Reduced Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI)

Abstract

BackgroundGulf War Illness (GWI) is a disease of unknown etiology with symptoms suggesting the involvement of an immune process. Here we tested the hypothesis that Human Leukocyte Antigen (HLA) composition might differ between veterans with and without GWI.MethodsWe identified 144 unique alleles of Class I and II HLA genes in 82 veterans (66 with and 16 without GWI). We tested the hypothesis that a subset of HLA alleles may classify veterans in their respective group using a stepwise linear discriminant analysis. In addition, each participant rated symptom severity in 6 domains according to established GWI criteria, and an overall symptom severity was calculated.FindingsWe found 6 Class II alleles that classified participants 84.1% correctly (13/16 control and 56/66 GWI). The number of copies of the 6 alleles was significantly higher in the control group, suggesting a protective role. This was supported by a significant negative dependence of overall symptom severity on the number of allele copies, such that symptom severity was lower in participants with larger numbers of allele copies.InterpretationThese results indicate a reduced HLA protection (i.e. genetic susceptibility) in veterans with GWI.FundingUniversity of Minnesota and U.S. Department of Veterans Affairs.

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

“…The cause (or causes) of GWI are unknown, as is the pathophysiology of the disorder. Diverse lines of evidence have implicated three major factors as triggers, including (i) various vaccinations (Georgopoulos et al, 2015, Israeli, 2012, Toubi, 2012), (ii) various chemical exposures (Institute of Medicine National Research Council, 2000, Steele et al, 2015) and (iii) various kinds of stress, and, typically, combinations thereof, since all GW veterans were vaccinated, exposed to low doses of nerve gas, and subjected to strenuous basic training. Beyond specific effects of each one of these factors (White et al, 2016), a common denominator shared by all is their effects on the immune system.…”

“…Recently, we focused our research on a different aspect of immune function, at the intersection of immunity and genetics, namely on the Human Leukocyte Antigen (HLA) (Georgopoulos et al, 2015). HLA genes are located in the Major Histocompatibility Complex (MHC) of chromosome 6 and play a central role in immune recognition (Meuer et al, 1982).…”

“…Indeed, we identified 6 Class II HLA alleles which, when present, conferred protection from GWI. Presence or absence of those alleles classified correctly healthy and GWI veterans, respectively and, depending of the number of copies of alleles present, conferred graded alleviation in GWI symptom severity (Georgopoulos et al, 2015). Those alleles were: DRB1*01:01, DRB1*08:11, DRB1*13:02, DQB1*02:02, DPB*01:01, and DPB1*06:01.…”

Supporting a Neuroimmune Basis of Gulf War Illness

“…A prior report in EBioMedicine by Georgopoulos and colleagues (Georgopoulos et al, 2015) provided insight into a basis for a genetic/immune role in GWI by showing that higher counts for six Class II human leukocyte antigen (HLA) alleles conferred protective effects in GW veterans based on lowered symptom severity. 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.…”

“…As discussed in the commentary of the prior report (Georgopoulos et al, 2015) provided by Wojcik and Lawrie (2015), illness results from war, in general, and the number of studies evaluating the role of stressors in GWI, as well as the implementation of programs to support soldiers both pre- and post-deployment, highlights the impact that stressors have on deployment-related disease. Previously, there has been a tendency to label GWI as a psychological disorder (see discussion by Steele, 2000, Research Advisory Committee on Gulf War Veterans' Illnesses, 2004).…”