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

Abstract

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.

Supporting a Neuroimmune Basis of Gulf War Illness

“…As such, both human and animal studies have suggested a connection between physiological stress and the immune system, both systemically and in the brain. The findings presented by James et al (2016) support the notion that GWI is a disease in which genetically-regulated sensitivity of the immune system interacts with exposures that occurred in the Gulf War to reprogram neural functioning. The importance of such studies is highlighted by the emphasis of the Gulf War Illness Research Program of the Department of Defense's Congressionally Directed Medical Research Programs (CDMRP), where the need for research to address the role of neurological and immune dysfunction, as well as genetic predisposition in GWI is a current priority.…”

“…The importance of such studies is highlighted by the emphasis of the Gulf War Illness Research Program of the Department of Defense's Congressionally Directed Medical Research Programs (CDMRP), where the need for research to address the role of neurological and immune dysfunction, as well as genetic predisposition in GWI is a current priority. Not only does the work of James et al (2016) address all of these areas of interest, but it also supports the expansion of this work into other relevant genetic/immune based studies. Such studies are underway in animal models where genetically defined strains of mice, which combine a toxicologically susceptible mouse strain with a more resistant strain (Jones et al, 2013) can be used to replicate a genetically diverse population to evaluate genetic-based neuroimmune susceptibility to GWI.…”

“…In a recent follow-up from this group (Engdahl et al, 2016), a difference in neural synchrony was found between ill and healthy GW veterans. In an important extension of these findings in the current issue, James et al (2016) integrate these “neuro” and immune components. Using analyses by magnetoencephalography (MEG), they show that the HLA alleles have their action via modulation of neural signaling patterns based on a sophisticated mapping of brain regional neural synchrony.…”

Human Leukocyte Antigen (HLA) and Gulf War Illness (GWI): HLA-DRB1*13:02 Spares Subcortical Atrophy in Gulf War Veterans

“…For example, compared to healthy control veterans, veterans with GWI showed an average of 10.4% reduction in cerebellar volume and 2 × the rate of reduction of cerebellar gray matter volume with age (− 14%/decade in GWI vs. − 6.9%/decade in controls). We concluded that the marked subcortical volume reduction observed in veterans with GWI is likely attributable to direct exposure to toxins, akin to toxic encephalopathy ( Valk and van der Knaap, 1992 ), in combination with lack of immunogenetic protection in GWI ( Georgopoulos et al, 2016 , James et al, 2016 ).…”

“…HLA genes are located in the Major Histocompatibility Complex (MHC) of chromosome 6 and play a central role in immune system functioning ( Meuer et al, 1982 ). We previously demonstrated that six HLA class II alleles (DRB1*01:01, DRB1*08:11, DRB1*13:02, DQB1*02:02, DPB*01:01, DPB1*06:01) successfully discriminate veterans with GWI from controls ( Georgopoulos et al 2016 ) and interact with brain function to influence symptoms of GWI ( James et al, 2016 ). We also found an inverse relation between GWI symptom severity and the number of copies of the 6 protective HLA alleles, and that the frequency of those 6 alleles in veterans with GWI is significantly lower than in unaffected veterans ( Georgopoulos et al 2016 ).…”