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Advances of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 May 2023) | Viewed by 60945

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Dr. Vincent C. Lombardi

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Department of Microbiology and Immunology, Reno School of Medicine, University of Nevada, Reno, NV 89557, USA
Interests: gut-brain axis; neuroimmune disease; GI-associated plasmacytoid dendritic cells; Alzheimer’s disease; myalgic encephalomyelitis
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Special Issue Information

Dear Colleagues,

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness of unknown etiology, characterized by multiple physical symptoms and comorbid conditions. Symptoms often reported by those with ME/CFS include unexplained fatigue that lasts for more than six months, post-exertional malaise, neurocognitive problems, unrefreshing sleep, and gastrointestinal issues. Clinical laboratory findings often include inflammatory sequelae, metabolic disturbances, self-reactive antibodies, and immune cell abnormalities. Although many of those who suffer from ME/CFS report that they developed the condition following a “flu-like” illness from which they never fully recover, an etiological agent has not been reproducibly identified. Likewise, many individuals infected by the SARS-CoV-2 virus often never fully recover and present with symptoms that significantly overlap with those of ME/CFS. This syndrome is typically referred to as long COVID-19 or post-acute sequelae of SARS COV-2 infection. In this Special Issue, which addresses the advances in research of myalgic encephalomyelitis/chronic fatigue syndrome, we aim to publish original research papers and reviews that focus on the involvement of the immune system in ME/CFS. Reports that leverage commonalities between ME/CFS and long COVID-19 to identify the mechanisms behind immune abnormalities are highly encouraged.

Dr. Vincent C. Lombardi
Guest Editor

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Keywords

ME/CFS
PASC
long COVID-19
inflammation
innate immunity
adaptive immunity
mast cell activation
post-infection syndrome
metabolism
autoantibodies

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Published Papers (8 papers)

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Research

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11 pages, 1111 KiB

Open AccessCommunication

Evidence of a Novel Mitochondrial Signature in Systemic Sclerosis Patients with Chronic Fatigue Syndrome

by Charmaine van Eeden, Desiree Redmond, Naima Mohazab, Maggie J. Larché, Andrew L. Mason, Jan Willem Cohen Tervaert and Mohammed S. Osman

Int. J. Mol. Sci. 2023, 24(15), 12057; https://doi.org/10.3390/ijms241512057 - 27 Jul 2023

Cited by 2 | Viewed by 2968

Abstract

Symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are common in rheumatic diseases, but no studies report the frequency of these in early systemic sclerosis. There are no known biomarkers that can distinguish between patients with ME/CFS, although mitochondrial abnormalities are often demonstrated. We sought to assess the prevalence of ME/CFS in limited cutaneous SSc (lcSSc) patients early in their disease (<5 years from the onset of non-Raynaud’s symptoms) and to determine if alterations in mitochondrial electron transport chain (ETC) transcripts and mitochondrial DNA (mtDNA) integrity could be used to distinguish between fatigued and non-fatigued patients. All SSc patients met ACR/EULAR classification criteria. ME/CFS-related symptoms were assessed through validated questionnaires, and the expression of ETC transcripts and mtDNA integrity were quantified via qPCR. SSc patients with ME/CFS could be distinguished from non-fatigued patients through ETC gene analysis; specifically, reduced expression of ND4 and CyB and increased expression of Cox7C. ND4 and CyB expression correlated with indicators of disease severity. Further prospective and functional studies are needed to determine if this altered signature can be further utilized to better identify ME/CFS in SSc patients, and whether ME/CFS in early SSc disease could predict more severe disease outcomes. Full article

(This article belongs to the Special Issue Advances of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS))

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17 pages, 3742 KiB

Open AccessArticle

Circulating miRNAs Expression in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

by Irene Soffritti, Sabine Gravelsina, Maria D’Accolti, Francesca Bini, Eleonora Mazziga, Anda Vilmane, Santa Rasa-Dzelzkaleja, Zaiga Nora-Krukle, Angelika Krumina, Modra Murovska and Elisabetta Caselli

Int. J. Mol. Sci. 2023, 24(13), 10582; https://doi.org/10.3390/ijms241310582 - 24 Jun 2023

