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Gulf War illness with or without post-traumatic stress disorder: differential symptoms and immune responses

The Original Article was published on 02 January 2024

Over one-third of 700,000 military personnel who served in the first Gulf War (GW) suffer from an assortment of symptoms, including cognitive and memory problems, musculoskeletal pain, gastrointestinal discomfort, fatigue, and respiratory issues [1, 2]. The precise etiology of Gulf War illness (GWI) is unclear. However, epidemiological and preclinical studies imply that exposures to the prophylactic drug pyridostigmine bromide, insecticides, pesticides, smoke from oil well fires, and interaction between these exposures and war-related stress underlie this illness [2]. As per the Kansas case definition, GWI is a chronic multi-symptom illness displaying one moderately severe and/or multiple symptoms of any severity in at least three of six symptom domains (fatigue, pain, neurological/cognitive/mood, skin, gastrointestinal, respiratory) [1, 2]. While the exact pathophysiological changes underlying GWI have not been identified, alterations in immune regulation and dysregulation of the redox balance have been observed in GWI, resulting in chronic systemic inflammation and neuroinflammation [2].

Post-traumatic stress disorder (PTSD) is a trauma-associated disorder that typically transpires in some individuals who underwent or viewed a petrifying, awful, or threatening event [3]. The symptoms comprise 1) re-experiencing in the form of recollections, nightmares, and terrifying thoughts; 2) avoidance typified by emotional detachment, avoidance of events, places, or objects; 3) hyperarousal distinguished by tensed feeling, being easily startled, and sleeping difficulties; and 4) cognitive and/or mood impairments indicated by difficulty remembering the traumatic event, anhedonia, undesirable views about oneself and the world [4]. PTSD is slightly more frequent in veterans (approximately 7%) than civilians (approximately 6%). However, the frequency of PTSD is much higher (approximately 35%) in GW veterans [5]. The presence of PTSD makes the diagnosis of GWI difficult because of many analogous symptoms and pathophysiological alterations.

A study by Sultana et al. [5] attempted to dissociate differential symptoms and immune cell responses in GWI with or without PTSD. The study comprised three cohorts of male GW veterans from Miami and Boston with or without GWI. Based on PTSD-related symptoms, the GWI group was further subdivided into with high or low probability of PTSD symptoms subgroups (GWIH and GWIL). The study employed multiple measures to assess symptom scales. Analysis of the blood samples comprised a complete blood cell count, cytokine analysis, flow cytometry, and natural killer (NK) cell cytotoxicity. Data were analyzed separately for the three cohorts; only one completed the exercise challenge. Compared with veterans without GWI, veterans in both GWIH and GWIL subgroups displayed worse symptoms, with the GWIH subgroup exhibiting the most severe symptoms. Interestingly, compared with veterans without GWI (healthy control group), the concentration of interleukin-15 (IL-15) was lower in the GWIL subgroup but not in the GWIH subgroup. The populations of CD3+CD56+ NK cells reduced in both GWIH and GWIL subgroups, but the differences did not reach statistical significance. However, the population of CD2+CD26+ cells increased by approximately 15% at peak exercise in veterans of the GWIL subgroup. While both GWI subgroups displayed a reduced percentage of basophils, the GWIL subgroup exhibited reduced NK cell activity compared with GWIH subgroup [5]. The GWIL subgroup from the Miami cohort also displayed reduced IL-15 following exercise challenge compared with GWIH subgroup.

The study by Sultana et al. [5] uncovered several significant findings aiding the differentiation of GWI with or without PTSD. First, while basophils reduced in both GWIL and GWIH subgroups at peak exercise, the reduction was greater in GWIL subgroup. As basophils regulate T cells to mediate immune response, lower levels support an altered immune profile in GWI. However, it remains to be investigated whether lower basophil numbers at peak exercise could be a biomarker of GWI compared with healthy sedentary veterans. The second important finding is that GWIL veterans displayed lower IL-15 levels (approximately 50–60%) than GWIH and healthy control group. Such reduced IL-15 level could potentially serve as a biomarker of GWI, as reduced IL-15 level was apparent at both rest and post-exercise in GWIL veterans (i.e., GWI subgroup without PTSD). Additionally, this subgroup displayed reduced NK cell activity and NK cell surface antigens (CD3CD56 or CD3CD16). These results are consistent with the role of IL-15 in the development, differentiation, and survival of NK cells [5, 6]. However, deficiency in NK cells in GWIL group was only significant at peak exercise. CD26 regulates T, B, myeloid, and NK cells, and abnormal CD26 levels have been observed in autoimmune diseases. Because of inter-relationships between CD2+CD26+ cells, IL-15, and NK cells, elevated levels of CD2+CD26+ cells typically mean higher levels of IL-15 and NK cell activity. The lack of such observation in the study by Sultana et al. [5] suggests a dysregulated immune response in GWI. Overall, the findings from the GWIL subgroup in this study re-iterated that PTSD is not the underlying factor for the development and clinical presentation of GWI.

Why IL-15 level did not differ between the GWIH and healthy control group is intriguing. One reason for this could be the association of PTSD with elevated IL-15 level, implying that the occurrence of PTSD comorbidity in veterans with GWI prevents the decreased IL-15 level, compared with veterans with GWI alone. Such observations highlight the need for further investigations on IL-15 level and NK cells in the immunological dysfunction associated with GWI and PTSD. One of the limitations of this study, also identified by the authors, is the lack of a PTSD-alone subgroup. The inclusion of a PTSD-alone subgroup in future studies would allow the analysis and differentiation between different biomarkers to further dissociate GWI without PTSD from GWI associated with PTSD. Furthermore, the exercise challenge was applied to only one cohort in the study. Such studies in larger cohorts of veterans with GWI would be critical to understanding differential responses of GWIL and GWIH subgroups and confirming a dysregulated immune response in GWI.

Availability of data and materials

All data needed to evaluate the conclusions of this commentary are present in the article.

Abbreviations

GW:

Gulf War

GWI:

Gulf War illness

GWIH :

Gulf War illness with high probability of PTSD symptoms

GWIL :

Gulf War illness with low probability of PTSD symptoms

IL-15:

Interleukin-15

PTSD:

Post-traumatic stress disorder

NK:

Natural killer

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Funding

This work was supported by grants from the Department of Defense (W81XWH-17-1-0447 and W81XWH1910548 to AKS) and the Texas A&M University School of Medicine.

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FN and AKS reviewed the findings in the manuscript and interpreted their implications. FN was a major contributor to writing the commentary. All authors read and approved the final manuscript.

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Correspondence to Ashok K. Shetty.

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Nguyen, F., Shetty, A.K. Gulf War illness with or without post-traumatic stress disorder: differential symptoms and immune responses. Military Med Res 11, 5 (2024). https://doi.org/10.1186/s40779-023-00508-1

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