Publications

Research Papers

Posted on November 4, 2025  •  8 minutes  • 1579 words

BEHIND-MS Research publications

• Genetic and environmental mediators of multiple sclerosis susceptibility but not early severity run in families

Van Luijn M. et al. Genetic and environmental mediators of multiple sclerosis susceptibility but not early severity run in families Multiple Sclerosis and Related Disorders 109 (2026)

We studied people at an early stage of Multiple Sclerosis (MS) after clinically isolated syndrome (CIS) and looked at their genes, vitamin D levels, body weight, Anti-Epstein Barr virus Nuclear Antigen-1 (anti-EBNA1) IgG antibodies and family history. We found that people with relatives who have MS tend to carry more genetic risk factors and are more likely to have traits linked to lower vitamin D and higher body weight, but anti-EBNA1 IgG titers did not differ and their disease did not progress faster in the early phase. This suggests that the risk of getting MS and how the disease develops are influenced by different factors.

• Multiple sclerosis-associated HLA demarcates EBV-specific CD8+ T cells with an exhausted and brain residency phenotype

Van Luijn M. et al. Multiple sclerosis-associated HLA demarcates EBV-specific CD8+ T cells with an exhausted and brain residency phenotype iScience 29, 115744 (2026).

The study looks at special immune cells (T cells) that help control Epstein-Barr virus (EBV) and how they differ in people with multiple sclerosis (MS). It found that people with a certain genetic type (HLA-B7) have weaker and more “tired” immune cells that are less effective at fighting EBV and may enter the brain more easily. This suggests that in some MS patients, the immune system struggles to control EBV, which could contribute to disease development.

• A novel multiplex approach for the comprehensive analysis of the Epstein-Barr virus-specific humoral immune response

Mautner, J. et al A novel multiplex approach for the comprehensive analysis of the Epstein-Barr virus-specific humoral immune response , Front. Cell. Infect. Microbiol. (2026)

We developed a novel test that evaluates immune responses against the full spectrum of Epstein–Barr virus (EBV) proteins rather than only a limited subset. Using blood samples from individuals with and without EBV infection, we validated the assay and found that its sensitivity and specificity were comparable to those of existing diagnostic methods. However, by targeting the entire EBV proteome, the test provides a far more comprehensive assessment of the immune response. This broader coverage may enable the discovery of new biomarkers for EBV-associated cancers and autoimmune diseases, while also supporting advances in diagnosis, risk assessment, and treatment strategies.

• B-cell abundance in perivascular cuffs associates with local lesion activity in multiple sclerosis

Van Luijn M. et al. B-cell abundance in perivascular cuffs associates with local lesion activity in multiple sclerosis acta neuropathol commun (2026).

In this publication, we found that CD4+ T cells were relatively more present than CD8+ T cells within perivascular cuffs (n=457) of MS brain donors (n=18), which associated with local lesion activity and abundance of both B cells and antibody-secreting cells. Within these cuffs, LMP-1+ B cells were only present sparsely (13/122 perivascular cuffs of 6/11 donors). In 6 of 6 MS brain donors, we detected EBV DNA in freshly isolated B cells from one or more post-mortem CNS compartments. In these MS donors, LMP-1+ B cells were detected in the meninges. This further supports local interaction between CD4+ T and B cells to be associated with lesion presence and that this can happen irrespective of local EBV presence.

• Integrin β1 Demarks Precursors of Brain-Residing Antibody-Secreting Cells in Multiple Sclerosis

Van Luijn M. et al. Integrin β1 Demarks Precursors of Brain-Residing Antibody-Secreting Cells in Multiple Sclerosis Neurol Neuroimmunol Neuroinflamm. 13(3):e200553 (2026)

Using single-cell technologies, we identified ITGB1 (integrin beta-1/CD29) as a distinct marker on circulating CXCR3+ B cells, which accumulate and become antibody-secreting cells in the MS brain. CD29 appeared to be more upregulated on circulating B cells turning into antibody-secreting cells after T-cell help in vitro, while it was highly expressed together with CXCR3 on postmortem CNS- and not blood-derived antibody-secreting cells of MS donors. When treating with cladribine, we found clues that CD29 was only upregulated on repopulating CXCR3+ B cells from MS patients with recurrent disease activity. Of note, these types of B cells are associated with increased EBV infection (van Langelaar et al., Eur J Immunol 2021).

• Multiple sclerosis-associated EBNA2 variants influence the response to peginterferon beta-1a therapy

Veroni C. et al. Multiple sclerosis-associated EBNA2 variants influence the response to peginterferon beta-1a therapy Journal of Autoimmunity, V. 159 (2026)

This study, involving both EU-funded consortia BEHIND-MS and EBV-MS, investigates how peginterferon beta-1a (peg-IFN) modulates the interaction between EBV and the immune system in people with MS. Despite the availability of newer disease-modifying therapies, peg-IFN remains a valuable option in selected clinical settings, including pregnancy, lactation and in aging patients. Our findings support a personalized medicine approach and further strengthen the link between EBV biology and MS pathogenesis.

