Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome.

Madlen Loebel,Nadine Unterwalder,Cornelia Doebis,Hans-Dieter Volk,Sandra Bauer,Volker Von Baehr,Leif G Hanitsch,Carmen Scheibenbogen,Kristin Strohschein,Uwe Koelsch,Carolin Giannini,Sybill Thomas,Petra Reinke,Christian Meisel,Michael Knops,Marc S Horwitz

doi:10.1371/journal.pone.0085387

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.

Highlights

Chronic Fatigue Syndrome (CFS) is characterized by severe fatigue with typical post-exertional delay to recover from exhaustion, cognitive dysfunctions and flu-like symptoms [1], [2]
We compared serum Epstein-Barr virus (EBV)-viral capsid antigen (VCA)-IgG, -IgM, and EBV nuclear antigen (EBNA) -IgG from patients of cohort 1 (n = 63, Table 1) and healthy controls (n = 57) (Figure 1A)
While we did not observe a difference in levels of VCA-IgG, IgG antibodies against EBNA were undetectable (#20 U/ml) in 12.7% of CFS patients in contrast to 3.5% of healthy controls (p = 0.06, Figure 1B)

Summary

Introduction

Chronic Fatigue Syndrome (CFS) is characterized by severe fatigue with typical post-exertional delay to recover from exhaustion, cognitive dysfunctions and flu-like symptoms [1], [2]. CFS is diagnosed based on clinical Center of Disease Control criteria scores known as Fukuda criteria [3] or on the Canadian Consensus Definition from 2004 [1]. Diminished natural killer (NK)-cell cytotoxicity and reduced NK-cell derived perforin have been repeatedly reported for CFS patients [8], [10], [11]. Increased frequencies of activated HLA-DR class II-positive CD8+ T cells were proposed as immunological activation markers in CFS [10], [12], [13]. Curriu et al reported diminished proliferation of T cells but enhanced frequencies of regulatory T cells [15]

Methods

Results

Conclusion