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.
Introduction
Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a life-limiting, multi-system disease for which there is no effective treatment (1). It is characterized by unexplained disabling fatigue and a combination of unspecific symptoms that last for at least 6 months (2, 3). At least nine disease definitions have been developed. Its prevalence ranges in between 0.1% and 2.5% of the general population (4), depending on the diagnostic criteria being applied (Supplemental Table 1). The annual incidence of cases with ME/CFS in the United Kingdom is of 14.8 per 100,000 people (5).
Pathogenesis of ME/CFS
The cause of this syndrome is unknown. However, there is a growing body of evidence supporting the role of dysfunction in immune, neuro-endocrine, and autonomic systems, and several biologically based theories are currently being investigated. Hormonal alterations have been identified in some individuals with ME/CFS, whereby hypocortisolism might produce fatigue-like symptoms (1, 6–8). Lipid and energy metabolism dysfunction are also thought to contribute to the etiology of ME/CFS. Genetic predisposition or common environmental exposure to infectious or toxic agents, may be associated with some family histories with high prevalence of ME/CFS (1, 9–14).
Infectious triggering a chronic inflammatory response has long been a hypothesized risk factor for the development of ME/CFS due to the large number of individuals with a history of infection prior to the onset of symptoms. Clinical manifestations of the disease such as chronic fatigue and flu-like symptoms, may be explained by the presence immunological alterations leading to reduced cytotoxic activity and altered metabolism of natural killer (NK) cells and T lymphocytes, reduced T cell responses to mitogens and other specific antigens, or the presence of chronic low-grade systemic inflammation with increased levels of proinflammatory cytokines and oxidative stress (1, 2, 15–18).
Another hypothesis is autoimmunity due to the presence of autoantibodies against nuclear, membrane and neurotransmitter receptor structures in some patients (1, 19). This hypothesis has prompted several research groups to seek for an association between the expression of certain HLA-II alleles and the development of ME/CFS. Accordingly, HLA-DQA1*01, HLA-DQB1*06 (20), DQB1*0303 (21), HLA-DQ3, HALA-DR4 and HLA-DR5 (22) have been associated with increased risk of ME/CFS, but the robustness of the data supporting this association is limited (20, 23). Thus, the possibility that some individuals with genetic predisposition may develop ME/CFS after stimulus (e.g., infection) and subsequent autoimmunity, remains to be demonstrated (12, 20, 22). In such cases, the diagnostic criteria could take into account the pathogen involved in the disease onset, which could potentially improve patient’ stratification and management.
Interestingly, ME/CFS was first described in reference to a post Epstein-Barr fatigue. Infection with viruses such as Epstein-Barr (EBV), but also with human herpesvirus (HHV) -6, cytomegalovirus (CMV), human parvovirus B19 and enteroviruses (24–30), as well as bacterial and parasite infections (31), have been suggested as risk factors. However, infection prior to its onset is not true of all ME/CFS patients and its etiological significance remains uncertain.
Here, we revisited the immunopathobiology of EBV infection before summarizing contradictory data about a possible association between chronic EBV infection and ME/CFS in some patients. Consistent with this hypothesis, we finalized this mini review describing possible therapeutic options against EBV.
Immunopathobiology of the Epstein-Barr Virus
EBV belongs to the family of γ-herpesvirus (32). Amongst other cell types, it infects B cells of adjacent lymphoid tissues before establishing a lifelong latent infection in memory B cells (I/0 latencies). Indeed, the virus maintains a latent state as an episome without expressing viral genes, allowing B cells with latency 0 and some B cells with latency I to escape immune surveillance (Figure 1A) (33–36).
Figure 1
Efficient B cell infection by EBV requires up to 5 envelope glycoproteins, whereby gp42 ultimately promotes entry of the virus into B cells through the interaction with host MHC class II molecules (37, 38). Gp42 binds to β1 domain of the β chain of HLA-DR -DQ, or –DP and blocks TCR-HLA-DR interactions impairing antigen presentation (37–39). Hence, gp42-expressing B cells show reduced ability to activate CD4 T cells (37). Furthermore, gp42 can be presented as a membrane protein bound to MHC-II molecules or in a soluble form (s-gp42). Both have been detected during the lytic phase in Burkitt lymphoma (latency I), suggesting that soluble gp42 is generated during EBV lytic infection and inhibits the presentation of HLA-II restricted antigens to T cells (40). Noteworthy, EBNA-1 specific cytotoxic CD4 T cells are decreased in patients with post-transplant lymphoproliferative disorders (41), in some pediatric forms of Burkitt lymphoma (42, 43), in EBV-positive lymphoma (44), in lymphomas associated with HIV infection (45), and in lymphoma infiltrating the central nervous system (45). By contrast, the immune response in healthy individuals is sufficient to control EBV infection (35, 46).
Genetic Predisposition to EBV Infection
The diversity of human leukocyte antigen (HLA) molecules results from selective pressure during co-evolution with pathogens (47, 48). A characteristic of HLA diversity is the long-term persistence of allelic lineages, which causes trans-species polymorphisms to be shared among closely related species (48). In humans, there are 13 allelic lineages of DRB1 (48) and, according to the phylogenetic relationship between the different DRB genes of primates (hominoids, New World and Old World monkeys) described by Bontrop et al, the DRB1*04, *03 and *02 lineages are the oldest, with the DRB1*04 lineage being the most ancestral (49). Since EBV is the only human-adapted member of the genus Lymphocryptovirus, transferred to a hominid ancestor (50), it could be hypothesized that immune evasion mechanisms of the EBV have more effectively evolved among older allelic lineages of DRB1. Such an hypothesis could help explaining why individuals with haplotypes DR2-DQ6, DR3-DQ2 or DR4-DQ8 are less resistant to EBV infection and are at greater risk of developing EBV-related disorders (Supplemental Table 2) (34).
Other genetic predisposition factors to consider are glutamic acid 46 (E46) and arginine 72 (R72) from HLA class II molecules (51). R72 is fully preserved in the HLA-DR, HLA-DQ and -DP sequences (52); by contrast, E46 is conserved in all HLA-DR,-DP alleles and only in a small subset of HLA-DQ alleles β * 02 (β * 0201, β * 0202 and β * 0203) (53). This suggests that individuals with HLA-DQ alleles β * 02 may have higher susceptibility to infection in tissues with cells expressing only HLA-DQ, as well as a higher rate of EBV infection in those cells expressing different HLA class II isotypes along with HLA-DQ β * 02 (53).
EBV-Associated Diseases
EBV is present in more than 90% of the population and the decreased ability of the immune system to control/eliminate EBV infection may be responsible for causing EBV-associated diseases (35, 54) such as rheumatoid arthritis (34, 55, 56), systemic lupus erythematosus (34, 57, 58), Sjögren’s syndrome (34), multiple sclerosis (59–61), myasthenia gravis (62), diabetes mellitus type 1 (53), fulminant type diabetes (63), celiac disease (64), autoimmune thyroiditis (65, 66), Hodgkin and non-Hodgkin lymphoma (35, 67) (Supplemental Table 2).
