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

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.

Cytomegalovirus, Epstein‐Barr virus, and human herpesvirus‐6 infections in patients with myalgic еncephalomyelitis/chronic fatigue syndrome

“…In a further global screening of serum antibody responses to an EBV peptide array, the same authors in serum of patients with ME/CFS revealed quite similar EBV IgG antibody response pattern as in sera of healthy controls except for the significantly enhanced IgG responses to several EBNA‐6 peptides 25 . On the contrary, according to a recent study, no increased EBV‐CA IgG reactivity over EBNA‐1 in ME/CFS cohorts is found and EBNA‐6 peptide IgG reactivity is not significantly different between the ME/CFS and healthy control samples 27 . In addition, some earlier studies also reported no differences in IgG titers against EBV‐CA, EBNA‐1 and EA 10,26,31 .…”

Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Not Due to Anti-mitochondrial Antibodies

“…Specific changes in the proteome of CSF of ME/CFS patients involved the accumulation of complement components, which signify antibody activity (19). In a recent publication from our group, the serological profile of the same ME/CFS patient cohorts demonstrated evidence of minor alterations of antibody reactivities against the ubiquitous herpesviruses when compared to healthy controls (20). These alterations may indicate shortcomings in humoral responses in ME/CFS which are hallmarks of autoimmune diseases.…”

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

“…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.…”

“…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. Along these lines, measuring the response in patients' sera using purified virus lysate would only detect antibodies to proteins that are components of the virion (capsid proteins, glycoproteins, and tegument proteins) but not proteins expressed during virus lytic/abortive-lytic replication (Figure 1).…”