High levels of type 2 cytokine-producing cells in chronic fatigue syndrome

Skowera, Ania; Cleare, Anthony J.; Blair, Dorothy; Bevis, L.; Wessely, Simon; Peakman, Mark

doi:10.1111/j.1365-2249.2004.02354.x

Cited by 110 publications

(76 citation statements)

References 71 publications

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“…However, plasma levels of IL-10 in our patients did correlate inversely with their total sleep period, and our own earlier work using neural nets (12) as well as that of other groups studying cytokines in CFS also reported a shift of the cytokine network away from a proinflammatory and toward an antiinflammatory balance (25,27). Thus, the modest change in IL-10 reported here is consistent with the suggestion that patients with CFS show a shift toward Th2-type cytokines.…”

Section: Discussionsupporting

confidence: 91%

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

Nakamura

Schwander

Donnelly

et al. 2010

Clin Vaccine Immunol

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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...

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Section: Discussionsupporting

confidence: 91%

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

Nakamura

Schwander

Donnelly

et al. 2010

Clin Vaccine Immunol

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“…While the former analyses are unable to specify the cellular source, examination of intracellular cytokine expression is a powerful means of directly enumerating Th1 and Th2 cells, and has been widely used in the definition of cellular responses in patients with Th1-biasing viruses. Indeed, as discussed previously, this technique was, in our hands, able to detect Th2 skewing in CFS patients (Skowera et al 2004), while the identical approach was unable to find Th1/Th2 disturbance in UK veterans with Gulf Warrelated illness. Thus, the outcome of these studies is a negative one in terms of relating Th2 skewing to Gulf War service or Gulf War-related illness.…”

Section: Immunological Studies (A)supporting

confidence: 56%

“…(STAT1, 4, 6, signal transducer and activator of transcription 1, 4, 6; T-bet, Th1-specific T box transcription factor; GATA3, GATA binding protein 3; c-Maf, proto-oncogene c-maf, musculoaponeurotic fibrosarcoma oncogene homologue, maf is a family of genes encoding bZIP transcription factors; NFAT, nuclear factor of activated T cell; TSLP, thymic stromal lymphopoietin.) property Th1 Th2 cytokine production interleukin-2 (IL-2) IL-4, IL-6 interferon-g (IFN-g 'stress' effects on immune function in vitro or in vivo are complex and do not follow a simple Th1/Th2 pattern (Glaser & Kielcolt-Glaser 2005) the peripheral blood of CFS patients, we observed a significant increase in Th2 effector memory cells over normal values (Skowera et al 2004), and other studies similarly support a Th2 bias in this condition (Hanson et al 2001). However, Th2 effector memory cell numbers were not associated with clinical status in CFS patients in our study, nor with total or allergen-specific IgE levels or self-reported allergy, leading us to conclude that Th2 skewing might not reflect a primary pathogenetic process.…”

Section: Immunological Studies (A)mentioning

confidence: 85%

Immunological dysfunction, vaccination and Gulf War illness

Peakman

Skowera

Hotopf

2006

Phil. Trans. R. Soc. B

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One candidate cause of Gulf War illness is vaccination against infectious diseases including medical counter-measures against biological weapons. One influential theory has suggested that such mass-vaccination caused a shift in immune response to a Type 2 cytokine pattern (Th2), which it was suggested was accompanied by a chronic fatigue syndrome-like illness. This article critically appraises this theory. We start by examining epidemiological evidence, which indicates that single vaccines are unlikely to be a substantial cause of Gulf War illness, but that there was a modest relationship with multiple vaccines, which was strongest in those vaccinated while deployed to the Gulf. These relationships may be affected by recall bias. We conclude by examining the results of immunological studies carried out in veterans or in a relevant setting in vitro . The balance of evidence from immunological studies on veterans returning from the War, including those developing multi-symptom illness, is that the immune response has not become polarized towards Th2. In summary, the epidemiological evidence for a multiple vaccine effect on Gulf War-related illness remains a potentially important aetiological lead, but mechanistic studies available at this stage do not identify any immunological basis for it.

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“…STAT5A is a critical element in the proliferation and survival of Th2 cells (Hebenstreit et al, 2005;Lin and Leonard, 2000). Differential expression in STAT5A in CFS likely affects the Th1-Th2 cytokine balance, possibly favouring an anti-inflammatory/Th1 like immune response, while suppressing pro-inflammatory immune reactions (Ihle, 2001;Kagami et al, 2001;Saiki et al, 2008;Skowera et al, 2004).…”

Section: Cytokine and Chemokine Genesmentioning

confidence: 99%

“…Such adverse effects may cause shifts in the inflammatory profile causing either an increase or decrease in pro-and anti-inflammatory cytokines (Gupta et al, 1997;Vojdani et al, 1997). The exact profile of cytokines in CFS remains to be determined, although, a number of studies suggest that CFS is characterised by a predominant anti-inflammatory immune state (Skowera et al, 2004) others advocate a pro-inflammatory immune profile (Swanik et al). This mixed picture suggests dysregulation of the balance in pro-and anti-inflammatory mechanisms.…”

Section: Cytokine and Chemokine Genesmentioning

confidence: 99%