Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multi-symptom illness characterized by debilitating fatigue and post-exertional malaise (PEM). Numerous studies have reported sex differences at the epidemiological, cellular, and molecular levels between male and female ME/CFS patients. To gain further insight into these sex-dependent changes, we evaluated differential gene expression by RNA-sequencing (RNA-Seq) in 33 ME/CFS patients (20 female, 13 male) and 34 matched healthy controls (20 female and 14 male) before, during, and after an exercise challenge intended to provoke PEM. Our findings revealed that pathways related to immune-cell signaling (including IL-12) and natural killer cell cytotoxicity were activated as a result of exertion in the male ME/CFS cohort, while female ME/CFS patients did not show significant enough changes in gene expression to meet the criteria for the differential expression. Functional analysis during recovery from an exercise challenge showed that male ME/CFS patients had distinct changes in the regulation of specific cytokine signals (including IL-1β). Meanwhile, female ME/CFS patients had significant alterations in gene networks related to cell stress, response to herpes viruses, and NF-κβ signaling. The functional pathways and differentially expressed genes highlighted in this pilot project provide insight into the sex-specific pathophysiology of ME/CFS.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion. Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM. Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs). Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells. During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options.

Gulf War Illness (GWI) is a multi-symptom disorder affecting 1990–1991 Persian Gulf War veterans and is characterized by post-exertional malaise, neurological symptoms, immune deregulation, and exhaustion. Causation is not understood, and effective diagnostics and therapies have not yet been developed. In this work, we analyzed stress-related, sex-specific transcriptomic shifts in GWI subjects and healthy controls through RNA sequencing of peripheral blood mononuclear cells (PBMCs). Blood samples at baseline (T0), at maximal exertion (T1), and four hours post-exertion (T2) were analyzed. In female subjects with GWI, pathways associated with pro-inflammatory processes were found to be deregulated, and in male GWI subjects, pathways related to IL-12 signaling and lymphocytic activation were deregulated at T1 compared to T0. During recovery from stress, pathways corresponding to immune responses and microglial cell activation were altered in female GWI subjects, and apoptotic signaling changed in males with GWI. Documented sex-specific immune deregulation leads to finding better biomarkers. Targeting sex-specific transcriptomic markers of the disease could lead to new therapies for GWI.

Gulf War Illness (GWI) is a multi-symptom disorder affecting 1990–1991 Persian Gulf War veterans and is characterized by post-exertional malaise, neurological symptoms, immune deregulation, and exhaustion. Causation is not understood, and effective diagnostics and therapies have not yet been developed. In this work, we analyzed stress-related, sex-specific transcriptomic shifts in GWI subjects and healthy controls through RNA sequencing of peripheral blood mononuclear cells (PBMCs). Blood samples at baseline (T0), at maximal exertion (T1), and four hours post-exertion (T2) were analyzed. In female sub-jects with GWI proinflammatory processes, and in male subjects IL-12 signaling and lymphocytic activation were deregulated at T1compared to T0. During recovery from stress, HCMV activity and microglia activation increased in female GWI subjects, and apoptotic signaling changed in males with GWI. Documented sex-specific immune deregulation warrants personalized markers and therapies. Targeting sex-specific transcriptomic markers of disease could lead to new therapies for GWI.