Tag: EBV

Detection of herpes viruses in patients with myalgic encephalomyelitis /chronic fatigue syndrome in Belarus

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial chronic disease. The etiology and pathogenesis of ME/CFS are unknown. There are many theories for the occurrence of this disease. but the most convincing is the infectious or viral theory of the emergence of CFS.

The aim of this study is to detect of herpes viruses 6, 7 types and Epstein-Barr  to examine the prevalence HHV-6, HHV-7 and EBV infections in Belarus CFS patients.

We examined 30 patients with CFS in whom fatigue during  more than 2 years (7), more than 1 year (11) and more than 6 months (12). The diagnosis was made on clinical grounds using the Fukuda criteria.

The presence of markers the active forms  infection HHV-6 and HHV-7 in CFS patients with a long period of fatigue  were detected in 16.6% and 26.6% respectively. IgM  antibodies to HHV-6 and EBV. positive, in 16.6% and 6.7% respectively in patients with long-term illness. Detection of IgG antibodies indicates a quiet carrier state, latent phase.

Source: ORLOVA, Svetlana et al. Detection of herpes viruses in patients with myalgic encephalomyelitis /chronic fatigue syndrome in Belarus. Polish Journal of Applied Sciences, [S.l.], v. 6, n. 2, p. 50-53, dec. 2021. ISSN 2451-1544. Available at: <https://pjas.pwsip.edu.pl/index.php/pjas/article/view/176>. Date accessed: 10 jan. 2022. doi: https://doi.org/10.34668/PJAS.2020.6.2.08. (Full text)

Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue

Abstract:

Background: Epstein-Barr virus (EBV) causes infectious mononucleosis (IM) that can lead to chronic fatigue syndrome. The CEBA-project (Chronic fatigue following acute EBV infection in Adolescents) has followed 200 patients with IM and here we present an immunological profiling of adolescents with IM related to clinical characteristics.

Methods: Patients were sampled within 6 weeks of debut of symptoms and after 6 months. Peripheral blood mononuclear cells (PBMC) were cultured and stimulated in vitro (n=68), and supernatants analyzed for cytokine release. Plasma was analyzed for inflammatory markers (n=200). The Chalder Fatigue Questionnaire diagnosed patients with and without chronic fatigue at 6 months (CF+ and CF- group, respectively) (n=32 and n=91, in vitro and plasma cohorts, respectively.

Results: Broad activation of PBMC at baseline, with high levels of RANTES (Regulated on activation, normal T-cell expressed and secreted) in the CF+ group, and broad inflammatory response in plasma with high levels of T-cell markers was obeserved. At 6 months, there was an increased β-agonist response and RANTES was still elevated in cultures from the CF+ group. Plasma showed decrease of inflammatory markers except for CRP which was consistently elevated in the CF+ group.

Conclusion: Patients developing chronic fatigue after IM have signs of T-cell activation and low-grade chronic inflammation at baseline and after 6 months.

Clinical trial registration: https://clinicaltrials.gov/, identifier NCT02335437.

Source: Fevang B, Wyller VBB, Mollnes TE, Pedersen M, Asprusten TT, Michelsen A, Ueland T, Otterdal K. Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue. Front Immunol. 2021 Dec 20;12:715102. doi: 10.3389/fimmu.2021.715102. PMID: 34987499; PMCID: PMC8721200. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721200/ (Full text)

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

Abstract:

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.

Source: Ruiz-Pablos M, Paiva B, Montero-Mateo R, Garcia N, Zabaleta A. Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome. Front Immunol. 2021 Nov 15;12:656797. doi: 10.3389/fimmu.2021.656797. PMID: 34867935; PMCID: PMC8634673. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634673/ (Full text)

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

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown. Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome. New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.

Source: Ariza ME. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back! Biomolecules. 2021 Jan 29;11(2):185. doi: 10.3390/biom11020185. PMID: 33572802. https://www.mdpi.com/2218-273X/11/2/185 (Full text)

Pain in adolescent chronic fatigue following Epstein-Barr virus infection

Abstract:

Objectives: Acute Epstein-Barr virus (EBV) infection is a trigger of Chronic Fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to investigate pain symptoms and pressure pain thresholds in fatigued and non-fatigued adolescents six months after acute EBV-infection, and in healthy controls. This study is part of the CEBA-project (CF following acute EBV infection in adolescents).

Methods: A total of 195 adolescents (12-20 years old) that had undergone an acute EBV infection six months prior to assessment were divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of seventy healthy controls was included. Symptoms were mapped with questionnaires. Pressure pain thresholds were measured through pressure algometry. One way ANOVA were used for between-group analyses. Linear regression analyses were used to explore associations between Pediatric Quality of Life (dependent variable), pain symptoms and other variables within the EBV (CF+) group.

Results: The EBV CF+ group had significantly higher scores for pain symptoms as compared with the EBV CF- group and healthy controls, but pressure pain threshold did not differ significantly. The number of pain symptoms as well as pain severity were strongly and independently associated with quality of life.

