Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!

Ariza, Maria E.

doi:10.3390/biom11020185

Cited by 53 publications

(75 citation statements)

References 125 publications

(170 reference statements)

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“…There are studies showing a statistically significant elevation of anti-EBV-dUTPase antibodies (75,76), a defective EBV-specific B and T cell response (77), a high rate of active EBV infection (28), serologic evidence of EBV reactivation with elevated IgM antibodies against late VCA antigen (78-80), and a positive up-regulation of EBV-induced gene 2 (EBI2) mRNA in peripheral blood mononuclear cells (PBMC) (3) from a subgroup of patients with ME/CFS. However, serological observations related to EBV were not always confirmed and, accordingly, the association between EBV infection and ME/ CFS is not established (81)(82)(83)(84)(85). Furthermore, the presence of an active EBV infection in a subgroup of ME/CFS patients has been actively debated, because most studies revealed no increase in EBV viral load in ME/CFS patients.…”

Section: A Hypothetical Association Between Ebv and Me/cfsmentioning

confidence: 99%

Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome

et al. 2021

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Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) affects approximately 1% of the general population. It is a chronic, disabling, multi-system disease for which there is no effective treatment. This is probably related to the limited knowledge about its origin. Here, we summarized the current knowledge about the pathogenesis of ME/CFS and revisit the immunopathobiology of Epstein-Barr virus (EBV) infection. Given the similarities between EBV-associated autoimmune diseases and cancer in terms of poor T cell surveillance of cells with EBV latency, expanded EBV-infected cells in peripheral blood and increased antibodies against EBV, we hypothesize that there could be a common etiology generated by cells with EBV latency that escape immune surveillance. Albeit inconclusive, multiple studies in patients with ME/CFS have suggested an altered cellular immunity and augmented Th2 response that could result from mechanisms of evasion to some pathogens such as EBV, which has been identified as a risk factor in a subset of ME/CFS patients. Namely, cells with latency may evade the immune system in individuals with genetic predisposition to develop ME/CFS and in consequence, there could be poor CD4 T cell immunity to mitogens and other specific antigens, as it has been described in some individuals. Ultimately, we hypothesize that within ME/CFS there is a subgroup of patients with DRB1 and DQB1 alleles that could confer greater susceptibility to EBV, where immune evasion mechanisms generated by cells with latency induce immunodeficiency. Accordingly, we propose new endeavors to investigate if anti-EBV therapies could be effective in selected ME/CFS patients.

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Section: A Hypothetical Association Between Ebv and Me/cfsmentioning

confidence: 99%

Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome

et al. 2021

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“…In this regard, a large proportion of patients report an acute infection at the onset of their symptoms ( 22 , 23 ). Herpesviruses such as the Epstein-Barr virus (EBV) and the human herpesvirus-6 (HHV6) were considered to be the main candidates for the causative agents of ME/CFS due to their high prevalence in adults and their reactivation observed in patients ( 11 , 24 , 25 ). To understand the role of these viruses on ME/CFS, many serological investigations were conducted with inconclusive or even contradicting findings ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank

et al. 2021

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The evidence of an association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and chronic herpesviruses infections remains inconclusive. Two reasons for the lack of consistent evidence are the large heterogeneity of the patients' population with different disease triggers and the use of arbitrary cutoffs for defining seropositivity. In this work we re-analyzed previously published serological data related to 7 herpesvirus antigens. Patients with ME/CFS were subdivided into four subgroups related to the disease triggers: S0-42 patients who did not know their disease trigger; S1-43 patients who reported a non-infection trigger; S2-93 patients who reported an infection trigger, but that infection was not confirmed by a lab test; and S3-48 patients who reported an infection trigger and that infection was confirmed by a lab test. In accordance with a sensitivity analysis, the data were compared to those from 99 healthy controls allowing the seropositivity cutoffs to vary within a wide range of possible values. We found a negative association between S1 and seropositivity to Epstein-Barr virus (VCA and EBNA1 antigens) and Varicella-Zoster virus using specific seropositivity cutoff. However, this association was not significant when controlling for multiple testing. We also found that S3 had a lower seroprevalence to the human cytomegalovirus when compared to healthy controls for all cutoffs used for seropositivity and after adjusting for multiple testing using the Benjamini-Hochberg procedure. However, this association did not reach statistical significance when using Benjamini-Yekutieli procedure. In summary, herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding could be eventually affected by the problem of multiple testing.

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“…Although its cause remains unknown, a growing body of evidence strongly associates ME/CFS with several microbial and viral infections, as potential trigger factors 3 , 4 . In addition, it has been hypothesized that reactivations of latent viral infections also play a role 5 , 6 due to several abnormalities at the level of the immune system 7 , 8 , 9 . On the molecular basis of the disease, peripheral blood mononuclear cells (PBMCs) show altered gene expression profiles [ 10 ], including a decreased abundance of the human angiotensin-converting enzyme 2 (ACE2) [ 11 ], the main cell entry receptor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 12 , 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in myalgic encephalomyelitis/chronic fatigue syndrome: A meta-analysis of public DNA methylation and gene expression data

Malato

Sotzny

Bauer

et al. 2021

Heliyon

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People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report a high frequency of viral infections and flu-like symptoms during their disease course. Since this reporting is in line with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed to explore whether the expression of the human angiotensin-converting enzyme-2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in this neglected clinical population. In particular, a low expression of ACE2 is usually indicative of a high risk of developing COVID-19. We then performed a meta-analysis of public data on CpG DNA methylation and gene expression of this enzyme and its homologous ACE protein in peripheral blood mononuclear cells and related subsets. We found that patients with ME/CFS have decreased methylation levels of four CpG probes in the ACE locus (cg09920557, cg19802564, cg21094739, and cg10468385) and of another probe in the promoter region of the ACE2 gene (cg08559914). We also found a decreased expression of ACE2 but not of ACE in patients with ME/CFS when compared to healthy controls. Accordingly, in newly collected data, we found evidence for a higher proportion of samples with an ACE2 expression below the limit of detection in patients with ME/CFS than in healthy controls. Altogether, patients with ME/CFS could be at a higher COVID-19 risk when infected by SARS-CoV-2. To further support this conclusion, similar research should be conducted for other human cell entry receptors and other cell types, namely, those mainly targeted by the virus.

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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!

Cited by 53 publications

References 125 publications

Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome

Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome

Herpesviruses Serology Distinguishes Different Subgroups of Patients From the United Kingdom Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Biobank

The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in myalgic encephalomyelitis/chronic fatigue syndrome: A meta-analysis of public DNA methylation and gene expression data

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