Tissue infiltrating B cells with EBV latency in a genetically predisposed individual, would trigger the activation of virus-specific IFN-γ producing Th1 CD4 T cells. High IFN-γ levels would induce the upregulation of MHC class II molecules (Figure 1B) on the surface of different cell types (e.g., epithelial cells, endothelial cells, pancreatic beta cells, fibroblasts, keratinocytes, glial cells, etc.), allowing them to function like non-professional antigen-presenting cells. Likewise, MHC class II upregulation would improve the infection capacity of EBV through the interaction with gp42 (68, 69). Co-expression of MHC-II molecules and CD21 (e.g., thymocytes, a subset of peripheral T lymphocytes, follicular dendritic cells, astrocytes and some epithelial cells) would further increase the risk of EBV infection through the interaction between gp350 and CD21 (69). These mechanisms have been hypothesized in patients with autoimmune thyroiditis with EBV transformed B cell infiltrate in the thyroid tissue (65, 66). The same principle could potentially apply to the intestinal mucosa in celiac disease (70), to the pancreatic islets in type 1 diabetes (53), to the central nervous system and multiple sclerosis (60, 71), to the exocrine glands and the Sjögren’s syndrome (34, 72), to the thymus and myasthenia gravis (62), as well as to the synovial joints and rheumatoid arthritis (38, 73, 74). Can the same principle be applied to a subgroup of patients with ME/CFS?
A Hypothetical Association Between EBV and ME/CFS
As mentioned above, EBV infection has been identified as a risk factor in a subgroup of ME/CFS patients (3, 28, 75). 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 (81–85). 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. If a third state of virus, defined as abortive/lytic/leaky replication (86) could explain the presence of certain EBV proteins (BRRF1 and BLLF3) with the potential capacity to contribute to the symptomatology of ME/CFS (82, 87), is an hypothesis that remains unconfirmed.
Multiple studies in patients with ME/CFS have demonstrated decreased cytotoxic activity of NK cells, increased IL-10 levels and augmented Th2 response. Also an expansion of Tregs and impaired T cell response to mitogens and other specific antigens (1, 2, 12, 16, 88–91). Based on the mechanisms of immune-escape developed by latency I (EBNA-1) cells, established after primary EBV infection, a cause-effect association between EBV infection and the disease onset in a subgroup of ME/CFS patients, could be hypothesized. Accordingly, IL-10 released by both EBV-transformed B cells and Tregs would favor a Th2 type immune response (43), and gp42-mediated disruption of TCR-MHC-II interaction would further decrease CD4 T cell activation, leading to poor CD4 T cell immunity to mitogens and other specific antigens, which have been described in some patients with ME/CFS (2). All these immune evasion mechanisms triggered by latent cells induce an immunodeficiency that allows EBV-transformed B cells, especially EBV latent I cells, to escape from immune surveillance. This could potentially help explaining the reduced EBNA-1-specific CD4 T-cell response, increased EBV latent cells (77), and increased EBV abortive lytic replication (EBV dUTPase in exosomes) (75), observed in a subgroup of patients with ME/CFS. If the infiltration and proliferation of EBV-transformed B cells in the intestinal mucosa is related to the chronic inflammation that is observed in some ME/CFS patients (15, 92–94), remains unknown. However, the results described above and the hypotheses we generated accordingly, must be interpreted with caution because there are numerous other studies that failed to reproduce the findings of decreased cytotoxic activity of NK cells, increased IL-10 levels and augmented Th2 response (83, 89, 90, 95–97). These discrepancies may be due to disease heterogeneity, different degrees of ME/CFS severity and duration, and different analytical methods (15, 28, 89, 97–99).
If the hypotheses described above were to be true, the subgroup of ME/CFS patients with EBV infection could have increased risk of developing autoimmune diseases (19, 100, 101), latent viral reactivations (e.g., herpesviruses, Parvovirus B19) and cancer (83, 102–107), namely EBV-associated lymphoma (108). Additionally, HLA-II alleles associated with increased EBV susceptibility may also explain the higher prevalence of cancer and autoimmune disorders (Figure 1C), such as rheumatoid arthritis and type 1 diabetes, in first-degree relatives of patients with ME/CFS (15, 19, 100, 109, 110). Notwithstanding, the high prevalence of EBV among the general population hinders the identification of this putative subset of patients who developed ME/CFS following infection. This is in agreement with EBV serological assessments performed in patients and healthy individuals, from where no conclusive results have been observed (85). Similarly, most studies reported no increase in EBV viral load in patients with ME/CFS (84, 111). If this is due to the fact that the possible trigger of some EBV-associated diseases are the EBV-latent cells rather than viral load (34, 35, 43, 63, 66, 67, 112–114), remains unknown in ME/CFS. Thus, to our knowledge, there is scarce evidence based in prospective cohort studies, describing rates and associations with post-infective fatigue syndrome (i.e., ME/CFS) following proven acute EBV.
Therapeutic Options Against EBV: Is There a Role in ME/CFS?
Limited knowledge about the origin of ME/CFS has hampered the development of effective treatment. Current strategies include administering nutritional supplements to overcome deficiencies and symptomatic treatment with analgesics, steroids or antidepressants (Supplemental Table 3) (1, 115). Thus, if a putative association between EBV infection and the onset of ME/CFS exists, the development of biomarkers that could identify patients in whom this may occur, would create a window of opportunity for tailored treatment against EBV.
B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS (116). Similarly, results of trials using antivirals have been inconclusive and, in some cases, contradictory (115). Accordingly, anecdotal observations of the resolution of symptoms in some ME/CFS patients with elevated levels of anti-EBV antibodies, after treatment with rituximab (100, 117) or antivirals (e.g., valaciclovir and valgancinclovir) (118, 119), have not been confirmed in large series. If B-cell depletion agents and antivirals were poised to show greater efficacy if used in a putative subgroup of patients in whom acute EBV triggered ME/CFS, remains obviously unknown. Furthermore there are no effective treatments to eradicate EBV latency in patients with EBV-associated disorders (120–122). Antiviral agents do not eradicate latent cells (120, 121), while rituximab does not remove all EBV-infected cells nor restores cellular immunity against EBV. Moreover, it induces further immunosuppression by targeting CD20 positive infected and uninfected healthy B cells (120, 122, 123). The combination of antiviral agents or intravenous immunoglobulins with rituximab can be used to treat EBV-associated disorders (121), but merely prolongs time until next relapse, since the combination of both therapies does not completely eliminate EBV infection in genetically predisposed hosts.
