Sex-Dependent Transcriptional Changes in Response to Stress in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Project

Abstract

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.

Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation

“…Previous studies have identified sex-specific changes in RNA or microRNA profiles from PBMCs in ME/CFS. 28 , 29 We also performed correlation analyses between gene expression profiles of classical monocytes from all of the female samples and identified higher correlations within the same subject (self) over interindividual comparisons. Notably, interindividual variations among cases were higher than controls, consistent with ME/CFS heterogeneity ( Figure S3 B).…”

Interdisziplinäres, kollaboratives D-A-CH Konsensus-Statement zur Diagnostik und Behandlung von Myalgischer Enzephalomyelitis/Chronischem Fatigue-Syndrom

“…B., dass sich bei Menschen mit ME/CFS und Immundefekten andere potenzielle Marker nachweisen ließen als bei Betroffenen ohne zusätzlichen Immundefekt [ 51 ]. Bei Patient:innen mit PCS und ME/CFS zeigte sich, dass auch Frauen und Männer unterschiedliche Marker aufweisen [ 52 , 53 ]. Zudem könnte hier auch die Dauer der Erkrankung sowie der aktuelle Gesundheitszustand der Patient:innen (beispielsweise Gesundheitszustand ohne akute Exazerbation durch post-exertionelle Malaise (PEM) und während der PEM (siehe unten)) eine Rolle spielen, wie Xiong et al.…”

Epigenetic reprograming in myalgic encephalomyelitis/chronic fatigue syndrome: A narrative of latent viruses

“…Multiple viral infections have long been implicated in the onset and chronicity of ME/CFS pathology, but no single pathogen has been identified. Viruses predominantly linked to ME/CFS belong to the family of herpesviruses that include large double-stranded DNA viruses, notably Epstein-Barr virus (EBV) [51][52][53][54][55][56][57], human herpesvirus-6 (HHV-6) [58][59][60], HHV-7 [58,59], herpes simplex virus-1 (HSV-1), and HSV-2 [3,7,61]. Herpesviruses are common infectious agents within the general population that establish life-long latency in humans.…”