Higher incidence of Epstein-Barr virus-induced lymphocyte transformation in multiple sclerosis

Tørring, Caroline; Andreasen, Claus Bo; Gehr, Nina Lykkegaard; Bjerg, Lasse; Petersen, Thor; Höllsberg, Per

doi:10.1111/ane.12249

Cited by 21 publications

(17 citation statements)

References 23 publications

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“…First, because it does not discriminate between DNA in virions and viral DNA in latently infected cells it does not actually measure the frequency of EBV-infected B cells in the blood, which is probably increased in patients with MS, as suggested by increased spontaneous EBV-induced transformation of peripheral blood B cells. [41][42][43] Second, the EBV DNA copy number in the blood does not reflect the EBV load in compartments where it is increased in MS, namely the brain, as indicated by elevated titres of anti-EBV antibodies in the cerebrospinal fluid 24 and the detection of EBV in brain tissue, 40,44,45 and in the oral mucosa. 37 During clinical attacks of MS there was expansion of both the EBV-specific CD4 + T-cell and EBV-specific CD8 + T-cell populations, with increased functionality of latent-specific, and decreased functionality of lytic-specific, CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Defective T‐cell control of Epstein–Barr virus infection in multiple sclerosis

et al. 2017

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Mounting evidence indicates that infection with Epstein–Barr virus (EBV) has a major role in the pathogenesis of multiple sclerosis (MS). Defective elimination of EBV-infected B cells by CD8+ T cells might cause MS by allowing EBV-infected autoreactive B cells to accumulate in the brain. Here we undertake a comprehensive analysis of the T-cell response to EBV in MS, using flow cytometry and intracellular IFN-γ staining to measure T-cell responses to EBV-infected autologous lymphoblastoid cell lines and pools of human leukocyte antigen (HLA)-class-I-restricted peptides from EBV lytic or latent proteins and cytomegalovirus (CMV), in 95 patients and 56 EBV-seropositive healthy subjects. In 20 HLA-A2+ healthy subjects and 20 HLA-A2+ patients we also analysed CD8+ T cells specific for individual peptides, measured by binding to HLA-peptide complexes and production of IFN-γ, TNF-α and IL-2. We found a decreased CD8+ T-cell response to EBV lytic, but not CMV lytic, antigens at the onset of MS and at all subsequent disease stages. CD8+ T cells directed against EBV latent antigens were increased but had reduced cytokine polyfunctionality indicating T-cell exhaustion. During attacks the EBV-specific CD4+ and CD8+ T-cell populations expanded, with increased functionality of latent-specific CD8+ T cells. With increasing disease duration, EBV-specific CD4+ and CD8+ T cells progressively declined, consistent with T-cell exhaustion. The anti-EBNA1 IgG titre correlated inversely with the EBV-specific CD8+ T-cell frequency. We postulate that defective CD8+ T-cell control of EBV reactivation leads to an expanded population of latently infected cells, including autoreactive B cells.

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Section: Discussionmentioning

confidence: 99%

Defective T‐cell control of Epstein–Barr virus infection in multiple sclerosis

et al. 2017

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“…The resultant increase in cross-reacting antibody titers can be of diagnostic value for measuring neuro-inflammation if specific thresholds were to be identified. In addition, MS patients were shown to have increased B-cell transformation events albeit with similar kinetics to healthy individuals suggesting an increased propensity for having latent-EBV infected B-cells (Torring et al, 2014). This suggests higher EBV reactivation events in MS patients due to the presence of more latent EBV infected B-cells.…”

Section: Discussionmentioning

confidence: 93%

Gender influence in EBV antibody response in multiple sclerosis patients from Kuwait

Al-Temaimi

Alroughani

Jacob

et al. 2015

Journal of Neuroimmunology

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“…Recently, Maurer et al , 111 using single‐cell reverse transcription‐PCR for EBER, found increased frequencies of EBV‐infected plasma cells and plasmablasts in the peripheral blood of MS patients. Spontaneous EBV‐induced transformation of peripheral blood B cells occurs more frequently in MS patients than in healthy subjects; 30 , 112 , 113 this could be due to an increased frequency of EBV‐infected B cells in the blood and/or impaired T‐cell‐mediated regression of EBV‐driven B‐cell outgrowth in vitro . In two of these studies, increased spontaneous transformation occurred in the presence of cyclosporine to inhibit T‐cell activity, 112 , 113 suggesting an increased frequency of circulating EBV‐infected B cells.…”

Section: Evidence For a Role Of Ebv In The Pathogenesis Of Msmentioning

confidence: 99%

Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy

2014

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Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the central nervous system (CNS) causing progressive disability. Many observations implicate Epstein–Barr virus (EBV) in the pathogenesis of MS, namely universal EBV seropositivity, high anti-EBV antibody levels, alterations in EBV-specific CD8+ T-cell immunity, increased spontaneous EBV-induced transformation of peripheral blood B cells, increased shedding of EBV from saliva and accumulation of EBV-infected B cells and plasma cells in the brain. Several mechanisms have been postulated to explain the role of EBV in the development of MS including cross-reactivity between EBV and CNS antigens, bystander damage to the CNS by EBV-specific CD8+ T cells, activation of innate immunity by EBV-encoded small RNA molecules in the CNS, expression of αB-crystallin in EBV-infected B cells leading to a CD4+ T-cell response against oligodendrocyte-derived αB-crystallin and EBV infection of autoreactive B cells, which produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells in the CNS. The rapidly accumulating evidence for a pathogenic role of EBV in MS provides ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection through vaccination, antiviral drugs or treatment with EBV-specific cytotoxic CD8+ T cells. Adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins was recently used to treat a patient with secondary progressive MS. Following the therapy, there was clinical improvement, decreased disease activity on magnetic resonance imaging and reduced intrathecal immunoglobulin production.

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Higher incidence of Epstein-Barr virus-induced lymphocyte transformation in multiple sclerosis

Abstract: The higher incidence suggests an increased frequency of latent EBV-infected B cells in MS.

Cited by 21 publications

References 23 publications

Defective T‐cell control of Epstein–Barr virus infection in multiple sclerosis

Defective T‐cell control of Epstein–Barr virus infection in multiple sclerosis

Gender influence in EBV antibody response in multiple sclerosis patients from Kuwait

Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy

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