Other treatments such as EBV-specific adoptive T cell immunotherapy could potentially yield some benefit (124), since EBNA-1 is expressed during the lytic cycle, as well as by almost all EBV-infected cells, with the exception of those with latency 0 (125–127). However, EBNA-1 is poorly immunogenic and is not always presented in MHC class II molecules of B cells with EBV latency (46); thus, these cells (especially those with latency I) could escape EBNA-1-specific T cell immunotherapy. Another alternative proposed by Dalton et al. is the use of low doses of DNA demethylation agents (e.g., decitabine and 5-azacitidine) during a short period (Figure 2A) for the treatment of latency I EBV-associated lymphoma, which induces the transformation of latent I B-cells into latent II and III, thereby allowing EBV-specific T cells to recognize them due to increased expression of immunogenic viral antigens (i.e., LMP1, EBNA2, EBNA3A and EBNA3C) (128). Such an effect could even persist after treatment interruption (128). Furthermore, DNA demethylation agents may restore the expression of HLA-II molecules in EBV-transformed lymphoblastoid cell lines (129, 130) and induce apoptosis in EBV-transformed epithelial cells (Figure 2B) (131, 132). Therefore, if our hypothesis about the presence of an acquired immunodeficiency after EBV infection in genetically predisposed individuals with EBV-associated diseases holds true, it could be speculated that low-dose DNA demethylation agents for short-term treatment followed by EBV-specific T cell immunotherapy (128) and antiviral agents (because of the increased lytic infection by the use of DNA demethylation agents) could be beneficial. Such an approach may also be potentially useful in cases where ME/CFS develops from other viruses such as the HHV-6, CMV and human parvovirus B19 (24–29), since these DNA viruses use CpG DNA methylation as an immune evasion mechanism. Namely, the viral genome is largely methylated during the latency phase thereby preventing viral expression and genome replication; instead, it is restored to a non-methylated state during the lytic phase during latency, which is restored to a non-methylated state during the lytic phase (133–136).
Figure 2
Conclusions and Future Directions
If the link between EBV infection and ME/CFS could be demonstrated, it would warrant future research endeavors on a potential association between decreased activation of CD4 T cells and HLA class II alleles with greater predisposition to EBV infection. Such biomarkers could help to better define a hypothetical subgroup of patients with EBV-associated ME/CFS. Additional research about the efficacy of anti-EBV therapies in these patients would then be warranted. The identification of successful treatment would potentially prevent the development of this or other diseases associated with this pathogen. Interestingly, a recent prospective study investigating risk factors for developing ME/CFS in college students following infectious mononucleosis, found that those who developed ME/CFS had more physical symptoms and immune irregularities at baseline (137). If the association between the expression of certain HLA-II alleles and higher susceptibility to develop ME/CFS exists, individuals with post infectious mononucleosis fatigue syndrome could be an interesting group to study and test the hypothesis discussed in this review.
Funding
Ramsay Award Program 2019 Cycle from the Solve ME/CFS Initiative.
Publisher’s Note
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Statements
Author contributions
All the authors listed have made a substantial, direct, and intellectual contribution to this manuscript and have approved it for publication.
Acknowledgments
We are grateful to the Solve ME/CFS initiative and to the University of Navarra for having supported and trusted our team for research on Myalgic Encephalomyelitis or Chronic Fatigue Syndrome. All Figures were Created with BioRender.com.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.656797/full#supplementary-material
References
1
Cortes RiveraMMastronardiCSilva-AldanaCArcos-BurgosMLidburyB. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review. Diagnostics (2019) 9(3):91.
2
LorussoLMikhaylovaSVCapelliEFerrariDNgongaGKRicevutiG. Immunological Aspects of Chronic Fatigue Syndrome. Autoimmun Rev Elsevier (2009) 8:287–91. doi: 10.1016/j.autrev.2008.08.003
3
KerrJR. Epstein-Barr Virus Induced Gene-2 Upregulation Identifies a Particular Subtype of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Front Pediatrics Front Media SA (2019) 7:59. doi: 10.3389/fped.2019.00059
4
BakkenIJTveitoKGunnesNGhaderiSStoltenbergCTrogstadLet al. Two Age Peaks in the Incidence of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Population-Based Registry Study From Norway 2008-2012. BMC Med (2014) 12(1):167. doi: 10.1186/s12916-014-0167-5
5
CollinSMBakkenIJNazarethICrawleyEWhitePD. Trends in the Incidence of Chronic Fatigue Syndrome and Fibromyalgia in the UK, 2001–2013: A Clinical Practice Research Datalink Study. J R Soc Med (2017) 110(6):231–44. doi: 10.1177/0141076817702530
6
Torres-HardingSSorensonMJasonLMaherKFletcherMAReynoldsNet al. The Associations Between Basal Salivary Cortisol and Illness Symptomatology in Chronic Fatigue Syndrome. J Appl Biobehav Res (2008) 13(3):157–80.
7
TakLMCleareAJOrmelJManoharanAKokICWesselySet al. Meta-Analysis and Meta-Regression of Hypothalamic-Pituitary-Adrenal Axis Activity in Functional Somatic Disorders. Biol Psychol (2011) 87(2):183–94. doi: 10.1016/j.biopsycho.2011.02.002
8
MorrisGAndersonGMaesM. Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways. Mol Neurobiol (2017) 54(9):6806–19. doi: 10.1007/s12035-016-0170-2
9
UnderhillRAO’gormanR. Prevalence of Chronic Fatigue Syndrome and Chronic Fatigue Within Families of CFS Patients. J Chronic Fatigue Syndr (2011) 13: (1):3–13. doi: 10.1300/J092v13n01_02
10
WalshCMZainalNMiddletonSJPaykelES. A Family History Study of Chronic Fatigue Syndrome. Psychiatr Genet (2001) 11(3):123–8. doi: 10.1097/00041444-200109000-00003
11
DibbleJJMcGrathSJPontingCP. Genetic Risk Factors of ME/CFS: A Critical Review. Hum Mol Genet (2020) 29(R1):R117–24. doi: 10.1093/hmg/ddaa169
12
UnderhillRA. Myalgic Encephalomyelitis, Chronic Fatigue Syndrome: An Infectious Disease. Med Hypotheses (2015) 85(6):765–73. doi: 10.1016/j.mehy.2015.10.011
13
ChuLValenciaIJGarvertDWMontoyaJG. Onset Patterns and Course of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Pediatr (2019) 7(FEB). doi: 10.3389/fped.2019.00012
14
AlbrightFLightKLightABatemanLCannon-AlbrightLA. Evidence for a Heritable Predisposition to Chronic Fatigue Syndrome. BMC Neurol (2011) 11(1):1–6. doi: 10.1186/1471-2377-11-62
15
MandaranoAHMayaJGiloteauxLPetersonDLMaynardMGottschalkCGet al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients Exhibit Altered T Cell Metabolism and Cytokine Associations. J Clin Invest (2020) 130(3):1491–505. doi: 10.1172/JCI132185
16
BrenuEWvan DrielMLStainesDRAshtonKJRamosSBKeaneJet al. Immunological Abnormalities as Potential Biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Transl Med (2011) 9(1):81. doi: 10.1186/1479-5876-9-81
17
NguyenTJohnstonSClarkeLSmithPStainesDMarshall-GradisnikS. Impaired Calcium Mobilization in Natural Killer Cells From Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients Is Associated With Transient Receptor Potential Melastatin 3 Ion Channels. Clin Exp Immunol (2017) 187(2):284. doi: 10.1111/cei.12882
18
Marshall-GradisnikSHuthTChackoAJohnstonSSmithPStainesD. Natural Killer Cells and Single Nucleotide Polymorphisms of Specific Ion Channels and Receptor Genes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Appl Clin Genet (2016) 9:39–47. doi: 10.2147/TACG.S99405
19
SotznyFBlancoJCapelliECastro-MarreroJSteinerSMurovskaMet al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an Autoimmune Disease. Autoimmun Rev (2018) 17(6):601–9. doi: 10.1016/j.autrev.2018.01.009
20
SmithJFritzELKerrJRCleareAJWesselySMatteyDL. Association of Chronic Fatigue Syndrome With Human Leucocyte Antigen Class II Alleles. J Clin Pathol (2005) 58(8):860–3. doi: 10.1136/jcp.2004.022681
21
LandeAFlugeØStrandEBFlåmSTSosaDDMellaOet al. Human Leukocyte Antigen Alleles Associated With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Sci Rep (2020) 10(1)):5267. doi: 10.1038/s41598-020-62157-x
22
KellerRHLaneJLKlimasNReiterWMFletcherMAvan RielFet al.Association between HLA Class II Antigens and the Chronic Fatigue Immune Dysfunction Syndrome. Clin Infect Dis (2021) 18 (Suppl 1):S154–6.
