Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition with unknown aetiology, Myalgic encephalomyelitis unclear pathophysiology and with no diagnostic test or biomarker available. Many patients report their ME/CFS began after an acute infection, and subsequent increased frequency of infections, such as colds or influenza, is common. These factors imply an altered immunological status exists in ME/CFS, in at least a proportion of patients, yet previous studies of peripheral immunity have been discrepant and inconclusive. The UK ME/CFS Biobank, which has collected blood samples from nearly 300 clinically-confirmed ME/CFS patients, enables large-scale studies of immunological function in phenotypically well-characterised participants. In this study, herpes virus serological status and T cell, B cell, NK cell and monocyte populations were investigated in 251 ME/CFS patients, including 54 who were severely affected, and compared with those from 107 healthy participants and with 46 patients with Multiple Sclerosis. There were no differences in seroprevalence for six human herpes viruses between ME/CFS and healthy controls, although seroprevalence for the Epstein-Barr virus was higher in multiple sclerosis patients. Contrary to previous reports, no significant differences were observed in NK cell numbers, subtype proportions or in vitro responsiveness between ME/CFS patients and healthy control participants. In contrast, the T cell compartment was altered in ME/CFS, with increased proportions of effector memory CD8+ T cells and decreased proportions of terminally differentiated effector CD8+ T cells. Conversely, there was a significantly increased proportion of mucosal associated invariant T cells (MAIT) cells, especially in severely affected ME/CFS patients. These abnormalities demonstrate that an altered immunological state does exist in ME/CFS, particularly in severely affected people. This may simply reflect ongoing or recent infection, or may indicate future increased susceptibility to infection. Longitudinal studies of ME/CFS patients are needed to help to determine cause and effect and thus any potential benefits of immuno-modulatory treatments for ME/CFS.
Highlights
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterised by unexplained persistent or recurrent incapacitating fatigue for over 6 months leading to substantial reductions in previous levels of occupational, educational, social and personal activities [1, 2] and, often, by moderate or severe physical disability and significant reductions in quality of life [3, 4]
Erythrocyte Sedimentation Rate (ESR), Erythrocyte sedimentation rate; CMV, Cytomegalovirus; EBV, Epstein–Barr virus [combined results for Viral capsid antigen (VCA) and Epstein-Barr nuclear antigen (EBNA)]; herpes simplex virus 1 (HSV1), Herpes simplex virus 1; HSV2, Herpes simplex virus 2; VZV, varicella-zoster virus; HHV6, Human herpesvirus 6; ME/CFSsa, people with ME/CFS with severe clinical manifestations; ME/CFSmm, people with ME/CFS with mild/moderate manifestations; MS, people with multiple sclerosis; HC, people recruited as healthy controls. *P-values—from χ2 tests for categorical variables and Kruskal-Wallis test for continuous variables
In a cohort of 250 well-characterised people living with ME/CFS, including a number who are severely affected, we have identified differences in peripheral immune cell phenotype compared to healthy control individuals
Summary
Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS) is characterised by unexplained persistent or recurrent incapacitating fatigue for over 6 months leading to substantial reductions in previous levels of occupational, educational, social and personal activities [1, 2] and, often, by moderate or severe physical disability and significant reductions in quality of life [3, 4]. CMV infection leaves a permanent footprint on the immune system including oligoclonal expansions and terminal differentiation of CD8+ T cells and expansion of a subset of highly differentiated NKG2C+ NK cells [28]; this NK population is further expanded by subsequent viral infection [28, 29]. It remains possible that the reported differences in T cell and NK cell phenotype and functional capacity between PWME and healthy controls may result from differences in the prevalence of immunomodulatory viruses such as CMV. All participants were screened for serological evidence of human cytomegalovirus (CMV), Epstein–Barr virus (EBV), herpes simplex virus 1 (HSV1), Herpes simplex virus 2 (HSV2), varicella-zoster virus (VZV), and human herpesvirus (HHV6) infections
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