Cytokines across the Night in Chronic Fatigue Syndrome with and without Fibromyalgia

Abstract

The symptoms of chronic fatigue syndrome (CFS) are consistent with cytokine dysregulation. This has led to the hypothesis of immune dysregulation as the cause of this illness. To further test this hypothesis, we did repeated blood sampling for cytokines while patients and matched healthy controls slept in the sleep lab. Because no one method for assaying cytokines is acknowledged to be better than another, we assayed for protein in serum, message in peripheral blood lymphocytes (PBLs), and function in resting and stimulated PBLs. We found no evidence of proinflammatory cytokine upregulation. Instead, in line with some of our earlier studies, we did find some evidence to support a role for an increase in interleukin-10, an antiinflammatory cytokine. Although the changes were small, they may contribute to the common complaint in CFS patients of disrupted sleep.Chronic fatigue syndrome (CFS) is a medically unexplained illness lasting at least 6 months and characterized by severe fatigue that produces a substantial reduction in activity accompanied by at least four of the following symptoms: sore throat, tender lymph nodes, headache, myalgia, arthralgia, unrefreshing sleep, difficulty concentrating, and the report of syndromic exacerbation following mild exertion (7). One major hypothesis for the cause of CFS is an immune dysregulation of unknown etiology with high levels of proinflammatory cytokines producing the CFS symptom complex. Two findings fostered this idea: first, approximately a third of CFS patients report a sudden, influenza-like onset of their illness (37), and second, administration of proinflammatory cytokines leads to many of the same symptoms seen in CFS (26). However, we recently reviewed the literature on this hypothesis and found relatively little empirical data to support it (20); a more recent small study did report higher levels of one such cytokine, serum transforming growth factor ␤, in patients than in controls (35); however, another group did not confirm this result (30). Other work extending the research to cellular production of proinflammatory cytokines was also negative (1).However, a very different and alternative hypothesis focuses on the common complaint in CFS of unrefreshing sleep (4).Recent work suggests that sleep is under the control of a cytokine/sleep network where normal sleep follows a balanced secretion of pro-and anti-inflammatory cytokines (13). We hypothesized that CFS might result from an imbalance of this network in favor of the anti-inflammatory cytokines which are sleep disrupting (14). Supporting this possibility is the result of a recent study (28) in which we sampled blood for cytokines every 20 min across a 24-h day in patients with fibromyalgia (FM) (28), a medically unexplained, diffuse pain syndrome that has substantial overlap with CFS (5). Of several pro-and anti-inflammatory cytokines studied, the only one to show differences from controls, i.e., increases, was the anti-inflammatory cytokine interleukin-10 (IL-10), and that was true only for nocturnal dat...

Exercise and Sleep Deprivation Do Not Change Cytokine Expression Levels in Patients with Chronic Fatigue Syndrome

“…We found that levels of IL-10, an anti-inflammatory cytokine, were significantly higher during nighttime sleep in patients than in matched controls but not during the period prior to sleep (8). We recently completed a large study using multiple methods to assay for cytokines during the sleep of CFS patients with and without FM (9). That study also found increases in nocturnal IL-10 in patients with CFS only but not in patients with both CFS and FM.…”

“…The subjects then awoke between 7:15 and 8:00 a.m., after which a final blood sample was taken. The sleep and cytokine data from this normal night have been published elsewhere (9).…”

“…The cell culture incubation periods and cell densities for the various cytokine ELISPOT assays were chosen on the basis of results from previously published studies (18)(19)(20) and the recommendations of the manufacturer of each kit. We also provided extensive methodological details about the three assays used to determine cytokine concentrations (9).…”

“…Following a night to habituate subjects to sleeping in the sleep lab and to eliminate from further study the subjects with sleep pathology (see our earlier paper [9] for details), subjects returned for a normal night of sleep. Upon arrival at the sleep lab, subjects underwent venous catheterization to allow remote blood sampling without disturbance, were instrumented for polysomnography, and went to bed at their usual bedtime.…”

“…Previously, we developed a preprocessing method that systematically removes extreme outlier values from cytokine data in order to improve the Gaussianity of their distributions (9). To do this, the outliers were defined as the data that exceeded the confidence area estimated from a locally weighted regression model.…”