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Lünemann, J. D. et al. Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain 129, 1493-1506

Neuroimmunology Branch, Cellular Immunology Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Brain (Impact Factor: 10.23). 07/2006; 129(Pt 6):1493-506. DOI: 10.1093/brain/awl067
Source: PubMed

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.

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    • "as we (Ben Fredj et al., 2012) and other investigators have recently reported (Levin et al., 2003; Giovannoni et al., 2006; Haahr & Hollsberg, 2006; Lunemann et al., 2006; Lindsey et al., 2009). Correale and collaborators demonstrated that the serum concentration of 25(OH)D and 1,25(OH)2D was lower in patients with MS than those in controls (Correale et al., 2009). "
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    ABSTRACT: Summary The vitamin D receptor (VDR) polymorphisms have been reported to be associated with multiple sclerosis (MS); however, evidence remains conflicting. In this report, we investigated the association between two single nucleotide polymorphisms (SNPs) TaqI and ApaI of VDR gene and risk development of MS. TaqI and ApaI SNPs were detected by PCR-RFLP from the DNA of 60 Tunisian patients with MS and 114 healthy controls. Our results show a significant difference of the allelic frequency distribution between the case and control groups for TaqI SNP (P = 0.01), but genotype frequencies were not significantly different (P = 0.07 and 0.23). When adjusting frequency distribution of different alleles and genotypes by age, we found that the difference between the T allele frequencies of this SNP in the group of patients age [15˗24] in comparison with the control group of the same age group was statistically significant (P = 0.026). Moreover, frequency of the T allele was significantly higher in male patients compared with controls of the same sex (P = 0.017). However, neither the genotype nor the allele frequency distribution was significantly different between the MS and control populations for the ApaI SNP. Our preliminary results indicate that VDR gene polymorphism could be associated with susceptibility to MS. The role of VDR gene polymorphism should be further studied in other large populations, and the distribution of other polymorphism, such as FokI and BsmI, should be also analysed to confirm another susceptibility polymorphisms gene for MS and to obtain more adequate strategies for treatment of MS.
    International Journal of Immunogenetics 04/2015; · 1.34 Impact Factor
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    • "as we (Ben Fredj et al., 2012) and other investigators have recently reported (Levin et al., 2003; Giovannoni et al., 2006; Haahr & Hollsberg, 2006; Lunemann et al., 2006; Lindsey et al., 2009). Correale and collaborators demonstrated that the serum concentration of 25(OH)D and 1,25(OH)2D was lower in patients with MS than those in controls (Correale et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The vitamin D receptor (VDR) polymorphisms have been reported to be associated with multiple sclerosis (MS); however, evidence remains conflicting. In this report, we investigated the association between two single nucleotide polymorphisms (SNPs) TaqI and ApaI of VDR gene and risk development of MS. TaqI and ApaI SNPs were detected by PCR-RFLP from the DNA of 60 Tunisian patients with MS and 114 healthy controls. Our results show a significant difference of the allelic frequency distribution between the case and control groups for TaqI SNP (P = 0.01), but genotype frequencies were not significantly different (P = 0.07 and 0.23). When adjusting frequency distribution of different alleles and genotypes by age, we found that the difference between the T allele frequencies of this SNP in the group of patients age [15-24] in comparison with the control group of the same age group was statistically significant (P = 0.026). Moreover, frequency of the T allele was significantly higher in male patients compared with controls of the same sex (P = 0.017). However, neither the genotype nor the allele frequency distribution was significantly different between the MS and control populations for the ApaI SNP. Our preliminary results indicate that VDR gene polymorphism could be associated with susceptibility to MS. The role of VDR gene polymorphism should be further studied in other large populations, and the distribution of other polymorphism, such as FokI and BsmI, should be also analysed to confirm another susceptibility polymorphisms gene for MS and to obtain more adequate strategies for treatment of MS. © 2015 John Wiley & Sons Ltd.
    International Journal of Immunogenetics 04/2015; 42(3). DOI:10.1111/iji.12197 · 1.34 Impact Factor
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    • "sing MS patients are contradictory . Ferrante et al . ( 1997 ) collected serial blood samples beginning at the onset of an exacerbation and frequently detected EBV DNA in PBMCs early in the relapse . However , Alvarez - Lafuente et al . ( 2006 ) and Sotelo et al . ( 2007 ) did not detect any increase in EBV DNA in relapse compared with remission . Lunemann et al . ( 2006 ) and Lindsey et al . ( 2009 ) measured EBV DNA levels in peripheral blood lymphocytes and found that the levels in MS were non - significantly higher than controls . Also our results fail to show any correlation between EBV presence and MS disease activity ."
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