Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome

Abstract

Epstein-Barr virus (EBV) has long been discussed as a possible cause or trigger of Chronic Fatigue Syndrome (CFS). In a subset of patients the disease starts with infectious mononucleosis and both enhanced and diminished EBV-specific antibody titers have been reported. In this study, we comprehensively analyzed the EBV-specific memory B- and T-cell response in patients with CFS. While we observed no difference in viral capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG titers were low or absent in 10% of CFS patients. Remarkably, when analyzing the EBV-specific memory B-cell reservoir in vitro a diminished or absent number of EBNA-1- and VCA-antibody secreting cells was found in up to 76% of patients. Moreover, the ex vivo EBV-induced secretion of TNF-α and IFN-γ was significantly lower in patients. Multicolor flow cytometry revealed that the frequencies of EBNA-1-specific triple TNF-α/IFN-γ/IL-2 producing CD4+ and CD8+ T-cell subsets were significantly diminished whereas no difference could be detected for HCMV-specific T-cell responses. When comparing EBV load in blood immune cells, we found more frequently EBER-DNA but not BZLF-1 RNA in CFS patients compared to healthy controls suggesting more frequent latent replication. Taken together, our findings give evidence for a deficient EBV-specific B- and T-cell memory response in CFS patients and suggest an impaired ability to control early steps of EBV reactivation. In addition the diminished EBV response might be suitable to develop diagnostic marker in CFS.

Myalgic encephalomyelitis/chronic fatigue syndrome and gulf war illness patients exhibit increased humoral responses to the herpesviruses‐encoded dUTPase: Implications in disease pathophysiology

“…Because of the overlapping symptoms observed between patients with GWI and ME/CFS, the higher incidence of ME/CFS in patients with GWI and the lack of information concerning the etiology of GWI, we next examined the potential involvement of herpesviruses in the pathophysiology of GWI. To determine whether there was evidence supporting the hypothesis that herpesviruses‐dUTPase proteins were expressed in patients with GWI, the anti‐dUTPase antibody profile to HHV‐6, EBV, and VZV encoded dUTPases as well as the human dUTPase were determined in a single serum sample from 58 patients diagnosed with GWI and compared to the antibody profiles obtained in patients diagnosed with ME/CFS ( n = 55) or healthy controls ( n = 151).…”

“…In over half of cases, ME/CFS onset is associated with acute “flu‐like” symptoms . There are multiple reports in the literature suggesting a role for viruses, particularly human herpesvirus‐6 (HHV‐6) and Epstein‐Barr virus (EBV) in ME/CFS. However, the data concerning a causal relationship between a virus and ME/CFS has not been conclusively demonstrated and remains a challenge because of the heterogeneity of the patient population and the realization of possibly multiple etiologies.…”

Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP) Proteins with Implications for Human Disease

“…These approaches consisted primarily of serological studies using many different virus proteins as antigens; some that are expressed early during the replication cycle of the virus and others that are expressed late. Since the antibody pattern against a virus early protein would not be the same as the antibody pattern against a virus late protein, serology studies using different virus proteins (early vs. late) as antigens could lead to variable results [81,82,83,84,85,86,87,88,89,90,91]. Other studies have employed culture methods and polymerase chain reaction (PCR) methods to determine increased viral load when compared to controls [64,81].…”

“…There are multiple reports in the literature suggesting a role for HHV-6 [81,82,83,84,85,86] and EBV [87,88,89,90,91] in ME/CFS, but none have examined whether multiple herpesviruses may be reactivated simultaneously in patients, thus contributing to the pathophysiology. The hypothesis that reactivation of multiple herpesviruses may be involved with ME/CFS is supported by clinical studies demonstrating improvement of symptomology in a subset of patients following long-term therapy with valganciclovir, a potent inhibitor of herpesvirus replication, and relapse upon discontinuation of treatment [97,98,99,100].…”

Chronic Fatigue Syndrome: Where is The Reality?

“…Many of the infectious agents that have been linked to ME/CFS, "including Epstein-Barr virus 14 , HHV-6 15 , Coxiella burnetii ("Q fever") 16 , Ross River virus in Australia 17 , and various enteroviruses" 18 are ones that can't be fully eradicated by the immune system even in healthy people and/or are capable of infecting the central nervous system. This suggests the possibility that some ME/CFS patients may have a chronic, low-level encephalitis.…”