23
UnderhillJAMahalingamMPeakmanMWesselyS. Lack of Association Between HLA Genotype and Chronic Fatigue Syndrome. Eur J Immunogenet (2001) 28(3):425–8. doi: 10.1046/j.1365-2370.2001.00235.x
24
CarruthersBMVan de SandeMIDe MeirleirKLKlimasNGBroderickGMitchellTet al. Myalgic Encephalomyelitis: International Consensus Criteria. J Internal Med (2011) 270:327–38. doi: 10.1111/j.1365-2796.2011.02428.x
25
DuboisRESeeleyJKBrusISakamotoKBallowMHaradaSet al. Chronic Mononucleosis Syndrome. South Med J (1984) 77(11):1376–82. doi: 10.1097/00007611-198411000-00007
26
JacobsonSKDalyJSThorneGMMcIntoshK. Chronic Parvovirus B19 Infection Resulting in Chronic Fatigue Syndrome: Case History and Review. Clin Infect Dis (1997) 24(6):1048–51. doi: 10.1086/513627
27
Ortega-HernandezO-DShoenfeldY. Infection, Vaccination, and Autoantibodies in Chronic Fatigue Syndrome, Cause or Coincidence? Ann N Y Acad Sci (2009) 1173(1):600–9. doi: 10.1111/j.1749-6632.2009.04799.x
28
ShikovaEReshkovaVKumanovaАRalevaSAlexandrovaDCapoNet al. Cytomegalovirus, Epstein-Barr Virus, and Human Herpesvirus-6 Infections in Patients With Myalgic Еncephalomyelitis/Chronic Fatigue Syndrome. J Med Virol (2020) 92(12):3682–8. doi: 10.1002/jmv.25744
29
SchreinerPHarrerTScheibenbogenCLamerSSchlosserANaviauxRKet al. Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. ImmunoHorizons (2020) 4(4):201–15. doi: 10.4049/immunohorizons.2000006
30
O’NealAJHansonMR. The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review. Front Med (2021) 0:908.
31
BestedACMarshallLM. Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Evidence-Based Approach to Diagnosis and Management by Clinicians. Rev Environ Health Walter Gruyter GmbH (2015) 30:223–49. doi: 10.1515/reveh-2015-0026
32
TzellosSFarrellP. Epstein-Barr Virus Sequence Variation—Biology and Disease. Pathogens (2012) 1(2):156–74. doi: 10.3390/pathogens1020156
33
KhammissaRAGFourieJChandranRLemmerJFellerL. Epstein-Barr Virus and Its Association With Oral Hairy Leukoplakia: A Short Review. Int J Dentistry Hindawi Publishing Corporation (2016) 2016:4941783. doi: 10.1155/2016/4941783
34
DraborgAHDuusKHouenG. Epstein-Barr Virus in Systemic Autoimmune Diseases. Clin Dev Immunol (2013) 2013:535738. doi: 10.1155/2013/535738
35
HattonOLHarris-ArnoldASchaffertSKramsSMMartinezOM. The Interplay Between Epstein-Barr Virus and B Lymphocytes: Implications for Infection, Immunity, and Disease. Immunol Res (2014) 58(2–3):268–76. doi: 10.1007/s12026-014-8496-1
36
HeathEBegue-PastorNChagantiSCroom-CarterDShannon-LoweCKubeDet al. Epstein-Barr Virus Infection of Naïve B Cells In Vitro Frequently Selects Clones With Mutated Immunoglobulin Genotypes: Implications for Virus Biology. Sugden B, Editor. PloS Pathog (2012) 8(5):e1002697. doi: 10.1371/journal.ppat.1002697
37
RessingMEVan LeeuwenDVerreckFAWGomezRHeemskerkBToebesMet al. Interference With T Cell Receptor-HLA-DR Interactions by Epstein-Barr Virus Gp42 Results in Reduced T Helper Cell Recognition. Proc Natl Acad Sci USA (2003) 100(20):11583–8. doi: 10.1073/pnas.2034960100
38
TrierNIzarzugazaJChailyanAMarcatiliPHouenG. Human MHC-II With Shared Epitope Motifs Are Optimal Epstein-Barr Virus Glycoprotein 42 Ligands—Relation to Rheumatoid Arthritis. Int J Mol Sci (2018) 19(1):317.
