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Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis.
Brain 2006; 129(Pt 6):1493-506B

Abstract

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-gamma 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.

Authors+Show Affiliations

Neuroimmunology Branch, Cellular Immunology Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. jlunemann@rockefeller.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16569670

Citation

Lünemann, Jan D., et al. "Increased Frequency and Broadened Specificity of Latent EBV Nuclear Antigen-1-specific T Cells in Multiple Sclerosis." Brain : a Journal of Neurology, vol. 129, no. Pt 6, 2006, pp. 1493-506.
Lünemann JD, Edwards N, Muraro PA, et al. Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain. 2006;129(Pt 6):1493-506.
Lünemann, J. D., Edwards, N., Muraro, P. A., Hayashi, S., Cohen, J. I., Münz, C., & Martin, R. (2006). Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain : a Journal of Neurology, 129(Pt 6), pp. 1493-506.
Lünemann JD, et al. Increased Frequency and Broadened Specificity of Latent EBV Nuclear Antigen-1-specific T Cells in Multiple Sclerosis. Brain. 2006;129(Pt 6):1493-506. PubMed PMID: 16569670.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. AU - Lünemann,Jan D, AU - Edwards,Nancy, AU - Muraro,Paolo A, AU - Hayashi,Shuhei, AU - Cohen,Jeffrey I, AU - Münz,Christian, AU - Martin,Roland, Y1 - 2006/03/28/ PY - 2006/3/30/pubmed PY - 2006/6/20/medline PY - 2006/3/30/entrez SP - 1493 EP - 506 JF - Brain : a journal of neurology JO - Brain VL - 129 IS - Pt 6 N2 - 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-gamma 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. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/16569670/Increased_frequency_and_broadened_specificity_of_latent_EBV_nuclear_antigen_1_specific_T_cells_in_multiple_sclerosis_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awl067 DB - PRIME DP - Unbound Medicine ER -