Transcriptional changes in circulating immune cells of patients with Gulf War Illness

Background: Gulf War Illness (GWI) is a severely debilitating condition with chronic symptoms affecting up to 30% of the veterans deployed to the 1990-91 Persian Gulf War. The symptoms include fatigue, musculoskeletal/joint pain and disturbances of multiple organ systems. The mechanisms of GWI are unknown, and the spectrum of symptoms involved suggests that GWI is most likely caused by an interaction of genetic predisposition and environmental factors. Hypothesis: Expression and splicing of genes responsible for immune defense, cytokine-mediated signaling is changed by Gulf War Illness. Methods: We used RNA-seq to evaluate gene expression and alternative exon usage in the peripheral blood mononuclear cells (PBMC) of 20 male GWI patients and 20 matched healthy controls (HC) at T0 (baseline), T1 (VO2max, exercise challenge) and T2 (4 hours of rest after T1). After alignment using STAR, we used DESeq2 to evaluate differences in gene expression and DEXSeq to evaluate differences in exon usage. We compared transcriptomes between individuals with GWI and HC at each time point, and in responses to the exercise challenge. Results: At T0, 35 genes were differentially expressed between HC and GWI patients. Eight genes continued to be differentially expressed between HC and GWI patients at T1. An increased abundance of differentially expressed genes related to immune disorders and signaling was observed. Additionally, the observed changes in gene expression between time points (in response to exercise challenge) were smaller in GWI patients as compared to HC. There were no significant differences in exon usage between GWI patients and controls at T0, T1 and T2. We found significant differences only in controls at recovery (between T1 and T2). Conclusion: Our findings provide novel insights into the molecular changes associated with GWI enhancing the current understanding of the pathophysiological mechanisms of the disease.