Cited by 4 | Viewed by 5464

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multifactorial disease that causes increasing morbidity worldwide, and many individuals with ME/CFS symptoms remain undiagnosed due to the lack of diagnostic biomarkers. Its etiology is still unknown, but increasing evidence supports a role of herpesviruses (including HHV-6A and HHV-6B) as potential triggers. Interestingly, the infection by these viruses has been reported to impact the expression of microRNAs (miRNAs), short non-coding RNA sequences which have been suggested to be epigenetic factors modulating ME/CFS pathogenic mechanisms. Notably, the presence of circulating miRNAs in plasma has raised the possibility to use them as valuable biomarkers for distinguishing ME/CFS patients from healthy controls. Thus, this study aimed at determining the role of eight miRNAs, which were selected for their previous association with ME/CFS, as potential circulating biomarkers of the disease. Their presence was quantitatively evaluated in plasma from 40 ME/CFS patients and 20 healthy controls by specific Taqman assays, and the results showed that six out of the eight of the selected miRNAs were differently expressed in patients compared to controls; more specifically, five miRNAs were significantly upregulated (miR-127-3p, miR-142-5p, miR-143-3p, miR-150-5p, and miR-448), and one was downmodulated (miR-140-5p). MiRNA levels directly correlated with disease severity, whereas no significant correlations were observed with the plasma levels of seven pro-inflammatory cytokines or with the presence/load of HHV-6A/6B genome, as judged by specific PCR amplification. The results may open the way for further validation of miRNAs as new potential biomarkers in ME/CFS and increase the knowledge of the complex pathways involved in the ME/CFS development. Full article

(This article belongs to the Special Issue Advances of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS))

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21 pages, 2305 KiB

Open AccessArticle

Sex-Dependent Transcriptional Changes in Response to Stress in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Project

by Jackson Gamer, Derek J. Van Booven, Oskar Zarnowski, Sebastian Arango, Mark Elias, Asha Kurian, Andrew Joseph, Melanie Perez, Fanny Collado, Nancy Klimas, Elisa Oltra and Lubov Nathanson

Int. J. Mol. Sci. 2023, 24(12), 10255; https://doi.org/10.3390/ijms241210255 - 17 Jun 2023

Cited by 4 | Viewed by 3353

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multi-symptom illness characterized by debilitating fatigue and post-exertional malaise (PEM). Numerous studies have reported sex differences at the epidemiological, cellular, and molecular levels between male and female ME/CFS patients. To gain further insight into these sex-dependent changes, we evaluated differential gene expression by RNA-sequencing (RNA-Seq) in 33 ME/CFS patients (20 female, 13 male) and 34 matched healthy controls (20 female and 14 male) before, during, and after an exercise challenge intended to provoke PEM. Our findings revealed that pathways related to immune-cell signaling (including IL-12) and natural killer cell cytotoxicity were activated as a result of exertion in the male ME/CFS cohort, while female ME/CFS patients did not show significant enough changes in gene expression to meet the criteria for the differential expression. Functional analysis during recovery from an exercise challenge showed that male ME/CFS patients had distinct changes in the regulation of specific cytokine signals (including IL-1β). Meanwhile, female ME/CFS patients had significant alterations in gene networks related to cell stress, response to herpes viruses, and NF-κβ signaling. The functional pathways and differentially expressed genes highlighted in this pilot project provide insight into the sex-specific pathophysiology of ME/CFS. Full article

(This article belongs to the Special Issue Advances of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS))

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13 pages, 2045 KiB

Open AccessArticle

Detection of Elevated Level of Tetrahydrobiopterin in Serum Samples of ME/CFS Patients with Orthostatic Intolerance: A Pilot Study

by Carl Gunnar Gottschalk, Ryan Whelan, Daniel Peterson and Avik Roy

Int. J. Mol. Sci. 2023, 24(10), 8713; https://doi.org/10.3390/ijms24108713 - 13 May 2023

Cited by 2 | Viewed by 6392

Abstract

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a multisystem chronic illness characterized by severe muscle fatigue, pain, dizziness, and brain fog. Many patients with ME/CFS experience orthostatic intolerance (OI), which is characterized by frequent dizziness, light-headedness, and feeling faint while maintaining an upright posture. Despite intense investigation, the molecular mechanism of this debilitating condition is still unknown. OI is often manifested by cardiovascular alterations, such as reduced cerebral blood flow, reduced blood pressure, and diminished heart rate. The bioavailability of tetrahydrobiopterin (BH4), an essential cofactor of endothelial nitric oxide synthase (eNOS) enzyme, is tightly coupled with cardiovascular health and circulation. To explore the role of BH4 in ME/CFS, serum samples of CFS patients (n = 32), CFS patients with OI only (n = 10; CFS + OI), and CFS patients with both OI and small fiber polyneuropathy (n = 12; CFS + OI + SFN) were subjected to BH4 ELISA. Interestingly, our results revealed that the BH4 expression is significantly high in CFS, CFS + OI, and CFS + OI + SFN patients compared to age-/gender-matched controls. Finally, a ROS production assay in cultured microglial cells followed by Pearson correlation statistics indicated that the elevated BH4 in serum samples of CFS + OI patients might be associated with the oxidative stress response. These findings suggest that the regulation of BH4 metabolism could be a promising target for understanding the molecular mechanism of CFS and CFS with OI. Full article

(This article belongs to the Special Issue Advances of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS))

