EBV-specific immune responses in patients with multiple sclerosis responding to IFNβ therapy

Comabella, Manuel; Kakalacheva, Kristina; Río, Jordi; Münz, Christian; Montalbán, Xavier; Lünemann, Jan D.

doi:10.1177/1352458511426816

Cited by 23 publications

(19 citation statements)

References 25 publications

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“…Our demonstration of significantly increased serological reactivity to EBNA-1 in the group of MS patients with disease activity during IFN-β therapy (IFNβ-non-responders) is in agreement with the findings from Farrell et al Further, the specific association between anti-EBNA-1 reactivity and disease activity is strengthened by a recent report from Comabella et al (2011) demonstrating a specific reduction in the proliferative T cell-mediated response to EBNA-1 during efficacious IFN-therapy. Our present demonstration of EBV EBNA-1 IgG as a relevant marker for disease activity, but not EBV EA IgM, or EBV EA IgG, is also in agreement with those reports.…”

Section: Discussionsupporting

confidence: 92%

Effects of interferon-beta therapy on elements in the antiviral immune response towards the human herpesviruses EBV, HSV, and VZV, and to the human endogenous retroviruses HERV-H and HERV-W in multiple sclerosis

Petersen

Møller-Larsen

Ellermann-Eriksen

et al. 2012

Journal of Neuroimmunology

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Section: Discussionsupporting

confidence: 92%

Effects of interferon-beta therapy on elements in the antiviral immune response towards the human herpesviruses EBV, HSV, and VZV, and to the human endogenous retroviruses HERV-H and HERV-W in multiple sclerosis

Petersen

Møller-Larsen

Ellermann-Eriksen

et al. 2012

Journal of Neuroimmunology

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“…The MOA of IFN-b in MS is not clear but is thought to involve anti-inflammatory mechanisms. Nevertheless, IFN-b is known to inhibit the infectivity of EBV, cytomegalovirus (CMV), and other viruses, influence proliferative T cell responses to EBNA1 [68], and decrease the memory B cell compartment that is considered to be a pathogenic cell subset and key trigger in MS [69]. It is tempting to suggest that the MOA of IFN-b and other disease-modifying therapies (DMTs) [70] includes overlapping antiviral and anti-inflammatory mechanisms that support future simultaneous testing of MS drugs with divergent MOAs.…”

Section: Antiviral Compoundsmentioning

confidence: 99%

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

Bar‐Or

Pender

Khanna

et al. 2020

Trends in Molecular Medicine

205

149

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New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein-Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention. HighlightsClinical studies show that depletion of B cells reduces disease burden in both relapsing-remitting and progressive multiple sclerosis (MS) patients.

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“…It is likely that such a strong reduction in the CD8+ T cell response to both viruses might due to the direct antiviral activity of the drug [41]. Recently, Comabella et al [50] reported that clinically effective IFN-β therapy is associated with downregulation of proliferative T cell responses to EBNA-1 without significant changes in the CD8+ T cell response against other (pooled) EBV antigens of the latent and lytic phase. Discrepancies with the present study could be due to technical issues, as discussed above.…”

Section: Discussionmentioning

confidence: 99%

Increased CD8+ T Cell Response to Epstein-Barr Virus Lytic Antigens in the Active Phase of Multiple Sclerosis

et al. 2013

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It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk. This evidence led to postulate that EBV infection plays a role in MS etiopathogenesis, although the mechanisms are debated. This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging. Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS. Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse.

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EBV-specific immune responses in patients with multiple sclerosis responding to IFNβ therapy

Abstract: Clinically effective IFNβ therapy is associated with a reduction of proliferative T-cell responses to EBNA1.

Cited by 23 publications

References 25 publications

Effects of interferon-beta therapy on elements in the antiviral immune response towards the human herpesviruses EBV, HSV, and VZV, and to the human endogenous retroviruses HERV-H and HERV-W in multiple sclerosis

Effects of interferon-beta therapy on elements in the antiviral immune response towards the human herpesviruses EBV, HSV, and VZV, and to the human endogenous retroviruses HERV-H and HERV-W in multiple sclerosis

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

Increased CD8+ T Cell Response to Epstein-Barr Virus Lytic Antigens in the Active Phase of Multiple Sclerosis

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