Brain Advance Access originally published online on March 28, 2006
Brain 2006 129(6):1493-1506; doi:10.1093/brain/awl067
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Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis
1 Neuroimmunology Branch, Cellular Immunology Section, National Institute of Neurological Disorders and Stroke Bethesda, MD, USA 2 Laboratory of Clinical Infectious Diseases, Medical Virology Section, National Institute of Allergy and Infectious Diseases, National Institute of Health Bethesda, MD, USA 3 Howard Hughes Medical Institute—National Institutes of Health Research Scholars Program Bethesda, MD, USA 4 Laboratory of Viral Immunobiology, Rockefeller University New York, USA 5 Department of Neurology, Division of Neuroimmunology, Charité University Medical Center, Humboldt University Berlin, Germany 6 Present address: Edifici Escola D'Infermeria, 2a Planta, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron, Universita Autonoma de Barcelona Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain
Correspondence to: Jan D. Lünemann, National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuroimmunology Branch, Cellular Immunology Section, Building.10, Room 5B16, 10 Center Drive, Bethesda, MD, 20892, USA E-mail: jlunemann{at}rockefeller.edu
Epidemiological studies consistently demonstrate that patients with multiple sclerosis are almost universally infected with Epstein–Barr virus (EBV) and that the risk of developing the disease increases with the level of EBV-specific antibody titers. The EBV-encoded nuclear antigen-1 (EBNA1) maintains the viral episome in replicating infected human B cells, and EBNA1-specific CD4+ T cells have been identified as a crucial part of the EBV-specific immune control in healthy individuals. We studied 20 untreated EBV seropositive patients with multiple sclerosis and 20 healthy EBV carriers matched demographically and for the expression of multiple sclerosis-associated HLA-DR alleles for their immunological control of EBV latency at the level of EBNA1-specific T cells. Using 51 overlapping peptides covering the C-terminal of EBNA1 domain of EBNA1 (amino acids 400–641), peptide-specific CD4+ memory T cells in patients with multiple sclerosis were found to be strikingly elevated in frequency, showed increased proliferative capacity and an enhanced interferon-
production. In contrast to EBNA1, T-cell responses to three other latent and three other lytic immunodominant EBV antigens and human cytomegalovirus (HCMV) epitopes did not differ between patients and controls, indicating a distinct role for EBNA1-specific T-cell responses in multiple sclerosis. CD4+ T cells from healthy virus carriers preferentially recognized multiple epitopes within the centre part of the C-terminal, whereas the stimulatory epitopes in multiple sclerosis patients covered the entire sequence of this domain of EBNA1. Quantification of EBV viral loads in peripheral blood mononuclear cells (PBMC) by real-time polymerase chain reaction (PCR) showed higher levels of EBV copy numbers in some patients with multiple sclerosis, although the overall difference in viral loads was not statistically significant compared with healthy virus carriers. We suggest that the accumulation of highly antigen-sensitive EBNA1-specific Th1 cells in multiple sclerosis is capable of sustaining autoimmunity by cross-recognition of autoantigens or by TCR-independent bystander mechanisms.
Key Words: multiple sclerosis; Epstein–Barr virus; T cell; autoimmunity
Abbreviations:
CMV, cytomegalovirus; EBV, Epstein–Barr virus; EBNA1, Epstein–Barr virus-encoded nuclear antigen-1; HD, healthy donors; IFN-, interferon-; IL, interleukin; PBMC, peripheral blood mononuclear cells; SI, stimulation indices; TCL, T-cell lines
.
Received January 11, 2006. Revised February 25, 2006. Accepted February 28, 2006.
*These senior authors contributed equally to this work.
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