Conclusions: CF and CFS following acute EBV-infection in adolescents is characterized by high pain symptom burden, which in turn is associated with a decline in quality of life. Pain in CF and CFS is of considerable clinical importance, and should be a focal point for further investigation and intervention in these patient groups.

Source: Brodwall EM, Pedersen M, Asprusten TT, Wyller VBB. Pain in adolescent chronic fatigue following Epstein-Barr virus infection [published online ahead of print, 2020 Sep 7]. Scand J Pain. 2020;/j/sjpain.ahead-of-print/sjpain-2020-0031/sjpain-2020-0031.xml. doi:10.1515/sjpain-2020-0031  https://pubmed.ncbi.nlm.nih.gov/32892183/

Commentary: Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Introduction: Studies to ascertain a possible relationship between herpesviruses and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have relied heavily on classical approaches, specifically, serological examination for antibodies against virus proteins, primarily structural, and/or increases in viral load (1–21). These data have been conflicting due in part to several features: the heterogeneity of the disease, high prevalence of the herpesviruses in the population since they can establish lifelong infections, and differences between laboratories. Two additional problems lead to conflicting data in serological studies: which viral antigens are to be used for detection, and what is the possible relationship, if any, of these viral antigens to ME/CFS? These are important questions that must be addressed for any data to provide meaningful insight into the possible contribution of a virus to the pathophysiology of ME/CFS. Although the experimental techniques used in Blomberg’s serological study were appropriate, the selection of specific herpesviruses and viral antigens studied gives a limited view of the humoral response in ME/CFS.

Discussion: Blomberg et al. (22) used a suspension multiplex immunoassay to detect antibodies against various herpesviruses’ antigens, derived from proteins expressed during latency or late lytic replication (Figure 1), with the goal of determining differences in antibody titers against these antigens between ME/CFS patients and controls. However, no rationale was given as to why these particular antigens were chosen and what association, if any, they may have with ME/CFS. This is important because the antigenic properties of the different virus proteins are not the same. As demonstrated in an eloquent study by Vaider-Shalt et al. (23), over the course of their evolution, herpes simplex virus 1 (HSV-1), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), and human cytomegalovirus have decreased the number of epitopes present in virus proteins in order to help them avoid immune detection. Thus, the ability of a virus protein to generate an antibody response is dependent upon the amount of protein present in the host and its antigenicity. It is also not clear why Blomberg et al. (22) included HSV-1/2, human cytomegalovirus, HHV-7, and varicella zoster virus (VZV) in their study since there are no up-to-date literature reports establishing a serological relationship between these viruses and ME/CFS.

Source: Ariza ME. Commentary: Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Front Immunol. 2020;11:1400. Published 2020 Jul 23. doi:10.3389/fimmu.2020.01400 https://www.frontiersin.org/articles/10.3389/fimmu.2020.01400/full (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a hyper-regulated immune system driven by an interplay between regulatory T cells and chronic human herpesvirus infections

Abstract:

Autoimmunity and chronic viral infections are recurrent clinical observations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a complex disease with an unknown cause. Given these observations, the regulatory CD4+ T cells (Tregs) show promise to be good candidates for the underlying pathology due to their known capacity to suppress the immune responses not only to body components but also against infections. Here we discussed the overlooked role of these cells in the chronicity of Human Herpes Virus 6 (HHV6), Herpes Simplex 1 (HSV1) and Epstein-Barr virus (EBV), as often reported as triggers of ME/CFS.

Using simulations of the Cross-regulation model for the dynamics of Tregs, we illustrated that mild infections might lead to a chronically activated immune responses under control of Tregs if the responding clone has a high autoimmune potential. Such infections promote persistent inflammation and possibly fatigue. We then hypothesized that ME/CFS is a condition characterized by a predominance of this type of infections under control of Tregs. In contrast, healthy individuals are hypothesized to trigger immune responses of a virus-specific clone with a low autoimmune potential.

According to this hypothesis, simple model simulations of the CD4+ T-cell repertoire could reproduce the increased density and percentages of Tregs observed in patients suffering from the disease when compared to healthy controls. A deeper analysis of Tregs in the pathogenesis of ME/CFS will help to assess the validity of this hypothesis.

Source: Nuno Sepúlveda, Jorge Carneiro, Eliana M. Lacerda and Luis C. Nacul. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a hyper-regulated immune system driven by an interplay between regulatory T cells and chronic human herpesvirus infections. Front. Immunol. | doi: 10.3389/fimmu.2019.02684. https://www.frontiersin.org/articles/10.3389/fimmu.2019.02684/abstract

Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors

Abstract:

Epstein-Barr virus (EBV) is a ubiquitous human virus which infects almost all humans during their lifetime and following the acute phase, persists for the remainder of the life of the individual. EBV infects B lymphocytes leading to their immortalisation, with persistence of the EBV genome as an episome. In the latent phase, EBV is prevented from reactivating through efficient cytotoxic cellular immunity.

