EBNA-1 titer gradient in families with multiple sclerosis indicates a genetic contribution

Mescheriakova, Julia; Nierop, Gijsbert P. van; Eijk, Annemiek A. van der; Kreft, Karim L.; Hintzen, Rogier Q.

doi:10.1212/nxi.0000000000000872

Cited by 17 publications

(15 citation statements)

References 29 publications

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“…6). Anti-EBNA1-reactivity has been implicated in MS epidemiology 20 , and the region AA365-425 is the target of stronger antibody responses in MS than in healthy individuals 5,[9][10][11][12] .…”

Section: Csf-derived Monoclonal Antibodies Bind Ebv Antigensmentioning

confidence: 99%

Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM

Lanz

Brewer

et al. 2022

Nature

523

282

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Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal uid (CSF) of MS patients contribute to in ammation and secrete oligoclonal immunoglobulins. Epstein-Barr virus (EBV) infection has been linked to MS epidemiologically, but its pathological role remains unclear. Here we demonstrate high-a nity molecular mimicry between the EBV transcription factor EBNA1 and the CNS protein GlialCAM, and provide structural and in-vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identi ed by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSFderived antibodies against MS-associated viruses. Sequence analysis, a nity measurements, and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment allowed for tracking the development of the naïve EBNA1-restricted antibody to a mature EBNA1/GlialCAM crossreactive antibody. Molecular mimicry is facilitated by a post-translational modi cation of GlialCAM. EBNA1 immunization exacerbates the mouse model of MS and anti-EBNA1/GlialCAM antibodies are prevalent in MS patients. Our results provide a mechanistic link for the association between MS and EBV, and could guide the development of novel MS therapies. Main TextThe presence of oligoclonal bands (OCB) in cerebrospinal uid (CSF) and the e cacy of B cell depleting therapies emphasize the importance of B cells in the pathobiology of multiple sclerosis (MS) 2 . Anti-viral antibodies against mumps, measles, varicella-zoster, and Epstein-Barr Virus (EBV) are often present in MS 4,5 , but their relevance is unclear. Anti-EBV antibody titers in over 99% of MS patients provide evidence for an epidemiological link between MS and EBV 6 . Symptomatic infectious mononucleosis during EBV infection increases risk for MS 7 . Molecular mimicry between virus and self-antigens is a potential mechanism that might explain this association 8 . Antibodies against certain EBV nuclear antigen 1 (EBNA1) regions have been found in MS patients, including the region AA365-426 5,9-12 , which we describe here in our identi cation of molecular mimicry between EBNA1 and the glial cellular adhesion molecule GlialCAM. The potential signi cance of this mimicry in the pathophysiology of MS is described in detail.The B cell repertoire in MS CSF plasmablasts is highly clonal CSF and blood samples were obtained from MS patients during the onset of disease (clinically isolated syndrome, n=5) or an acute episode of relapsing-remitting MS (n=4). Patients with a CSF pleocytosis of >10 cells/µl were selected (Extended Data Table 1, Supplementary Discussion). Single B cells were sorted by ow cytometry (Extended Data Fig. 1a,b). Characteristic phenotypic differences of B cells in blood and CSF were observed 13,14 , including (i) high plasmablast (PB) counts in CS...

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Section: Csf-derived Monoclonal Antibodies Bind Ebv Antigensmentioning

confidence: 99%

Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM

Lanz

Brewer

et al. 2022

Nature

523

282

View full text Add to dashboard Cite

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“…a first symptomatic episode suggestive of MS) and early MS are seropositive for EBV antigens [37,38]. Furthermore, abundant EBNA1 IgG levels and a history of symptomatic EBV infection (infectious mononucleosis) in HLA-DRB1*1501 carriers have been associated with an increased odds ratio for MS [39,40]. EBV infection was recently shown to increase 32-fold the risk of MS, consistently preceding symptom onset and the detection of the neurofilament light chain in serum, one of the earliest markers of preclinical MS [41].…”

Section: Discussionmentioning

confidence: 99%

Anti-EBNA1 IgG titre is not associated with fatigue in multiple sclerosis patients

Fleischer

Schuh

Bickmann

et al. 2022

Neurol Neurochir Pol.