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18 pages, 1468 KiB

Open AccessArticle

Skin Temperature Circadian Rhythms and Dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Role of Endothelin-1 in the Vascular Tone Dysregulation

by Trinitat Cambras, Maria Fernanda Zerón-Rugerio, Antoni Díez-Noguera, Maria Cleofé Zaragozá, Joan Carles Domingo, Ramon Sanmartin-Sentañes, Jose Alegre-Martin and Jesus Castro-Marrero

Int. J. Mol. Sci. 2023, 24(5), 4835; https://doi.org/10.3390/ijms24054835 - 2 Mar 2023

Cited by 5 | Viewed by 4992

Abstract

There is accumulating evidence of autonomic dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); however, little is known about its association with circadian rhythms and endothelial dysfunction. This study aimed to explore the autonomic responses through an orthostatic test and analysis of the peripheral skin temperature variations and vascular endothelium state in ME/CFS patients. Sixty-seven adult female ME/CFS patients and 48 healthy controls were enrolled. Demographic and clinical characteristics were assessed using validated self-reported outcome measures. Postural changes in blood pressure, heart rate, and wrist temperature were recorded during the orthostatic test. Actigraphy during one week was used to determine the 24-h profile of peripheral temperature and activity. Circulating endothelial biomarkers were measured as indicators of endothelial functioning. Results showed that ME/CFS patients presented higher blood pressure and heart rate values than healthy controls in the supine and standing position (p < 0.05 for both), and also a higher amplitude of the activity rhythm (p < 0.01). Circulating levels of endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM-1) were significantly higher in ME/CFS (p < 0.05). In ME/CFS, ET-1 levels were associated with the stability of the temperature rhythm (p < 0.01), and also with the self-reported questionnaires (p < 0.001). This suggests that ME/CFS patients exhibited modifications in circadian rhythm and hemodynamic measures, which are associated with endothelial biomarkers (ET-1 and VCAM-1). Future investigation in this area is needed to assess dysautonomia and vascular tone abnormalities, which may provide potential therapeutic targets for ME/CFS. Full article

(This article belongs to the Special Issue Advances of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS))

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15 pages, 1228 KiB

Open AccessArticle

Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures

by Derek J. Van Booven, Jackson Gamer, Andrew Joseph, Melanie Perez, Oskar Zarnowski, Meha Pandya, Fanny Collado, Nancy Klimas, Elisa Oltra and Lubov Nathanson

Int. J. Mol. Sci. 2023, 24(3), 2698; https://doi.org/10.3390/ijms24032698 - 31 Jan 2023

Cited by 6 | Viewed by 13884

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion. Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM. Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs). Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells. During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options. Full article

(This article belongs to the Special Issue Advances of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS))

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Review

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27 pages, 2377 KiB

Open AccessReview

Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

by Jessica Maya

Int. J. Mol. Sci. 2023, 24(15), 11937; https://doi.org/10.3390/ijms241511937 - 26 Jul 2023

Cited by 5 | Viewed by 7907

Abstract

Millions globally suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The inflammatory symptoms, illness onset, recorded outbreak events, and physiological variations provide strong indications that ME/CFS, at least sometimes, has an infectious origin, possibly resulting in a chronic unidentified viral infection. Meanwhile, studies exposing generalized metabolic disruptions in ME/CFS have stimulated interest in isolated immune cells with an altered metabolic state. As the metabolism dictates the cellular function, dissecting the biomechanics of dysfunctional immune cells in ME/CFS can uncover states such as exhaustion, senescence, or anergy, providing insights into the consequences of these phenotypes in this disease. Despite the similarities that are seen metabolically between ME/CFS and other chronic viral infections that result in an exhausted immune cell state, immune cell exhaustion has not yet been verified in ME/CFS. This review explores the evidence for immunometabolic dysfunction in ME/CFS T cell and natural killer (NK) cell populations, comparing ME/CFS metabolic and functional features to dysfunctional immune cell states, and positing whether anergy, exhaustion, or senescence could be occurring in distinct immune cell populations in ME/CFS, which is consistent with the hypothesis that ME/CFS is a chronic viral disease. This comprehensive review of the ME/CFS immunometabolic literature identifies CD8+ T cell exhaustion as a probable contender, underscores the need for further investigation into the dysfunctional state of CD4+ T cells and NK cells, and explores the functional implications of molecular findings in these immune-cell types. Comprehending the cause and impact of ME/CFS immune cell dysfunction is critical to understanding the physiological mechanisms of ME/CFS, and developing effective treatments to alleviate the burden of this disabling condition. Full article

(This article belongs to the Special Issue Advances of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS))

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29 pages, 3110 KiB

Open AccessReview

Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID

by Warren P. Tate, Max O. M. Walker, Katie Peppercorn, Anna L. H. Blair and Christina D. Edgar

Int. J. Mol. Sci. 2023, 24(6), 5124; https://doi.org/10.3390/ijms24065124 - 7 Mar 2023

Cited by 11 | Viewed by 13013

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood. While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person. A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options. Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination. Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation. The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients. Full article

(This article belongs to the Special Issue Advances of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS))

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