39
SpriggsMKArmitageRJComeauMRStrockbineLFarrahTMacduffBet al. The Extracellular Domain of the Epstein-Barr Virus BZLF2 Protein Binds the HLA-DR Beta Chain and Inhibits Antigen Presentation. J Virol (1996) 70(8):5557–63. doi: 10.1128/jvi.70.8.5557-5563.1996
40
RessingMEvan LeeuwenDVerreckFAWKeatingSGomezRFrankenKLMCet al. Epstein-Barr Virus Gp42 Is Posttranslationally Modified To Produce Soluble Gp42 That Mediates HLA Class II Immune Evasion. J Virol (2005) 79(2):841–52. doi: 10.1128/JVI.79.2.841-852.2005
41
JonesKNourseJPMorrisonLNguyen-VanDMossDJBurrowsSRet al. Expansion of EBNA1-Specific Effector T Cells in Posttransplantation Lymphoproliferative Disorders. Blood (2010) 116(13):2245–52. doi: 10.1182/blood-2010-03-274076
42
MoormannAMHellerKNChelimoKEmburyPPloutz-SnyderROtienoJAet al. Children With Endemic Burkitt Lymphoma Are Deficient in EBNA1-Specific IFN-γ T Cell Responses. Int J Cancer (2009) 124(7):1721–6. doi: 10.1002/ijc.24014
43
FutagbiGGyanBNunooHTettehJWelbeckJRennerLet al. High Levels of IL-10 and CD4+CD25hi+ Treg Cells in Endemic Burkitt’s Lymphoma Patients. Biomedicines (2015) 3(3):224–36. doi: 10.3390/biomedicines3030224
44
HellerKNArreyFSteinherzPPortlockCChadburnAKellyKet al. Patients With Epstein Barr Virus-Positive Lymphomas Have Decreased CD4 + T-Cell Responses to the Viral Nuclear Antigen 1. Int J Cancer (2008) 123(12):2824–31. doi: 10.1002/ijc.23845
45
PiriouEVan DortKNanlohyNMVan OersMHJMiedemaFVan BaarleD. Loss of EBNA1-Specific Memory CD4+ and CD8+ T Cells in HIV-Infected Patients Progressing to AIDS-Related Non-Hodgkin Lymphoma. Blood (2005) 106(9):3166–74. doi: 10.1182/blood-2005-01-0432
46
LeungCSHaighTAMackayLKRickinsonABTaylorGS. Nuclear Location of an Endogenously Expressed Antigen, EBNA1, Restricts Access to Macroautophagy and the Range of CD4 Epitope Display. Proc Natl Acad Sci USA (2010) 107(5):2165–70. doi: 10.1073/pnas.0909448107
47
MeyerDVitorVRBitarelloBDDéboraDYNunesK. A Genomic Perspective on HLA Evolution. Immunogenetics Springer Verlag (2018) 70:5–27. doi: 10.1007/s00251-017-1017-3
48
YasukochiYSattaY. A Human-Specific Allelic Group of the MHC DRB1 Gene in Primates. J Physiol Anthropol (2014) 33(1):14. doi: 10.1186/1880-6805-33-14
49
BontropREOttingNDe GrootNGDoxiadisGGM. Major Histocompatibility Complex Class II Polymorphisms in Primates. Immunol Rev (1999) 167:339–50. doi: 10.1111/j.1600-065X.1999.tb01403.x
50
EhlersBSpießKLeendertzFPeetersMBoeschCGathererDet al. Lymphocryptovirus Phylogeny and the Origins of Epstein-Barr Virus. J Gen Virol (2010) 91(3):630–42. doi: 10.1099/vir.0.017251-0
51
McShaneMPMullenMMHaanKMJardetzkyTSLongneckerR. Mutational Analysis of the HLA Class II Interaction With Epstein-Barr Virus Glycoprotein 42. J Virol (2003) 77(13):7655–62. doi: 10.1128/JVI.77.13.7655-7662.2003
52
MullenMMHaanKMLongneckerRJardetzkyTS. Structure of the Epstein-Barr Virus Gp42 Protein Bound to the MHC Class II Receptor HLA-Dr1. Mol Cell (2002) 9(2):375–85. doi: 10.1016/S1097-2765(02)00465-3
53
HaanKMLongneckerR. Coreceptor Restriction Within the HLA-DQ Locus for Epstein-Barr Virus Infection. Proc Natl Acad Sci USA (2000) 97(16):9252–7. doi: 10.1073/pnas.160171697
54
HislopADTaylorGS. T-Cell Responses to EBV. Curr Topics Microbiol Immunol (2015) 325–53. doi: 10.1007/978-3-319-22834-1_11
55
MagnussonMBrisslertMZendjanchiKLindhMBokarewaMI. Epstein–Barr Virus in Bone Marrow of Rheumatoid Arthritis Patients Predicts Response to Rituximab Treatment. Rheumatology (2010) 49(10):1911–9. doi: 10.1093/rheumatology/keq159
56
FranssilaRHedmanK. Viral Causes of Arthritis. Best Pract Research: Clin Rheumatol (2006) 20:1139–57. doi: 10.1016/j.berh.2006.08.007
57
DraborgAIzarzugazaJMGHouenG. How Compelling Are the Data for Epstein–Barr Virus Being a Trigger for Systemic Lupus and Other Autoimmune Diseases? Curr Opin Rheumatol (2016) 28(4):398–404. doi: 10.1097/BOR.0000000000000289
58
DraborgAHDuusKHouenG. Epstein-Barr Virus and Systemic Lupus Erythematosus. Clin Dev Immunol (2012) 2012 p. 370516. doi: 10.1155/2012/370516
59
AscherioAMungerKLLennetteETSpiegelmanDHernánMAOlekMJet al. Epstein-Barr Virus Antibodies and Risk of Multiple Sclerosis: A Prospective Study. J Am Med Assoc (2001) 286(24):3083–8. doi: 10.1001/jama.286.24.3083
60
GuanYJakimovskiDRamanathanMWeinstock-GuttmanBZivadinovR. The Role of Epstein-Barr Virus in Multiple Sclerosis: From Molecular Pathophysiology to In Vivo Imaging. Neural Regener Res (2019) 14(3):373.
61
XiaoDYeXZhangNOuMGuoCZhangBet al. A Meta-Analysis of Interaction Between Epstein-Barr Virus and HLA-DRB1∗1501 on Risk of Multiple Sclerosis. Sci Rep (2015) 5(1):18083.
62
CavalcantePMarcuzzoSFranziSGalbardiBMaggiLMottaTet al. Epstein-Barr Virus in Tumor-Infiltrating B Cells of Myasthenia Gravis Thymoma: An Innocent Bystander or an Autoimmunity Mediator? Oncotarget (2017) 8(56):95432–49. doi: 10.18632/oncotarget.20731
63
FujiyaAOchiaiHMizukoshiTKiyotaAShibataTSuzukiAet al. Fulminant Type 1 Diabetes Mellitus Associated With a Reactivation of Epstein-Barr Virus That Developed in the Course of Chemotherapy of Multiple Myeloma. J Diabetes Investig (2010) 1(6):286–9. doi: 10.1111/j.2040-1124.2010.00061.x
64
HarleyJBChenXPujatoMMillerDMaddoxAForneyCet al. Transcription Factors Operate Across Disease Loci, With EBNA2 Implicated in Autoimmunity. Nat Genet (2018) 50(5):699–707. doi: 10.1038/s41588-018-0102-3
65
StiefelPAparicioRDolores NietoMAlfaroV. Infección Por El Virus De Epstein-Barr Y Enfermedad De Graves-Basedow: ¿Simple Casualidad O Algo Más? Med Clin (Barc) (2006) 126(7):278–9. doi: 10.1157/13085286
66
JanegovaAJanegaPRychlyBKuracinovaKBabalP. The Role of Epstein-Barr Virus Infection in the Development of Autoimmune Thyroid Diseases. Endokrynol Pol (2015) 66(2):132–6. doi: 10.5603/EP.2015.0020
67
BeltraminoMCalmetRGatica ValdésM. Virus De Epstein-Barr Y Su Relación Con El Desarrollo De Enfermedades Linfoproliferativas. Hematología (2005) 9(2):39–54.