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Introduction. Fatigue is the most frequent symptom in multiple sclerosis (MS), although it is still poorly understood due to its complexity and subjective nature. There is an urgent need to identify reliable biomarkers to improve disease prognosis and therapeutic strategies. Epstein-Barr virus (EBV) is the major environmental risk factor associated with MS aetiology, and trials with EBV-targeted T cell therapies have reduced fatigue severity in MS patients.Aim of the study. We investigated whether the serum amount of immunoglobulin (Ig)G-specific for EBV antigens could be a suitable prognostic marker for the assessment of MS-related fatigue. Material and methods.A total of 194 MS patients were enrolled. We quantified EBV nuclear antigen 1 (EBNA1) and EBV viral capsid antigen (VCA) immunoglobulin (Ig) G levels and B cell-activating factor of the tumour necrosis factor family (BAFF) concentration in the serum of patients with relapsing-remitting MS (RRMS) and chronic progressive MS (CPMS), and we analysed their correlation with aspects of fatigue and other clinical disease parameters. Results.A complete EBV seropositivity could be detected in our cohort. After adjusting for confounding variables and covariates, neither EBNA1 nor VCA antibody titres were associated with levels of fatigue, sleepiness, depression, or with any of the clinical values such as expanded disability status scale, lesion count, annual relapse rate, or disease duration. However, patients with RRMS had significantly higher EBNA1 IgG titre than those with CPMS, whereas this was not the case under therapies targeting CD20 + cells. BAFF levels in serum were inversely proportional to anti-EBNA1 IgG.Conclusions and clinical implications. Our results show that EBNA1 IgG titre is not associated with the presence or level of fatigue. Whether the increased EBNA1 titre in RRMS plays a direct role in disease progression, or is only a consequence of excessive B cell activation, remains to be answered in future studies.

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“…However, the literature is controversial regarding the association of antibodies against EBV with prognosis or clinical severity of MS. While some epidemiological as well as laboratory studies have suggested an association between EBV and MS [11,28,29], a number of other studies have failed to find a correlation between EBV antibodies and disease course or clinical disease activity in MS patients [30][31][32].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of IL-1β and IL-6 Expression following EBNA-1 and BRLF-1 Peptide Treatment in Epstein-Barr Virus-Positive Multiple Sclerosis Patients

et al. 2022

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Introduction: Epstein-barr virus (EBV/HHV-4) has been implicated in the pathogenesis of Multiple sclerosis (MS). This study was conducted to investigate the levels of pro-inflammatory cytokines IL-1β and IL-6 in healthy Epstein-Barr virus (EBV) carriers and MS patients with prior EBV infection in response to treatment with Epstein–Barr virus nuclear antigen 1 (EBNA-1) and Replication and transcription activator (BRLF-1/Rta) peptide antigens in whole blood cell culture to assess the cytokine expression across all cells in the peripheral blood. Methods: Isolated whole blood cells from the included participants were incubated at a concertation of 106 cells/ml with BRLF1 or EBNA1. The amount of IL-1β and IL-6 transcripts were measured with quantitative RT-PCR at day 3 after incubation. MTT assay was conducted to examine cytotoxicity of the peptides and their effect on cell viability. Changes in cytokine expression and cell viability were analyzed using one-way and two-way ANOVA, respectively. Results: Ten MS patients and ten healthy donors were enrolled in the study. Treatment with the peptide antigens resulted in increased cytokines expression in both MS patients and healthy subjects. Furthermore, IL-1β levels were higher in MS patients compared to healthy EBV carriers. MTT assay revealed no significant difference in cell viability between the two groups. Discussion: The higher levels of IL-1β in response to EBV antigens in MS patients may reflect the host neuroinflammatory environment and support the notion that immune response against EBV has a role as an aggravating factor in the progression of MS by contributing to the neuroinflammatory cascade.

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EBNA-1 titer gradient in families with multiple sclerosis indicates a genetic contribution

Cited by 17 publications

References 29 publications

Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM

Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM

Anti-EBNA1 IgG titre is not associated with fatigue in multiple sclerosis patients

Evaluation of IL-1β and IL-6 Expression following EBNA-1 and BRLF-1 Peptide Treatment in Epstein-Barr Virus-Positive Multiple Sclerosis Patients

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