in IL-10 and CD2+ cell abundance and their link to two pathway clusters. The first consisted of pathways supporting neuronal development and migration whereas the second was related to androgen-mediated activation of NF-κB. These exploratory results suggest an over-expression of known exercise response mechanisms as well as illness-specific changes that may involve an overlapping stress-potentiated neuro-inflammatory response.

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Available from: Saurabh Vashishtha, Jun 01, 2015
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    • "While the cause of CFS is not known, many proposed risk factors including infection , environmental exposures, allergies, physiological and psychosocial stress, act through the immune system and inflammatory response [1] [2] [3] [4] [5] [6] [7] [8]. Inflammatory markers have been associated with specific symptoms common in CFS; chronic fatigue, heart rate variability, sleep quality, cognitive problems and post-exertional malaise [9] [10] [11] [12] [13] [14] [15] [16] [17]. Changes in cytokine profiles have been suggested as biomarkers of CFS [18] [19] [20] [21] [22]. "
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    ABSTRACT: Recent evidence suggests immune and inflammatory alterations are important in chronic fatigue syndrome (CFS). This study was done to explore the association of functionally important genetic variants in inflammation and immune pathways with CFS. Peripheral blood DNA was isolated from 50 CFS and 121 non-fatigued (NF) control participants in a population-based study. Genotyping was performed with the Affymetrix Immune and Inflammation Chip that covers 11K single nucleotide polymorphisms (SNP) following the manufacturer's protocol. Genotyping accuracy for specific genes was validated by pyrosequencing. Golden Helix SVS software was used for genetic analysis. SNP functional annotation was done using SPOT and GenomePipe programs. CFS was associated with 32 functionally important SNPs: 11 missense variants, 4 synonymous variants, 11 untranslated regulatory region (UTR) variants and 6 intronic variants. Some of these SNPs were in genes within pathways related to complement cascade (SERPINA5, CFB, CFH, MASP1 and C6), chemokines (CXCL16, CCR4, CCL27), cytokine signaling (IL18, IL17B, IL2RB), and toll-like receptor signaling (TIRAP, IRAK4). Of particular interest is association of CFS with two missense variants in genes of complement activation, rs4151667 (L9H) in CFB and rs1061170 (Y402H) in CFH. A 5'UTR polymorphism (rs11214105) in IL18 also associated with physical fatigue, body pain and score for CFS case defining symptoms. This study identified new associations of CFS with genetic variants in pathways including complement activation providing additional support for altered innate immune response in CFS. Additional studies are needed to validate the findings of this exploratory study. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Human immunology
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    • "A variety of physiological stressors were present during the GW and such stressors in combination with other GW exposures have been postulated to contribute to the development of GWI (Friedman et al. 1996; Sapolsky 1998). Moreover, physiological stress in the form of exercise can serve as a proinflammatory immune dysregulator (e.g., early and excessive activation of IL-1a, IL-10, and IL-4) in ill veterans with associated adverse outcomes (e.g., increases in tender points, altered brain activation during memory recall tasks) (Cook et al. 2010; Broderick et al. 2013; Rayhan et al. 2013). When we used exogenous CORT as a stressor mimic prior to DFP, it was remarkably proinflammatory, causing a large increase in the DFP-induced expression of cytokines/chemokines brain wide. "
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    ABSTRACT: Gulf War Illness (GWI) is a multi-symptom disorder with features characteristic of persistent sickness behavior. Among conditions encountered in the GW theater were physiological stressors (e.g., heat/cold/physical activity/sleep deprivation), prophylactic treatment with the reversible AChE inhibitor, pyridostigmine bromide (PB), the insect repellent, DEET, and potentially the nerve agent, sarin. Prior exposure to the anti-inflammatory glucocorticoid, CORT, at levels associated with high physiological stress, can paradoxically prime the CNS to produce a robust proinflammatory response to neurotoxicants and systemic inflammation; such neuroinflammatory effects can be associated with sickness behavior. Here, we examined whether CORT primed the CNS to mount neuroinflammatory responses to GW exposures as a potential model of GWI. Male C57BL/6 mice were treated with chronic (14d) PB/DEET, subchronic (7-14d) CORT, and acute exposure (day 15) to diisopropyl fluorophosphate (DFP), a sarin surrogate and irreversible AChE inhibitor. DFP alone caused marked brain-wide neuroinflammation assessed by qPCR of TNF-α, IL6, CCL2, IL-1β, LIF and OSM. Pretreatment with high physiological levels of CORT greatly augmented (up to 300-fold) the neuroinflammatory responses to DFP. Anti-inflammatory pretreatment with minocycline suppressed many proinflammatory responses to CORT+DFP. Our findings are suggestive of a possible critical, yet unrecognized interaction between the stressor/environment of the GW theater and agent exposure(s) unique to this war. Such exposures may in fact prime the CNS to amplify future neuroinflammatory responses to pathogens, injury or toxicity. Such occurrences could potentially result in the prolonged episodes of sickness behavior observed in GWI. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Mar 2015 · Journal of Neurochemistry
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    • "Physiological dysfunction in GWI made evident following exercise has been reported for gene expression and imaging parameters [36], [37], [38]. Our finding of prolongation of post-exercise PCr-R represents a further instance in which exercise unmasks altered physiology in GWI. "
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    ABSTRACT: Approximately 1/3 of 1990-1 Gulf War veterans developed chronic multisymptom health problems. Implicated exposures bear mechanisms that adversely affect mitochondria. Symptoms emphasize fatigue, cognition and muscle (brain and muscle are aerobically demanding); with protean additional domains affected, compatible with mitochondrial impairment. Recent evidence supports treatments targeting cell bioenergetics (coenzyme10) to benefit Gulf War illness symptoms. However, no evidence has directly documented mitochondrial or bioenergetic impairment in Gulf War illness.
    Full-text · Article · Mar 2014 · PLoS ONE
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