Cytokine signature associated with disease severity in chronic fatigue syndrome patients

Abstract

Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine's preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.

Keywords: chronic fatigue syndrome; cytokines; immune monitoring; myalgic encephalomyelitis; severity.

Fig. 1.

Mean cytokine levels in healthy controls (Con) and ME/CFS patients grouped by mild, moderate (Mod), and severe (Sev) disease. Means for pMFI ± 1 SE for each cytokine are shown within vertical brackets. The dotted horizontal line within each cytokine panel represents the average value for healthy controls. Statistically significant comparisons of disease severity level vs. healthy controls (adjusted P < 0.05, Table 3) are in red. Results were adjusted for multiple comparisons, and covariates of age, sex, race, and nonspecific binding. Depression of resistin and elevation of TGF-β in cases overall are each evident (Table 2) as are nonlinear trends across disease severity levels in ICAM1 and resistin (Table 4).

Fig. 2.

Mean cytokine levels with statistically significant linear trends in ME/CFS patients grouped by mild, moderate (Mod), and severe (Sev) disease compared with healthy controls (Con). Mean pMFI ± 1 SE are shown as vertical brackets for each cytokine. P values shown are for the significance of the linear trend. Only statistically significant linear trends adjusted for multiple comparisons (P < 0.05) are shown. All results shown in this figure were also adjusted for age, sex, race, and nonspecific binding. The dotted horizontal line within each cytokine panel represents the average value for healthy controls.