Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome.
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.
Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
Madlen
M
Loebel
Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany ; Julius Wolff Institute, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
Kristin
K
Strohschein
Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
Carolin
C
Giannini
Labor Berlin GmbH, Immunology Department, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
Uwe
U
Koelsch
Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
Sandra
S
Bauer
Institute for Medical Diagnostics, Berlin, Germany.
Cornelia
C
Doebis
Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
Sybill
S
Thomas
Labor Berlin GmbH, Immunology Department, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
Nadine
N
Unterwalder
Institute for Medical Diagnostics, Berlin, Germany.
Volker
V
von Baehr
Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany ; Department Nephrology, Charité University Medicine Berlin, Germany.
Petra
P
Reinke
Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
Michael
M
Knops
Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
Leif G
LG
Hanitsch
Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany ; Labor Berlin GmbH, Immunology Department, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
Christian
C
Meisel
Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany ; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany.
Hans-Dieter
HD
Volk
Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany ; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany.
Carmen
C
Scheibenbogen
D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D015673:Fatigue Syndrome, Chronic / Q000276:immunology* / Q000821:virology; D005260:Female; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007156:Immunologic Memory; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets; D013601:T-Lymphocytes / Q000276:immunology*; D014779:Virus Replication
D000914:Antibodies, Viral; D017931:DNA Primers