68
GhasemiFTessierTMGameiroSFMaciverAHCecchiniMJMymrykJS. High MHC-II Expression in Epstein–Barr Virus-Associated Gastric Cancers Suggests That Tumor Cells Serve an Important Role in Antigen Presentation. Sci Rep (2020) 10(1):1–16. doi: 10.1038/s41598-020-71775-4
69
HaanKMKwokWWLongneckerRSpeckP. Epstein-Barr Virus Entry Utilizing HLA-DP or HLA-DQ as a Coreceptor. J Virol (2000) 74(5):2451–4. doi: 10.1128/JVI.74.5.2451-2454.2000
70
PerfettiVBaldantiFLentiMVVanoliABiagiFGattiMet al. Detection of Active Epstein–Barr Virus Infection in Duodenal Mucosa of Patients With Refractory Celiac Disease. Clin Gastroenterol Hepatol (2016) 14(8):1216–20. doi: 10.1016/j.cgh.2016.03.022
71
PenderMPBurrowsSR. Epstein–Barr Virus and Multiple Sclerosis: Potential Opportunities for Immunotherapy. Clin Transl Immunol (2014) 3(10):e27. doi: 10.1038/cti.2014.25
72
FoxRILuppiMKangHPisaP. Reactivation of Epstein-Barr Virus in Sjögren’s Syndrome. Springer Semin Immunopathol (1991) 13(2):217–31. doi: 10.1007/BF00201470
73
MahabadiMFaghihilooEAlishiriGHAtaeeMHAtaeeRA. Detection of Epstein-Barr Virus in Synovial Fluid of Rheumatoid Arthritis Patients. Electron Physician (2016) 8(3):2181–6. doi: 10.19082/2181
74
ToussirotERoudierJ. Pathophysiological Links Between Rheumatoid Arthritis and the Epstein-Barr Virus: An Update. Joint Bone Spine Elsevier Masson; (2007) 74:418–26. doi: 10.1016/j.jbspin.2007.05.001
75
PhDMVWCoxBPhDWPLArizaME. Epstein-Barr Virus Dutpase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Clin Ther (2019) 41(5):848–63.
76
HalpinPWilliamsMVKlimasNGFletcherMABarnesZArizaME. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Gulf War Illness Patients Exhibit Increased Humoral Responses to the Herpesviruses-Encoded Dutpase: Implications in Disease Pathophysiology. J Med Virol (2017) 89(9):1636–45. doi: 10.1002/jmv.24810
77
LoebelMStrohscheinKGianniniCKoelschUBauerSDoebisCet al. Deficient EBV-Specific B- and T-Cell Response in Patients With Chronic Fatigue Syndrome. PloS One (2014) 9(1):85387. doi: 10.1371/journal.pone.0085387
78
KawaiKKawaiA. Studies on the Relationship Between Chronic Fatigue Syndrome and Epstein-Barr Virus in Japan. Intern Med (1992) 31(3):313–8. doi: 10.2169/internalmedicine.31.313
79
SairenjiTYamanishiKTachibanaYBertoniGKurataT. Antibody Responses to Epstein-Barr Virus, Human Herpesvirus 6 and Human Herpesvirus 7 in Patients With Chronic Fatigue Syndrome. Intervirology (1995) 38(5):269–73. doi: 10.1159/000150450
80
LernerAMBeqajSHDeeterRGFitzgeraldJT. IgM Serum Antibodies to Epstein-Barr Virus Are Uniquely Present in a Subset of Patients With the Chronic Fatigue Syndrome. In Vivo (Brooklyn) (2004) 18(2)):101–6.
81
LoebelMEckeyMSotznyFHahnEBauerSGrabowskiPet al. Serological Profiling of the EBV Immune Response in Chronic Fatigue Syndrome Using a Peptide Microarray. PloS One (2017) 12(6):e0179124. doi: 10.1371/journal.pone.0179124
82
AME. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back! Biomolecules (2021) 11(2):1–17. doi: 10.3390/biom11020185
83
RasaSNora-KrukleZHenningNEliassenEShikovaEHarrerTet al. Chronic Viral Infections in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). J Transl Med (2018) 16(1):268. doi: 10.1186/s12967-018-1644-y
84
CameronCFlamandLJuwanaHMiddeldorpJNaingZRawlinsonWet al. Serological and Virological Investigation of the Role of the Herpesviruses EBV, CMV and HHV-6 in Post-Infective Fatigue Syndrome. J Med Virol (2010) 82(10):1684–8. doi: 10.1002/jmv.21873
85
SotoNEStrausSE. Chronic Fatigue Syndrome and Herpesviruses: The Fading Evidence. Herpes (2000) 7(2):46–50.
