Using gene expression signatures to identify novel treatment strategies in gulf war illness

Craddock, Travis J. A.; Harvey, Jeanna M.; Nathanson, Lubov; Barnes, Zachary; Klimas, Nancy G.; Fletcher, Mary A; Broderick, Gordon

doi:10.1186/s12920-015-0111-3

Cited by 24 publications

(16 citation statements)

References 83 publications

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“…Regulation of glucocorticoid responsiveness is complex however there is evidence that the latter is also reduced by exposure to proinflammatory cytokines, such as tumor necrosis factor a (TNFa) and interleukin-1b (IL-1b), 18 both of which are suggested to play a role in GWI. 4,19 Among its broad-reaching effects GR interacts with receptor tyrosine kinase to promote BDNFinduced release of glutamate. SiRNA transfection inducing a decrease in endogenous GR has been shown to decrease BDNFdependent binding of phospholipase C-g (PLC-g) to tyrosine kinase B (TrkB) resulting in the suppression of neurotransmitter release.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

Rice

Craddock

Folcik

et al. 2014

Systems Biomedicine

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“…Now, there is a link between chronic infections and the development of autoimmune disorders (Sherbet, 2009). In addition, a possible, direct connection of GWI to autoimmunity has been suggested (Asa et al, 2000, Israeli, 2012, Georgopoulos et al, 2015) and supported by the emergence of methotrexate, an immunosuppressive drug, as a possible treatment for GWI (Craddock et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

“…Vaccinations obviously target the immune system by inducing immune responses to the pathogens, but also to the adjuvants, contained in the vaccines (Israeli, 2012, Toubi, 2012); chemical exposure to subclinical levels of sarin have been shown to depress immune function (Henderson et al, 2001); and stress has since long been identified as affecting immune function (see reviews by O'Leary, 1990, Webster Marketona and Glasera, 2008). Recent studies have documented immune dysfunction in GWI (Whistler et al, 2009), and even identified an immunosuppressant (methotrexate) as an optimal possible treatment for GWI (Craddock et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Brain Correlates of Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI)

et al. 2016

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BackgroundWe recently reported that six alleles from class II genes of the Human Leukocyte Antigen (HLA) confer protection from Gulf War Illness (GWI) (Georgopoulos et al., 2015). The most significant effect is exerted on Neurological-Cognitive-Mood (NCM), Pain, and Fatigue symptoms, such that higher number of copies of the protective alleles are associated with lower symptom severity. Here we tested the hypothesis that this effect is exerted by modulating the strength of neural synchronicity.MethodsEighty-one Gulf War veterans (65 with GWI and 16 healthy controls) underwent a magnetoencephalography (MEG) scan to assess the strength of brain synchronicity by computing zero-lag crosscorrelations (and their Fisher z transforms) between prewhitened MEG time series. A high-resolution HLA genotyping determined the number of copies, k, of the 6 protective alleles above in each participant. We tested the hypothesis above by regressing NCM, Pain and Fatigue symptom severity against the interaction term, k × z (HLA-related effect), while including z (non-HLA-related effect), gender and age as covariates. The k × z and z terms assessed HLA- and non-HLA-related effects, respectively, of neural synchronicity on symptom severity. The distributions of these effects in sensor space were visualized using statistical heatmaps.FindingsWe found significant, graded HLA- and non-HLA-related effects: (a) NCM > Pain > Fatigue for HLA-related effects, (b) NCM > Fatigue > Pain for non-HLA-related effects, and (c) HLA-related > non-HLA-related effects for all symptoms. These effects had widespread but distinct distributions in sensor space that allowed the orderly separation of the 6 terms (3 symptom domains × 2 HLA factors) in a multidimensional plot, where one dimension separated the symptoms and the other the HLA relation.InterpretationThese findings demonstrate the presence of substantial, widespread, distinct and orderly HLA- and non-HLA-related neural influences on NCM, Pain and Fatigue symptom severity in GWI.FundingU.S. Department of Veterans Affairs and University of Minnesota.

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“…This study was designed to build on this research and investigate these markers and biological systems using a methodology to identify genomic modules and their applications in potential secondary pharmacologic actions. 12 In addition, this study was formulated to investigate the differentiation of ME/CFS via gender and to investigate gene-expression covariance with fatigue measures in ME/CFS. Therefore, this study used biological variables to pinpoint potential treatment targets, as treatment options for ME/CFS are currently limited, as well as preliminary diagnostic markers through biomarker and measures of fatigue.…”

Section: Introductionmentioning

confidence: 99%