EBV reactivates (lytic phase) under conditions of psychological stress with consequent weakening of cellular immunity, and EBV reactivation has been shown to occur in a subset of individuals with each of a variety of cancers, autoimmune diseases, the autoimmune-like disease, chronic fatigue syndrome/myalgic encephalitis and under other circumstances such as being an inpatient in an intensive care unit.

Chronic EBV reactivation is an important mechanism in the pathogenesis of many such diseases, yet is rarely tested for in immunocompetent individuals. This review summarises the pathogenesis of EBV infection, EBV reactivation and its role in disease, and methods which may be used to detect it. Known inhibitors of EBV reactivation and replication are discussed, including drugs licensed for treatment of other herpesviruses, licensed or experimental drugs for various other indications, compounds at an early stage of drug development and nutritional constituents such as vitamins and dietary supplements.

Source: Kerr JR. Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors. J Clin Pathol. 2019 Jul 17. pii: jclinpath-2019-205822. doi: 10.1136/jclinpath-2019-205822. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31315893

A Validated Scale for Assessing the Severity of Acute Infectious Mononucleosis

Abstract:

OBJECTIVES: To develop a scale for the severity of mononucleosis.

STUDY DESIGN: One to 5 percent of college students develop infectious mononucleosis annually, and about 10% meet criteria for chronic fatigue syndrome (CFS) 6 months following infectious mononucleosis. We developed a severity of mononucleosis scale based on a review of the literature. College students were enrolled, generally when they were healthy. When the students developed infectious mononucleosis, an assessment was made as to the severity of their infectious mononucleosis independently by 2 physicians using the severity of mononucleosis scale. This scale was correlated with corticosteroid use and hospitalization. Six months following infectious mononucleosis, an assessment is made for recovery from infectious mononucleosis or meeting 1 or more case definitions of CFS.

RESULTS: In total, 126 severity of mononucleosis scales were analyzed. The concordance between the 2 physician reviewers was 95%. All 3 hospitalized subjects had severity of mononucleosis scores ≥2. Subjects with severity of mononucleosis scores of ≥1 were 1.83 times as likely to be given corticosteroids. Students with severity of mononucleosis scores of 0 or 1 were less likely to meet more than 1 case definition of CFS 6 months following infectious mononucleosis.

CONCLUSIONS: The severity of mononucleosis scale has interobserver, concurrent and predictive validity for hospitalization, corticosteroid use, and meeting criteria for CFS 6 months following infectious mononucleosis.

Copyright © 2019 Elsevier Inc. All rights reserved.

Source: Katz BZ, Reuter C, Lupovitch Y, Gleason K, McClellan D, Cotler J, Jason LA. A Validated Scale for Assessing the Severity of Acute Infectious Mononucleosis. J Pediatr. 2019 Mar 7. pii: S0022-3476(19)30123-4. doi: 10.1016/j.jpeds.2019.01.035. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30853204

Serological profiling of the EBV immune response in Chronic Fatigue Syndrome using a peptide microarray

Abstract:

BACKGROUND: Epstein-Barr-Virus (EBV) plays an important role as trigger or cofactor for various autoimmune diseases. In a subset of patients with Chronic Fatigue Syndrome (CFS) disease starts with infectious mononucleosis as late primary EBV-infection, whereby altered levels of EBV-specific antibodies can be observed in another subset of patients.

METHODS: We performed a comprehensive mapping of the IgG response against EBV comparing 50 healthy controls with 92 CFS patients using a microarray platform. Patients with multiple sclerosis (MS), systemic lupus erythematosus (SLE) and cancer-related fatigue served as controls. 3054 overlapping peptides were synthesised as 15-mers from 14 different EBV proteins. Array data was validated by ELISA for selected peptides. Prevalence of EBV serotypes was determined by qPCR from throat washing samples.

RESULTS: EBV type 1 infections were found in patients and controls. EBV seroarray profiles between healthy controls and CFS were less divergent than that observed for MS or SLE. We found significantly enhanced IgG responses to several EBNA-6 peptides containing a repeat sequence in CFS patients compared to controls. EBNA-6 peptide IgG responses correlated well with EBNA-6 protein responses. The EBNA-6 repeat region showed sequence homologies to various human proteins.

CONCLUSION: Patients with CFS had a quite similar EBV IgG antibody response pattern as healthy controls. Enhanced IgG reactivity against an EBNA-6 repeat sequence and against EBNA-6 protein is found in CFS patients. Homologous sequences of various human proteins with this EBNA-6 repeat sequence might be potential targets for antigenic mimicry.

Source: Loebel M, Eckey M, Sotzny F, Hahn E, Bauer S, Grabowski P, Zerweck J, Holenya P, Hanitsch LG, Wittke K, Borchmann P, Rüffer JU, Hiepe F, Ruprecht K, Behrends U, Meindl C, Volk HD, Reimer U, Scheibenbogen C. Serological profiling of the EBV immune response in Chronic Fatigue Syndrome using a peptide microarray. PLoS One. 2017 Jun 12;12(6):e0179124. doi: 10.1371/journal.pone.0179124. eCollection 2017. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179124 (Full article)