Brain Advance Access originally published online on June 11, 2008
Brain 2008 131(7):1712-1721; doi:10.1093/brain/awn108
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Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis
1Division of Immunology and Allergy, 2Division of Neurology and 3Institute of Microbiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Correspondence to: Renaud A. Du Pasquier, Services de neurologie et d'i;mmunologie et allergie, BT-06, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland E-mail: renaud.du-pasquier{at}chuv.ch
Epstein-Barr virus (EBV) has been associated with multiple sclerosis (MS), however, most studies examining the relationship between the virus and the disease have been based on serologies, and if EBV is linked to MS, CD8+ T cells are likely to be involved as they are important both in MS pathogenesis and in controlling viruses. We hypothesized that valuable information on the link between MS and EBV would be ascertained from the study of frequency and activation levels of EBV-specific CD8+ T cells in different categories of MS patients and control subjects. We investigated EBV-specific cellular immune responses using proliferation and enzyme linked immunospot assays, and humoral immune responses by analysis of anti-EBV antibodies, in a cohort of 164 subjects, including 108 patients with different stages of MS, 35 with other neurological diseases and 21 healthy control subjects. Additionally, the cohort were all tested against cytomegalovirus (CMV), another neurotropic herpes virus not convincingly associated with MS, nor thought to be deleterious to the disease. We corrected all data for age using linear regression analysis over the total cohorts of EBV- and CMV-infected subjects. In the whole cohort, the rate of EBV and CMV infections were 99% and 51%, respectively. The frequency of IFN-
secreting EBV-specific CD8+ T cells in patients with clinically isolated syndrome (CIS) was significantly higher than that found in patients with relapsing–remitting MS (RR-MS), secondary-progressive MS, primary-progressive MS, patients with other neurological diseases and healthy controls. The shorter the interval between MS onset and our assays, the more intense was the EBV-specific CD8+ T-cell response. Confirming the above results, we found that EBV-specific CD8+ T-cell responses decreased in 12/13 patients with CIS followed prospectively for 1.0 ± 0.2 years. In contrast, there was no difference between categories for EBV-specific CD4+ T cell, or for CMV-specific CD4+ and CD8+ T-cell responses. Anti-EBV-encoded nuclear antigen-1 (EBNA-1)-specific antibodies correlated with EBV-specific CD8+ T cells in patients with CIS and RR-MS. However, whereas EBV-specific CD8+ T cells were increased the most in early MS, EBNA-1-specific antibodies were increased in early as well as in progressive forms of MS. Our data show high levels of CD8+ T-cell activation against EBV—but not CMV—early in the course of MS, which support the hypothesis that EBV might be associated with the onset of this disease.
Key Words: Epstein-Barr virus; multiple sclerosis; cellular immune response; humoral immune response; CD8+ T cells
Abbreviations: EBV, Epstein-Barr virus; MS, multiple sclerosis; EBNA-1, EBV-encoded nuclear antigen-1; EA, early antigen; LMP2, latent membrane protein-2; CMV, cytomegalovirus; CIS, clinically isolated syndrome; RR-MS, relapsing-remitting MS; SP-MS, secondary-progressive MS; PP-MS, primary-progressive MS; MRI, magnetic resonance imaging; IEF, isoelectric focusing; HLA, Human leucocyte antigen; PBMC, peripheral blood mononuclear cells; ICS, intracellular cytokine staining assay; ELISPOT, enzyme linked immunospot; PHA-L, phyto-hemagglutinin lectin; SFC, spot-forming cells; PAs, proliferation assays; SI, stimulation index; cpm, counts per minute; ELISA, enzyme-linked immunosorbent assay; AU, arbitrary units; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein
Received February 11, 2008. Revised May 7, 2008. Accepted May 9, 2008.
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