86
LaichalkLLThorley-LawsonDA. Terminal Differentiation Into Plasma Cells Initiates the Replicative Cycle of Epstein-Barr Virus In Vivo. J Virol (2005) 79(2):1296–307. doi: 10.1128/JVI.79.2.1296-1307.2005
87
HongGKDelecluseHJGruffatHMorrisonTEFengW-HSergeantAet al. The BRRF1 Early Gene of Epstein-Barr Virus Encodes a Transcription Factor That Enhances Induction of Lytic Infection by BRLF1. J Virol (2004) 78(10):4983–92. doi: 10.1128/jvi.78.10.4983-4992.2004
88
ter WolbeekMvan DoornenDLJKavelaarsAvan de PutteEMSchedlowskiMHeijnenCJ. Longitudinal Analysis of Pro- and Anti-Inflammatory Cytokine Production in Severely Fatigued Adolescents. Brain Behav Immun (2007) 21(8):1063–74. doi: 10.1016/j.bbi.2007.04.007
89
GiloteauxLO’NealACastro-MarreroJLevineSMHansonMR. Cytokine Profiling of Extracellular Vesicles Isolated From Plasma in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study. J Transl Med (2020) 18118(1):1–17. doi: 10.1186/s12967-020-02560-0
90
YangTYangYWangDLiCQuYGuoJet al. The Clinical Value of Cytokines in Chronic Fatigue Syndrome. J Transl Med (2019) 17(1):213. doi: 10.1186/s12967-019-1948-6
91
BroderickGFuiteJKreitzAVernonSDKlimasNFletcherMA. A Formal Analysis of Cytokine Networks in Chronic Fatigue Syndrome. Brain Behav Immun (2010) 24(7):1209. doi: 10.1016/j.bbi.2010.04.012
92
LakhanSEKirchgessnerA. Gut Inflammation in Chronic Fatigue Syndrome. Nutr Metab (2010) 7:79. doi: 10.1186/1743-7075-7-79
93
GiloteauxLGoodrichJKWaltersWALevineSMLeyREHansonMR. Reduced Diversity and Altered Composition of the Gut Microbiome in Individuals With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Microbiome (2016) 4(1):30. doi: 10.1186/s40168-016-0171-4
94
Nagy-SzakalDWilliamsBLMishraNCheXLeeBBatemanLet al. Fecal Metagenomic Profiles in Subgroups of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Microbiome (2017) 5(1):44. doi: 10.1186/s40168-017-0261-y
95
GuptaSAggarwalSSeeDStarrA. Cytokine Production by Adherent and Non-Adherent Mononuclear Cells in Chronic Fatigue Syndrome. J Psychiatr Res (1997) 31(1):149–56. doi: 10.1016/s0022-3956(96)00063-5
96
BorishLSchmalingKDiClementiJDStreibJNegriJJonesJF. Chronic Fatigue Syndrome: Identification of Distinct Subgroups on the Basis of Allergy and Psychologic Variables. J Allergy Clin Immunol (1998) 102(2):222–30. doi: 10.1016/s0091-6749(98)70090-9
97
CorbittMEaton-FitchNStainesDCabanasHMarshall-GradisnikS. A Systematic Review of Cytokines in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID). BMC Neurol (2019) 19(1):207. doi: 10.1186/s12883-019-1433-0
98
BlundellSRayKKBucklandMWhitePD. Chronic Fatigue Syndrome and Circulating Cytokines: A Systematic Review. Brain Behav Immun (2015) 50:186–95. doi: 10.1016/j.bbi.2015.07.004
99
JonsjöMAOlssonGLWicksellRKAlvingKHolmströmLAndreassonA. The Role of Low-Grade Inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) - Associations With Symptoms. Psychoneuroendocrinology (2020) 113:104578. doi: 10.1016/j.psyneuen.2019.104578
100
FlugeØRisaKLundeSAlmeKRekelandIGSapkotaDet al. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study With Rituximab Maintenance Treatment. Van Der Feltz-Cornelis C, Editor. PloS One (2015) 10(7):e0129898. doi: 10.1371/journal.pone.0129898
101
LiHYuXLilesCKhanMVanderlinde-WoodMGallowayAet al. Autoimmune Basis for Postural Tachycardia Syndrome. J Am Heart Assoc (2014) 3(1):e000755. doi: 10.1161/JAHA.113.000755
102
AppayVZaundersJJPapagnoLSuttonJJaramilloAWatersAet al. Characterization of CD4 + CTLs Ex Vivo. J Immunol (2002) 168(11):5954–8. doi: 10.4049/jimmunol.168.11.5954
103
KumarAPerdomoMFKanteleAHedmanLHedmanKFranssilaR. Granzyme B Mediated Function of Parvovirus B19-Specific CD4+ T Cells. Clin Transl Immunol (2015) 4(7):e39. doi: 10.1038/cti.2015.13
104
AlcamiAKoszinowskiUH. Viral Mechanisms of Immune Evasion. Immunol Today (2000) 21:447–55. doi: 10.1016/S0167-5699(00)01699-6
105
MuraroEMerloAMartorelliDCangemiMSantaSDDolcettiRet al. Fighting Viral Infections and Virus-Driven Tumors With Cytotoxic CD4+ T Cells. Front Immunol (2017) 8:197. doi: 10.3389/fimmu.2017.00197
106
JasonLACorradiKGressSWilliamsSTorres-HardingS. Causes of Death Among Patients With Chronic Fatigue Syndrome. Health Care Women Int (2006) 27(7):615–26. doi: 10.1080/07399330600803766
107
LeeJ-SLacerdaEMNaculLKingdonCCNorrisJO’BoyleSet al. Salivary DNA Loads for Human Herpesviruses 6 and 7 Are Correlated With Disease Phenotype in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Med (2021) 0:656692/full. doi: 10.3389/fmed.2021.656692/full
108
ChangCMWarrenJLEngelsEA. Chronic Fatigue Syndrome and Subsequent Risk of Cancer Among Elderly US Adults. Cancer (2012) 118(23):5929–36. doi: 10.1002/cncr.27612
109
EndicottNA. Chronic Fatigue Syndrome in Private Practice Psychiatry: Family History of Physical and Mental Health. J Psychosom Res (1999) 47(4):343–54. doi: 10.1016/s0022-3999(99)00013-6
110
BlombergJGottfriesC-GElfaitouriARizwanMRosénA. Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model. Front Immunol (2018) 9(FEB):15. doi: 10.3389/fimmu.2018.00229
111
KristiansenMSStabursvikJO'LearyECPedersenMAsprustenTLeegaardTTet al. Clinical Symptoms and Markers of Disease Mechanisms in Adolescent Chronic Fatigue Following Epstein-Barr Virus Infection: An Exploratory Cross-Sectional Study. Brain Behav Immun (2019) 80:551–63. doi: 10.1016/j.bbi.2019.04.040
112
DraborgAHJacobsenSWestergaardMMortensenSLarsenJLHouenGet al. Reduced Response to Epstein-Barr Virus Antigens by T-Cells in Systemic Lupus Erythematosus Patients. Lupus Sci Med (2014) 1(1):15. doi: 10.1136/lupus-2014-000015
113
PenderMPCsurhesPABurrowsJMBurrowsSR. Defective T-Cell Control of Epstein–Barr Virus Infection in Multiple Sclerosis. Clin Transl Immunol (2017) 6(1):e126. doi: 10.1038/cti.2016.87
114
ToussirotÉRoudierJ. Epstein-Barr Virus in Autoimmune Diseases. Best Pract Research: Clin Rheumatol Baillière Tindall (2008) 22:883–96. doi: 10.1016/j.berh.2008.09.007
115
RichmanSMorrisMCBroderickGCraddockTJAKlimasNGFletcherMA. Pharmaceutical Interventions in Chronic Fatigue Syndrome: A Literature-Based Commentary. Clin Ther (2019) 41(5):798–805. doi: 10.1016/j.clinthera.2019.02.011
116
FlugeØRekelandIGLienKThürmerHBorchgrevinkPCSchäferCet al. B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Ann Intern Med (2019) 170(9):585–93. doi: 10.7326/M18-1451
117
FlugeØBrulandORisaKStorsteinAKristoffersenEKSapkotaDet al. Benefit From B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. Reindl M, Editor. PloS One (2011) 6(10):e26358. doi: 10.1371/journal.pone.0026358
118
LernerAMBeqajSHDeeterRGFitzgeraldJT. Valacyclovir Treatment in Epstein-Barr Virus Subset Chronic Fatigue Syndrome: Thirty-Six Months Follow-Up. In Vivo (Brooklyn) (2007) 21(5):707–14.
