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.

Severity, predictors and clinical correlates of Post-COVID syndrome (PCS) in Germany: A prospective, multi-centre, population-based cohort study

“…Furthermore, our findings underline the necessity to further study the pathogenesis and course of fatigue in the context of PCS as well as other communicable and non-communicable diseases because the causes of this phenomenon are still elusive and its importance might have been underestimated in the past. 23 , 24 , 25 …”

Revisiting IgG Antibody Reactivity to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Its Potential Application to Disease Diagnosis

“…Infections by the ubiquitous Epstein-Barr virus (EBV) are linked to multiple sclerosis, rheumatoid arthritis, systemic erythematosus lupus, lymphomas, among other known diseases (1)(2)(3). A less-known disease where EBV infections are also important is Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (4)(5)(6). The hallmark symptom of this condition is an unexplained but persistent fatigue that cannot be alleviated by rest and that can increase upon minimal physical and emotional effort (7,8).…”

CD4+ Cytotoxic T Cells Involved in the Development of EBV-Associated Diseases

“…Thus, EBNA-1-specific cytotoxic CD4 T lymphocytes appear to have a protective role in vivo, as deduced from their reduction/absence or altered function in the EBV-associated diseases discussed here, and in other diseases, such as post-transplant lymphoproliferative disease (PTLD) [ 269 ] and in EBV-related Hodgkin’s and non-Hodgkin’s lymphomas [ 15 , 75 , 270 , 271 , 272 , 273 ]. It may be that their “exhaustion” is caused by chronic exposure to viral antigens by participating in the immune response against the virus [ 214 , 274 , 275 , 276 , 277 ], or it may be an effect of the evasion mechanisms of B lymphocytes and macrophages that are infected by EBV [ 214 , 249 , 278 , 279 ]. In both cases, an immunodeficiency would develop that cannot control viral latency.…”

“…Finally, the immune evasion microenvironment generated by these EBV-transformed cells and the clonal growth of EBV-latent epithelial cells would lead to the development of the disease [ 282 , 285 , 286 ]. This model could even explain the involvement of EBV in the development of chronic fatigue syndrome or myalgic encephalomyelitis [ 214 , 278 ] and long COVID-19 [ 287 ]. Both diseases present similar EBV reactivations and chronic symptoms, which could suggest a common EBV immunopathology [ 278 , 287 , 288 , 289 ].…”