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

Abstract

BackgroundGulf War Illness (GWI) is a multisystem disorder that has affected a substantial number of veterans who served in the 1990–91 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. We reported previously on the protective role of six Human Leukocyte Antigen (HLA) alleles in GWI (Georgopoulos et al., 2016) and their association with regional brain function (James et al., 2016). More recently, we reported on the presence of subcortical brain atrophy in GWI (Christova et al., 2017) and discussed its possible relation to immune mechanisms. Here we focused on one of the six HLA GWI-protective HLA alleles, DRB1*13:02, which has been found to have a protective role in a broad range of autoimmune diseases (Furukawa et al., 2017), and tested its effects on brain volumes.MethodsSeventy-six Gulf War veterans (55 with GWI and 21 healthy controls) underwent a structural Magnetic Resonance Imaging (sMRI) scan to measure the volumes of 9 subcortical brain regions to assess differences between participants with (N = 11) and without (N = 65) HLA class II allele DRB1*13:02.FindingsWe found that DRB1*13:02 spared subcortical brain atrophy in Gulf War veterans; overall subcortical volume was 6.6% higher in carriers of DRB1*13:02 (P = 0.007). The strongest effect was observed in the volume of cerebellar gray matter which was 9.6% higher (P = 0.007) in carriers of DRB1*13:02 than in non-carriers. By contrast, DRB1*13:01 had no effect.InterpretationThese findings document the protective effect of DRB1*13:02 on brain atrophy in Gulf War veterans and are in keeping with recent results documenting sharing of brain mechanisms between GWI and other immune-related diseases (Georgopoulos et al., 2017). We hypothesize that the protective role of DRB1*13:02 is due to its successful elimination of external antigens to which Gulf War veterans were exposed, antigens that otherwise would persist causing low-grade inflammation and possibly leading to autoimmunity.Funding source (W81XWH-15-1-0520), , and .

The effects of human leukocyte antigen DRB1*13 and apolipoprotein E on age-related variability of synchronous neural interactions in healthy women

“…Successful elimination of such antigens depends on a match between a specific antigen and one's HLA composition. A mismatch, on the other hand, prevents elimination of the antigen, and the “persistent antigen” [ 16 ] may lead to inflammation, cell damage, autoimmunity [ 40 ], and atrophy [ 14 ]. Evidence suggests that antigens related to several common illnesses including influenza A, hepatitis B and C, and herpes virus bind to HLA DRB1*13:02 and HLA DRB1*13:01 [ 41 ], thereby facilitating elimination of those antigens.…”

“…In summary, neuroprotection by DRB1*13 could be exerted by (a) eliminating persistent neurotoxic antigens [ 16 ], (b) limiting the presence of cathepsin S, a known endogenous harmful substance in brain aging [ 48 ], to which DRB1*13:02 binds with high, and DRB1*13:01 with lower, affinity [ 49 ], and (c) limiting the presence of amyloid A beta by facilitating the production of autoantibodies against it [ 47 ]. Concerning apoE, the detrimental effects of E4 and various mechanisms of action have been well established and investigated, as reviewed above.…”

“…Like apoE, however, some HLA genes appear to be protective in terms of cognitive function and brain health [ [13] , [14] , [15] ]. For example, the HLA DRB1 gene has been linked to enhanced cognitive performance among healthy adults [ 15 ], and studies of this gene at the protein level have shown that the DRB1*13:02 allele protects against age-related brain atrophy in cognitively healthy adults [ 14 ] and in Gulf War Illness [ 16 ]. Furthermore, the DRB1*13:02 allele has been shown to exert protective effects against several neuroimmune conditions [ 13 , [17] , [18] , [19] ].…”

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

“…Subjects with MDD have an overall decreased volume of grey matter (Matsuo et al, 2017), and more specifically regions of the brain associated with emotional processing such as the area 9 of the dorsolateral pre-frontal cortex (Cotter et al, 2002) and the amygdala (Hamidi et al, 2004). Furthermore, in subjects with Gulf War Veterans Illness (GWVI), a set of disorders specific to veterans of the Gulf War and characterized by fatigue, memory impairment, and depression, there was an established increase of subcortical atrophy, which was increased in veterans who lacked the DRB1*13:02 HLA Allele (James et al, 2017). This MHCII allele is known to confer protection against auto inflammatory conditions such as rheumatoid arthritis (Feitsma et al, 2008) and provides an interesting link between autoinflammatory conditions and genetic contributions to pathogen recognition by the innate immune system.…”

Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness

“…Furthermore, the observation that a subset of veterans developed GWI, while nearly all soldiers were likely exposed to some combination of toxicants in theater, strongly supports the hypothesis that veterans with GWI may harbor some specific genetic-susceptibility. In the most recent publication from the Georgopoulos group, James et al (2017) expand upon several of their previous studies verifying the protective role of HLA alleles related to brain function ( Georgopoulos et al, 2015 , James et al, 2016 ) in the observed subcortical brain atrophy associated with GWI ( Christova et al, 2017 ). Here, James et al’s (2017) evaluation of subcortical brain volumes in Gulf War veterans supported the suspected protective effect of the HLA class II allele DRB1*13:02 by finding a significantly higher subcortical volume in carriers of this allele.…”