119
MontoyaJGKogelnikAMBhangooMLunnMRFlamandLMerrihewLEet al. Randomized Clinical Trial to Evaluate the Efficacy and Safety of Valganciclovir in a Subset of Patients With Chronic Fatigue Syndrome. J Med Virol (2013) 85(12):2101–9. doi: 10.1002/jmv.23713
120
HeslopHE. How I Treat EBV Lymphoproliferation. Blood (2009) 114(19):4002–8. doi: 10.1182/blood-2009-07-143545
121
PenderMP. Preventing and Curing Multiple Sclerosis by Controlling Epstein-Barr Virus Infection. Autoimmun Rev (2009) 8:563–8. doi: 10.1016/j.autrev.2009.01.017
122
SavoldoBRooneyCMQuiros-TejeiraRECaldwellYWagnerHLeeTet al. Cellular Immunity to Epstein-Barr Virus in Liver Transplant Recipients Treated With Rituximab for Post-Transplant Lymphoproliferative Disease. Am J Transplant (2005) 5(3):566–72. doi: 10.1111/j.1600-6143.2004.00693.x
123
SuzanFAmmorMRibragV. Fatal Reactivation of Cytomegalovirus Infection After Use of Rituximab for a Post-Transplantation Lymphoproliferative Disorder. N Engl J Med (2001) 345(13):1000–0. doi: 10.1056/NEJM200109273451315
124
NikiforowSBottomlyKMillerG. CD4+ T-Cell Effectors Inhibit Epstein-Barr Virus-Induced B-Cell Proliferation. J Virol (2001) 75(8):3740–52. doi: 10.1128/JVI.75.8.3740-3752.2001
125
SchaeferBCStromingerJLSpeckSH. A Simple Reverse Transcriptase PCR Assay to Distinguish EBNA1 Gene Transcripts Associated With Type I and II Latency From Those Arising During Induction of the Viral Lytic Cycle. J Virol (1996) 70(11):8204–8. doi: 10.1128/jvi.70.11.8204-8208.1996
126
AmyesEHattonCMontamat-SicotteDGudgeonNRickinsonABMcMichaelAJet al. Characterization of the CD4+ T Cell Response to Epstein-Barr Virus During Primary and Persistent Infection. J Exp Med (2003) 198(6):903–11. doi: 10.1084/jem.20022058
127
FrappierL. The Epstein-Barr Virus EBNA1 Protein. Scientifica (Cairo) (2012) 2012:1–15. doi: 10.6064/2012/438204
128
DaltonTDoubrovinaEPankovDReynoldsRScholzeHSelvakumarAet al. Epigenetic Reprogramming Sensitizes Immunologically Silent EBV+ Lymphomas to Virus-Directed Immunotherapy. Blood (2020) 135(21):1870–81. doi: 10.1182/blood.2019004126
129
TurriniRMerloADolcettiRZanovelloPRosatoA. Differential Down-Modulation of HLA Class I and II Molecule Expression on Human Tumor Cell Lines Upon In Vivo Transfer. Cancer Immunol Immunother (2011) 60(11):1639–45. doi: 10.1007/s00262-011-1086-3
130
MerloATurriniRBobisseSZamarchiRAlaggioRDolcettiRet al. Virus-Specific Cytotoxic CD4 + T Cells for the Treatment of EBV-Related Tumors. J Immunol (2010) 184(10):5895–902. doi: 10.4049/jimmunol.0902850
131
NishikawaJIizasaHYoshiyamaHNakamuraMSaitoMSasakiSet al. The Role of Epigenetic Regulation in Epstein-Barr Virus-Associated Gastric Cancer. Int J Mol Sci (2017) 18(8):1606. doi: 10.3390/ijms18081606
132
NakamuraMNishikawaJSaitoMSakaiKSasakiSHashimotoSet al. Decitabine Inhibits Tumor Cell Proliferation and Up-Regulates E-Cadherin Expression in Epstein-Barr Virus-Associated Gastric Cancer. J Med Virol (2017) 89(3):508–17. doi: 10.1002/jmv.24634
133
GallinellaG. Parvovirus B19 Achievements and Challenges. ISRN Virol (2013) 2013:1–33. doi: 10.5402/2013/898730
134
BonviciniFManaresiEDi FurioFde FalcoLGallinellaG. Parvovirus B19 DNA CpG Dinucleotide Methylation and Epigenetic Regulation of Viral Expression. PloS One (2012) 7(3):e33316. doi: 10.1371/journal.pone.0033316
135
FlowerKThomasDHeatherJRamasubramanyanSJonesSSinclairAJ. Epigenetic Control of Viral Life-Cycle by a DNA-Methylation Dependent Transcription Factor. PloS One (2011) 6(10):e25922. doi: 10.1371/journal.pone.0025922
136
MinarovitsJ. Epigenotypes of Latent Herpesvirus Genomes. Curr Topics Microbiol Immunol (2006) 310:61–80. doi: 10.1007/3-540-31181-5_5
137
JasonLACotlerJIslamMFSunnquistMKatzBZ. Risks for Developing ME/CFS in College Students Following Infectious Mononucleosis: A Prospective Cohort Study. Clin Infect Dis (2020) ciaa1886. doi: 10.1093/cid/ciaa1886
Summary
Keywords
chronic fatigue syndrome, myalgic encephalomyelitis, EBV EBNA-1, HLA-II alleles, cancer, CD4+ CTL, autoimmunity, immunotherapy
Citation
Ruiz-Pablos M, Paiva B, Montero-Mateo R, Garcia N and Zabaleta A (2021) Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome. Front. Immunol. 12:656797. doi: 10.3389/fimmu.2021.656797
Received
21 January 2021
Accepted
19 October 2021
Published
15 November 2021
Volume
12 - 2021
Edited by
Linda F. Van Dyk, University of Colorado Denver, United States
Reviewed by
Andrew R. Lloyd, Kirby Institute, Australia; Hirokazu Kanegane, Tokyo Medical and Dental University, Japan
Updates
Copyright
© 2021 Ruiz-Pablos, Paiva, Montero-Mateo, Garcia and Zabaleta.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Manuel Ruiz-Pablos, manruipa@gmail.com; Aintzane Zabaleta, azabaletaa@unav.es
This article was submitted to Viral Immunology, a section of the journal Frontiers in Immunology
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