Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis
- 13 April 2006
- journal article
- research article
- Published by Oxford University Press (OUP) in Brain
- Vol. 129 (6), 1493-1506
- https://doi.org/10.1093/brain/awl067
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-γ 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.Keywords
This publication has 45 references indexed in Scilit:
- IMMUNOLOGY OF MULTIPLE SCLEROSISAnnual Review of Immunology, 2005
- Expression of the Epstein-Barr virus nuclear antigen-1 (EBNA-1) in the mouse can elicit the production of anti-dsDNA and anti-Sm antibodiesJournal of Autoimmunity, 2004
- Epstein-Barr Virus Nuclear Antigen 1The Journal of Experimental Medicine, 2004
- Endogenous Presentation of CD8+ T Cell Epitopes from Epstein-Barr Virus–encoded Nuclear Antigen 1The Journal of Experimental Medicine, 2004
- CD8 T Cell Recognition of Endogenously Expressed Epstein-Barr Virus Nuclear Antigen 1The Journal of Experimental Medicine, 2004
- Persistence of the Epstein–Barr Virus and the Origins of Associated LymphomasNew England Journal of Medicine, 2004
- Dendritic Cells Initiate Immune Control of Epstein-Barr Virus Transformation of B Lymphocytes In VitroThe Journal of Experimental Medicine, 2003
- Comprehensive Screening for Human Immunodeficiency Virus Type 1 Subtype-Specific CD8 Cytotoxic T Lymphocytes and Definition of Degenerate Epitopes Restricted by HLA-A0207 and -CW0304 AllelesJournal of Virology, 2002
- Epstein-Barr virus: exploiting the immune systemNature Reviews Immunology, 2001
- Phenotypic and Functional Separation of Memory and Effector Human CD8+ T CellsThe Journal of Experimental Medicine, 1997