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Gulf War illness (GWI) as a neuroimmune disease

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Abstract

Gulf War illness (GWI) is a chronic disease characterized by the involvement of several organs, including the brain (Christova et al., Exp Brain Res doi:10.1007/s00221-017-5010-8, 2017). In a previous study (Georgopoulos et al., J Neural Eng 4:349–355, 2015), we identified six protective alleles from Class II human leukocyte antigen (HLA) genes, and more recently, we investigated the brain correlates of this protection (James et al., EBioMedicine 13:72–79, 2016). Those and other studies (Israeli, Lupus, 21:190–194, 2012) suggested an involvement of the immune system in GWI. In a recent study (Engdahl et al., EBioMedicine doi:10.1016/j.ebiom.2016.08.030, 2016), we showed that the brain pattern of synchronous neural interactions (SNI; Georgopoulos et al., J Neural Eng 4:349–355, 2007) in GWI is distinctly different from that in healthy controls. Here we focused on the SNI itself, as a basic measure of neural communication (irrespective of specific connections) and compared it between GWI and seven other diseases that cover a broad spectrum of etiology and pathophysiology. Specifically, we sought to determine which, if any, of those diseases might resemble GWI SNI, overall and within the HLA protective domain, and thus gain further knowledge regarding the nature of GWI brain abnormality. We studied a total of 962 participants from a healthy control population (N = 583) and eight different diseases, including GWI (N = 40), schizophrenia (SZ; N = 21), Alzheimer’s disease (AD; N = 66), posttraumatic stress disorder (PTSD; N = 159), major depressive disorder (MDD; N = 10), relapsing–remitting multiple sclerosis (RRMS; N = 43), Sjögren’s syndrome (SS; N = 32), and rheumatoid arthritis (RA; N = 8). They all underwent a resting-state magnetoencephalographic (MEG) scan to calculate SNIs. Data were analyzed using analysis of covariance (ANCOVA) with disease as fixed factor, and sex and age as covariates. We found that GWI SNIs differed significantly from control SZ, AD, PTSD and MDD but not from RRMS, SS and RA. In addition, we compared GWI to RRMS, SS and RA with respect to SNIs of MEG sensor pairs that were related to the HLA alleles protective for GWI (James et al., EBioMedicine 13:72–79, 2016). We found that GWI SNIs did not differ significantly from any of these three diseases but they did so from control SZ, AD, PTSD and MDD. These findings indicate that (a) GWI brain synchronicity does not differ significantly from that of known immune-related diseases (RRMS, SS, RA), and (b) that this SNI similarity is present within the HLA-related SNIs. In contrast, GWI SNIs differed significantly from those of the other diseases. We conclude that altered brain communication in GWI likely reflects immune-related processes, as postulated previously (James et al., EBioMedicine 13:72–79, 2016). By extension, these findings also indicate that functional brain abnormalities in RRMS, SS and RA might be, in part, due to lack of protective HLA alleles as documented for GWI (Georgopoulos et al., EBioMedicine 3:79–85, 2015).

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Acknowledgements

This work was partially supported by a service directed grant from the United States Department of Veterans Affairs, a grant for the United States Department of Defense (Award Number W81XWH-15-1-0520), and the American Legion Brain Sciences Chair. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

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Author notes

  1. Adam F. Carpenter, Brian E. Engdahl, Arthur C. Leuthold, and Scott M. Lewis contributed equally and are listed in alphabetical order.

Authors and Affiliations

  1. Brain Sciences Center (11B), Minneapolis Veterans Affairs Health Care System, One Veterans Drive, Minneapolis, MN, 55417, USA

    Apostolos P. Georgopoulos, Lisa M. James, Adam F. Carpenter, Brian E. Engdahl, Arthur C. Leuthold & Scott M. Lewis

  2. Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA

    Apostolos P. Georgopoulos, Lisa M. James, Brian E. Engdahl & Arthur C. Leuthold

  3. Center for Cognitive Sciences, University of Minnesota, Minneapolis, MN, 55455, USA

    Apostolos P. Georgopoulos, Lisa M. James & Brian E. Engdahl

  4. Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, 55455, USA

    Apostolos P. Georgopoulos & Lisa M. James

  5. Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, 55455, USA

    Apostolos P. Georgopoulos, Adam F. Carpenter & Scott M. Lewis

  6. Department of Psychology, University of Minnesota, Minneapolis, USA

    Brian E. Engdahl

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  1. Apostolos P. Georgopoulos
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Correspondence to Apostolos P. Georgopoulos.

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Georgopoulos, A.P., James, L.M., Carpenter, A.F. et al. Gulf War illness (GWI) as a neuroimmune disease. Exp Brain Res 235, 3217–3225 (2017). https://doi.org/10.1007/s00221-017-5050-0

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