Altered immune pathway activity under exercise challenge in Gulf War Illness: An exploratory analysis

Broderick, Gordon; Ben‐Hamo, Rotem; Vashishtha, Saurabh; Efroni, Sol; Nathanson, Lubov; Barnes, Zachary; Fletcher, Mary A; Klimas, Nancy G.

doi:10.1016/j.bbi.2012.11.007

Cited by 71 publications

(75 citation statements)

References 91 publications

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“…[1][2][3] Our work and that of others strongly suggest that pathogenesis of this complex illness includes an immunologic [4][5][6][7] and an endocrine component. 8 Based on this, we proposed an illness model whereby GWI may involve a chronic imbalance in co-regulation between the nervous, endocrine and immune systems.…”

Section: Introductionmentioning

confidence: 69%

“…8 Though our data shows a broad range of values for IFN-g levels in peripheral blood from GWI subjects 7 , this Th1 cytokine tends to be elevated in this illness group (p=0 .07 in a 2-way ANOVA). 6 One would expect a trend toward lower expression of Th2 cytokines in GWI but these remain essentially normal in the case of IL-4 and IL-5, or increased in the case of IL-13, suggesting insensitivity to the normal IFN-g induced down-regulation of Th2 polarization. 22 In T helper cells down-modulation of IFN-gR2 acts as a negative regulatory mechanism that attenuates IFN-g/signal transducer and activator of transcription-1 (STAT-1) signaling and limits the apoptotic effect of IFN-g.…”

Section: Discussionmentioning

confidence: 97%

“…Summary statistics are presented in Supplementary Table S6. Additional details regarding this cohort and the laboratory assays performed are also available in Broderick et al 6 Statistical Comparison against Clinical Data Using Brown' s Method. Brown's theoretical approximation 12 of Fisher's statistics was used to calculate the significance of alignment between experimental data and a given model predicted state.…”

Section: Methodsmentioning

confidence: 99%

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Gulf War Illness: Is there lasting damage to the endocrine-immune circuitry?

Rice

Craddock

Folcik

et al. 2014

Systems Biomedicine

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We reported previously that the persistence of complex immune, endocrine and neurological symptoms that afflict up to one third of veterans from the 1990-91 Gulf War might be supported by a misdirected regulatory drive. Here we use a detailed model of immune signaling in concert with an overarching circuit model of known sex and stress hormone co-regulation to explore how the failure of regulatory elements may further establish a self-perpetuating imbalance that closely resembles Gulf War Illness (GWI). Defects to the model were imparted iteratively and the stable regulatory modes supported by these altered immune-endocrine circuits were identified using repeated simulation experiments. In each case the predicted homeostatic regimes were compared to experimental data collected in male GWI (n=20 ) and matched healthy veterans (n=22 ). We found that alignment of GWI with a new homeostatic regime improved significantly when cortisol's normal anti-inflammatory activity was interrupted. Alignment improved further when this cortisol insensitivity was compounded by the loss of the normal antagonistic effects of Th1 cytokines on Th2 lymphocyte activation. Together these simulation results suggest altered glucocorticoid gene regulation compounded by possible changes in IGF-1 regulation of Th1:Th2 immune balance may be key underlying features of GWI.

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Section: Introductionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

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Gulf War Illness: Is there lasting damage to the endocrine-immune circuitry?

Rice

Craddock

Folcik

et al. 2014

Systems Biomedicine

Self Cite

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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].…”

Section: Introductionmentioning

confidence: 97%

Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome

et al. 2015

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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 (SNPs) 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.

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“…elevated C4a split product levels) and oxidative stress system responses (i.e. enhanced oxidative stress combined with a delayed and reduced antioxidant response), and alteration of the gene expression profile of immune cells [20][21][22][23]. Although these immune responses to exercise are known to be related to symptoms of postexertional malaise in patients with ME/CFS [20], it remains unclear whether they are normalized following (multidisciplinary) rehabilitation.…”

mentioning

confidence: 99%