Blood Interferon – Chronic Fatigue Syndrome
A study published in the February issue of the new journal Science Advances is perhaps the first to identify distinct stages of chronic fatigue syndrome (CFS). Importantly, it demonstrates some immune signatures early in the course of CFS that are not present in subjects with longer duration of illness.
Chronic fatigue syndrome is a disabling disorder with complex features that can include fatigue, memory and concentration deficits, sleep disturbances, headache, joint and muscle pain, postexertional malaise, and gastrointestinal and immune system dysfunction, lasting for 6 months or more.
The diagnosis of CFS is largely based on recognition of signs and symptoms by experienced clinicians. Although laboratory assays play a role in the diagnostic process, they are used to rule out other conditions that can mimic aspects of CFS, rather than as biomarkers to facilitate early diagnosis. Efforts to identify immune biomarkers in CFS have produced inconsistent result.
Although efforts were made to identify a specific biological pattern, there are no trustful biomarkers or validated laboratory test for the diagnosis or management of CSF.
In an attempt to discover reliable biological markers related to chronic fatigue syndrome, Mady Hornig and colleagues from the Center for Infection and Immunity at the Columbia University’s Mailman School of Public Health, New York, USA determined the levels of 51 cytokines and chemokines in chronic fatigue syndrome patients from two large multicenter studies.
This is the first study to demonstrate altered plasma immune signatures early in the course of chronic fatigue syndrome that are not present in subjects with longer duration of illness.
In the Science Advances study these authors reported specific cytokine patterns during the early phase (≤3 years) of CSF, including high plasma levels of IL-1α, IL-1RA, IL-4, IL-8, IL-12p40, IL-13, IL-17A, TNF-α and MCP1. Of particular interest was the marked association of interferon (IFN)-γ with the early phase of illness that was detected through logistic regression modeling.
IFNγ is a product of activated T cells [particularly CD8+ and CD4+ T helper 1 (TH1) cells], natural killer cells, as well as activated macrophages in the periphery and microglia in the central nervous system. Some studies in CFS, but not all, have found plasma levels of IFNγ to be elevated, with effects restricted to males in one study.
IFNγ may accelerate degradation of tryptophan, resulting in depletion of the neurotransmitters serotonin and melatonin in the central nervous system through activation of indoleamine-2,3-dioxygenase, a rate-limiting enzyme in the kynurenine pathway. Activation of this pathway also results in increased levels of quinolinic acid, a neurotoxic compound that acts as an agonist at glutamatergic [NMDA (N-methyl-d-aspartate)] receptors
Of note, IFN- γ is known to modulate brain’s neuronal activity, affecting mood, sleep, temperature regulation and the endocrine system. Also, high levels of IFN- γ can lead to depressive states and physical tiredness similar to the observed in CSF patients, due to the degradation of tryptophan and reducing brain levels of serotonin and melatonin (M Maes et al., 2007; AH Miller et al., 2013).
The Hornig et al. study is consistent with the hypothesis of a viral trigger of this condition and, as discussed by the Center for Infection and Immunity Website at Columbia University, it may also substantiate the idea that ME/CFS reflects an infectious ‘hit-and-run’event. Overall; the study indicates that CSF is an immunological and not a psychological disease.
Early in the course of CFS, as determined by this study, specific immune profiles may have important implications for early diagnosis. This may also suggest new therapeutic and immunomodulatory interventions, which in this condition may be transient or time-limited.
Source: Science Advances, 2015, 1, no1:e1400121. DOI: 10.1126/sciadv.140012
Read More: Science Advances
Updates
2016
A 2016 study by Lindsey Russel et al. suggested that IL-1α, 6 and 8 adjusted for illness duration may serve as robust biomarkers, independent of age, in screening for ME/CFS.
Another 2016 study by Abdolamir Landi et al. suggested that the clustered reduction of IL-7, IL-16 and VEGF-A may have physiological relevance to ME/CFS disease. The authors believe that this profile is ME/CFS-specific since measurement of the same analytes present in chronic infectious and autoimmune liver diseases, where persistent fatigue is also a major symptom, failed to demonstrate the same changes.
2019
A 2019 study by Alice Russell et al. presented interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. It is known that IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation.
According to the authors, this is the first study to investigate IFN-α induced persistent fatigue as a proxy model of Chronic Fatigue Syndrome. The authors found that around 30% of patients reported persistent fatigue (PF) at the follow-up six-months after the end of IFN-α treatment, despite the original immune stimulus no longer being present.
They also found that those who developed persistent fatigue had a more rapid increase in fatigue early during IFN-α treatment, as well as higher IL-10 levels before treatment, and IL-10 and IL-6 levels early on during IFN-α treatment – that is, more than one year before the persistent fatigue phenotype was established.
However, this initial immune activation was no longer associated with persistent fatigue at the six-month follow-up, when the persistent fatigue phenotype was established, nor was it present in a group of CFS patients used as a clinical reference group.
Highlights
- Baseline fatigue is not associated with the development of persistent fatigue after IFN-α.
- IFN-α-induced persistent fatigue is associated with increased baseline IL-10.
- Patients who develop persistent fatigue experience greater increases in IL-6 and 10 in response to IFN-α.
- Persistently fatigued patients recover at a similar rate, but from a more severe acute response to the initial trigger.
- Once established, neither the persistent fatigue phenotype, nor CFS, are associated with peripheral immune activation.
2025
A 2025 review by Jonathan Edwards, Geraldine Cambridge and Jacqueline M Cliff proposed a hypothesis for ME/CFS that centers on a form of persistent, inappropriate, ‘neuroimmune hypervigilance’ mediated primarily by T lymphocyte-macrophage interaction but influenced by IgG antibody binding to the gamma interferon-inducible high affinity immunoglobulin receptor FcγRI. This proposed mechanism could explain why the illness resembles post-infective T cell-mediated autoinflammatory syndromes in age of onset and time course but has a female preponderance similar to autoantibody-mediated disease.
In brief, the authors suggest that the available evidence relating to ME/CFS points to a role for both antibodies and T cells in a form of ‘hypervigilant’ immune activation in which both FcγRI and gamma interferon may have a central place.
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