Cytokine profiling of extracellular vesicles isolated from plasma in myalgic encephalomyelitis/chronic fatigue syndrome: a pilot study

Ludovic Giloteaux, Adam O'Neal, Jesús Castro-Marrero, Susan M Levine, Maureen R Hanson, Ludovic Giloteaux, Adam O'Neal, Jesús Castro-Marrero, Susan M Levine, Maureen R Hanson

Abstract

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease of unknown etiology lasting for a minimum of 6 months but usually for many years, with features including fatigue, cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Dysregulation of cytokine signaling could give rise to many of these symptoms. Cytokines are present in both plasma and extracellular vesicles, but little investigation of EVs in ME/CFS has been reported. Therefore, we aimed to characterize the content of extracellular vesicles (EVs) isolated from plasma (including circulating cytokine/chemokine profiling) from individuals with ME/CFS and healthy controls.

Methods: We included 35 ME/CFS patients and 35 controls matched for age, sex and BMI. EVs were enriched from plasma by using a polymer-based precipitation method and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM) and immunoblotting. A 45-plex immunoassay was used to determine cytokine levels in both plasma and isolated EVs from a subset of 19 patients and controls. Linear regression, principal component analysis and inter-cytokine correlations were analyzed.

Results: ME/CFS individuals had significantly higher levels of EVs that ranged from 30 to 130 nm in size as compared to controls, but the mean size for total extracellular vesicles did not differ between groups. The enrichment of typical EV markers CD63, CD81, TSG101 and HSP70 was confirmed by Western blot analysis and the morphology assessed by TEM showed a homogeneous population of vesicles in both groups. Comparison of cytokine concentrations in plasma and isolated EVs of cases and controls yielded no significant differences. Cytokine-cytokine correlations in plasma revealed a significant higher number of interactions in ME/CFS cases along with 13 inverse correlations that were mainly driven by the Interferon gamma-induced protein 10 (IP-10), whereas in the plasma of controls, no inverse relationships were found across any of the cytokines. Network analysis in EVs from controls showed 2.5 times more significant inter-cytokine interactions than in the ME/CFS group, and both groups presented a unique negative association.

Conclusions: Elevated levels of 30-130 nm EVs were found in plasma from ME/CFS patients and inter-cytokine correlations revealed unusual regulatory relationships among cytokines in the ME/CFS group that were different from the control group in both plasma and EVs. These disturbances in cytokine networks are further evidence of immune dysregulation in ME/CFS.

Keywords: Cytokines; Extracellular vesicles; Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Plasma.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Sizing and quantification of Extracellular Vesicles. Size in nm (a), total concentration (b), 30–130 nm concentration (c) and > 130 nm concentration (d) of particles per ml of plasma in ME/CFS subjects and healthy controls (CTRL) as determined by Nanoparticle Tracking Analysis. The yellow dot represents the mean
Fig. 2
Fig. 2
Characterization of Extracellular Vesicles. (a) Morphology of isolated EVs from ME/CFS was confirmed by transmission electron microscopy (a representative image is shown; scale bars: 200 nm and 500 nm) and (b) Western blot analysis of isolated EVs from healthy controls (CTRL) and ME/CFS subjects as representative samples. Thirty μg of protein was loaded in each lane and probed with specific antibodies to EV protein markers. Cytochrome C (mitochondrial marker) was used as negative control for EV and positive for PBMCs
Fig. 3
Fig. 3
Principal Component analysis of cytokine levels in ME/CFS vs. controls. In plasma (a), in EVs (b) and (c) cytokine levels in EVs vs. plasma. The Hopkins statistic values H are shown for each PCA
Fig. 4
Fig. 4
Cytokine–cytokine correlations in plasma. Network diagrams of cytokine interactions in plasma of ME/CFS patients (a), and in controls (b). Grey edges indicate positive correlations and black bold lines negative associations. The Venn diagram (c) shows the number of significant cytokine-cytokine associations common to both groups and unique to each group. In red are the number of negative correlations. All correlations in this analysis were determined using partial Spearman’s ranked correlation adjusted for age and BMI
Fig. 5
Fig. 5
Cytokine–cytokine correlations in extracellular vesicles. Network diagrams of cytokine interactions in EVs of ME/CFS patients (a), and in controls (b). Grey edges indicate positive correlations and black bold lines negative associations. The Venn diagram (c) shows the number of significant cytokine-cytokine associations common to both groups and unique to each group. In red are the number of negative correlations. All correlations in this analysis were determined using partial Spearman’s ranked correlation adjusted for age and BMI

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