Abstract
Myalgic encephalomyelitis, also referred to as chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by myalgia and a sometimes severe limitation of physical activity and cognition. It is exacerbated by physical and mental activity. Its cause is unknown, but frequently starts with an infection. The eliciting infection (commonly infectious mononucleosis or an upper respiratory infection) can be more or less well diagnosed. Among the human herpesviruses (HHV-1-8), HHV-4 (Epstein-Barr virus; EBV), HHV-6 (including HHV-6A and HHV-6B), and HHV-7, have been implicated in the pathogenesis of ME/CFS. It was therefore logical to search for serological evidence of past herpesvirus infection/reactivation in several cohorts of ME/CFS patients (all diagnosed using the Canada criteria). Control samples were from Swedish blood donors. We used whole purified virus, recombinant proteins, and synthetic peptides as antigens in a suspension multiplex immunoassay (SMIA) for immunoglobulin G (IgG). The study on herpesviral peptides based on antigenicity with human sera yielded novel epitope information. Overall, IgG anti-herpes-viral reactivities of ME/CFS patients and controls did not show significant differences. However, the high precision and internally controlled format allowed us to observe minor relative differences between antibody reactivities of some herpesviral antigens in ME/CFS versus controls. ME/CFS samples reacted somewhat differently from controls with whole virus HHV-1 antigens and recombinant EBV EBNA6 and EA antigens. We conclude that ME/CFS samples had similar levels of IgG reactivity as blood donor samples with HHV-1-7 antigens. The subtle serological differences should not be over-interpreted, but they may indicate that the immune system of some ME/CFS patients interact with the ubiquitous herpesviruses in a way different from that of healthy controls.
Highlights
Myalgic encephalomyelitis, referred to as chronic fatigue syndrome (ME/CFS), is a common syndrome which includes post-exertional malaise (PEM), brain fog, unrefreshing sleep, hemodynamic abnormality, myalgia, and headache
We addressed the following questions, using suspension multiplex immunoassay (SMIA): Can antibodies against synthetic herpesviral peptides, useful for serological differentiation of ME/CFS from blood donors (BD), be found? Can the frequency of seropositivity with HHV1-7 indicate if infection with a certain herpesvirus is more or less common among ME/CFS patients compared to controls? Can differences between ME/CFS and control samples, in degree of seroreactivity with HHV1-7 antigens be detected? Can previous reports of aberrant EBV viral capsid antigen (VCA), early antigen D (EA-D), Epstein-Barr virus nuclear antigen 1 (EBNA1), and EBNA6 antibody formation in ME/CFS be corroborated? Can previously found distinct EBNA1 peptide antibody patterns reported in multiple sclerosis (MS) be found in ME/CFS sera?
Validations for HHV-4 whole virus, VCA and EBNA1 SMIAs are shown in Table S2, in Supplementary Materials
Summary
Referred to as chronic fatigue syndrome (ME/CFS), is a common syndrome which includes post-exertional malaise (PEM), brain fog, unrefreshing sleep, hemodynamic abnormality, myalgia, and headache. EBV can transactivate promoters involved in autoimmunity [30]. The aim of this investigation was to search for serological evidence for or against an involvement of a herpesvirus, either as a trigger, or as a chronically active infection, in ME/CFS. It was part of a search for biomarkers for ME/CFS, in several cohorts of ME/CFS patients. The multiplex format allowed internally controlled measurements, increasing the precision of serological comparisons
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