• EBV Dysregulation Is Associated With Immune Imbalance in Multiple Sclerosis

Veroni C. et al. EBV Dysregulation Is Associated With Immune Imbalance in Multiple Sclerosis: Evidence From Integrated Viral and Host Analyses Neurology: Neuroimmunology & Neuroinflammation 13.2 (2026): e200545.

This study analyzed EBV activity and immune gene expression in peripheral blood from therapy-naïve people with MS compared with healthy donors, using an integrated virologic and immunologic approach that enabled multivariate analysis of viral and host immune parameters within the same samples. MS patients showed increased anti-EBNA1 antibody titers, higher EBV DNA/RNA detection and viral load, and a higher frequency of EBV transcriptional profiles consistent with latency II/III activation and lytic reactivation, with similar patterns detectable in a subset of CSF samples. Broad immune activation was observed in MS patients, characterized by upregulation of cytotoxic effector pathways, type I interferon signalling, and chemokine-driven immune cell trafficking. Importantly, integrative multivariate analysis identified a virus-host transcriptional signature linking the EBV lytic gene BZLF1 to inflammatory mediators , antiviral type I interferon responses, and chemokines involved in immune cell migration, which significantly discriminated MS patients from healthy donors. The results support the hypothesis that EBV latency disruption and lytic reactivation contribute to immune dysregulation in MS.

• EBV infection and HLA-DR15 jointly drive multiple sclerosis by myelin peptide presentation

Wang, J., Magliozzi, R., et al. EBV infection and HLA-DR15 jointly drive multiple sclerosis by myelin peptide presentation Cell, v. 189, iss. 2, (2026)

This publication shows that EBV infection alters the transcriptome of B cells, which leads to presentation of MBP peptides on HLA-DR15 molecules. MBP peptide-specific CD4 + T cells are found in the peripheral immune compartment and CNS, where they recognize the same MBP peptides on HLA-DR15 molecules. Roberta Magliozzi from the BEHIND-MS consortium contributed to this publication by performing EBV-detection analyses in the meninges and perivascular vessels of the examined MS brain tissue.

• EBV Early Lytic Antigens, EBNA2 and PDL-1, in Progressive Multiple Sclerosis Brain: A Coordinated Contribution to Viral Immune Evasion

Serafini, B. et al. EBV Early Lytic Antigens, EBNA2 and PDL-1, in Progressive Multiple Sclerosis Brain: A Coordinated Contribution to Viral Immune Evasion , Int. J. Mol. Sci. (2026)

This study shows that EBV-infected cells exploit the inhibitory PD-1/PD-L1 immune checkpoint to evade immune surveillance not only during latency but also during early lytic and abortive phases of the viral life cycle. It is the first study describing, in secondary progressive MS brain tissue, that PD-L1 is expressed by EBV-infected B cells, including EBNA2-positive cells and cells expressing early lytic antigens, within meningeal tertiary lymphoid structures (TLSs), and that its expression is favoured by a local immunoregulatory milieu. These findings identify meningeal TLSs as immune-permissive niches sustaining an intracerebral EBV reservoir and highlight PD-1/PD-L1 signalling as a key mechanism of EBV persistence in the progressive MS brain.

• EBV induces CNS homing of B cells attracting inflammatory T cells

Münz, C. et al. EBV induces CNS homing of B cells attracting inflammatory T cells . Nature 646, 171–179 (2025).

You have free access to the accepted version via the Zurich Open Repository and Archive.

This study demonstrates that infection of a specific B cell subset by the Epstein Barr virus (EBV) initiates lymphocyte infiltration into the central nervous system (CNS). The respective EBV infected B cell subset then attracts proinflammatory T cells that cause prodromal multiple sclerosis signs.

• Epstein–Barr virus induces aberrant B cell migration and diapedesis via FAK-dependent chemotaxis pathways

Delecluse, S., Baccianti, F., Zala, M., et al. & Delecluse, H.J. Epstein–Barr virus induces aberrant B cell migration and diapedesis via FAK-dependent chemotaxis pathways Nat Commun (2025).

Many people are infected with the Epstein-Barr virus (EBV), and most are unaware of it. However, EBV can sometimes cause cancer, and this pathogen also appears to play an important role in multiple sclerosis and other autoimmune diseases. Researchers at the German Cancer Research Center (DKFZ) and the Kidney Center at Heidelberg University Hospital have discovered that EBV increases the ability of infected immune cells to migrate. In this way, the pathogen promotes its spread in the body – a discovery that may have therapeutic implications.

• Increased EBNA1-specific antibody response in primary-progressive multiple sclerosis

Comabella M. et al. & Lünemann JD. Increased EBNA1-specific antibody response in primary-progressive multiple sclerosis J Neurol. (2024)

While the association between EBA and MS has been primarily studied in most prevalent form of MS (relapse-onset MS, RMS), this study examines immune responses to ubiquitous viruses, including EBV, in patients with primary-progressive multiple sclerosis (PPMS). Immune responses to EBV were increased in PPMS patients compared to healthy controls, but not to other ubiquitous viruses tested, suggesting a connection between an altered response to EBV and the development of PPMS/RMS.