Accumulation of EVV–induced cross-reactive immune responses is associated with MS, 2024, Hannes Vietzen et al

[Mij]

In summary, we report that MS patients are hallmarked by an accumulation of immune responses specifically directed against EBV EBNA381–452 and cross-reacting with CNS GlialCAM370–389–, CRYAB2–21–, MBP205–224–, and ANO2135–154–derived epitopes. Although, our findings provide additional insights into the pathogenesis of MS, further longitudinal studies are required to assess the individual increase of EBNA381–452–derived antibody responses.
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[Sly Saint]

Accumulation of Epstein-Barr virus–induced cross-reactive immune responses is associated with multiple sclerosis

Multiple sclerosis (MS) is a chronic autoinflammatory and demyelinating disease of the central nervous system (CNS). The individual risk of developing MS substantially increases after a primary infection with the ubiquitous EBV (1). MS pathogenesis was associated earlier with the development of high-level antibodies directed against the EBV nuclear antigen-1 (EBNA-1), which cross-reacts with distinct CNS-derived proteins and may result in autoreactive immune responses (1). Recent studies have already identified a conserved sequence in the EBNA-1 region, EBNA381–452, as a main factor for potential molecular mimicry and autoreactivity (1). However, it is unknown whether potent EBNA381–452–specific immune responses may in fact trigger MS pathogenesis in the individual host.

The aim of this study was thus to investigate whether a distinct antibody signature against EBNA381–452 is associated with high cross-reactive autoimmune responses that further evolve into MS. Therefore, we recruited a study cohort of 270 EBV-seropositive MS patients that were matched to 270 healthy controls regarding age, sex, and time point of EBV seroconversion (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI184481DS1). From all study participants, plasma samples were available at the time point of primary EBV infection as well as at MS diagnosis and, in controls, at a matched time point after EBV seroconversion, respectively.

JCI - Accumulation of Epstein-Barr virus–induced cross-reactive immune responses is associated with multiple sclerosis

article about the paper

Elevated antibody responses to Epstein-Barr virus linked to increased risk of multiple sclerosis

In a recent study published in the Journal of Clinical Investigation, a group of researchers investigated the role of a distinct antibody signature against the Epstein-Barr virus nuclear antigen-1 (EBNA1, specifically EBNA381-452) and its association with high cross-reactive autoimmune responses that may contribute to the development of multiple sclerosis (MS).

Background
MS is a chronic autoimmune disease characterized by inflammation and demyelination in the central nervous system (CNS). The risk of developing MS is thought to significantly increase following infection with Epstein-Barr virus (EBV), as antibodies against EBNA1 can cross-react with CNS proteins, potentially leading to undesirable autoreactive immune responses.

A specific sequence in EBNA1, known as EBNA381-452, has been implicated in this process. However, the exact mechanisms by which immune responses specific to EBNA381-452 might trigger MS onset remain incompletely understood, highlighting the need for further research to clarify their role in disease pathogenesis.

About the study
The study included a cohort of 270 EBV-seropositive MS patients, matched with 270 healthy controls based on age, sex, and the timing of EBV seroconversion. Plasma samples collected from each participant were analyzed at three key time points: during primary EBV infection, at the time of MS diagnosis for patients, and at a matched time point for the controls.

Researchers observed that MS patients had not only higher antibody levels but also elevated T and B cell counts responsive to both EBV and central nervous system proteins, suggesting a broader immune involvement in MS progression.

To evaluate specific immune responses, the researchers used an EBNA381-452-derived peptide library to analyze the detailed specificity of EBNA381-452-specific antibody responses in both MS patients and healthy controls. These antibody responses were measured against various epitopes, including those that cross-react with CNS-derived proteins such as glial cell adhesion molecule (GlialCAM), alpha-crystallin B chain (CRYAB), myelin basic protein (MBP), and anoctamin 2 (ANO2).

The individual antibody responses against four EBNA-derived peptides and their corresponding cross-reactive CNS-derived peptides (specific regions include EBNA386-405/GlialCAM370-389, EBNA393-412/CRYAB2-21, EBNA409-428/MBP205-224, and EBNA426-445/ANO2135-154) were quantified. The analysis focused on identifying any detectable EBNA381-452-specific antibody responses during the initial EBV infection phase and at the time of MS diagnosis.

The researchers also assessed the correlation between the levels of **specific immune cell types—**Cluster of Differentiation (CD)19+ B cells, CD4+ T cells, and CD8+ T cells, which are reactive to both EBNA and CNS peptides—by collecting peripheral blood mononuclear cells (PBMCs) from a subset of 20 MS patients and 80 healthy controls.

The data were analyzed to determine the presence of highly elevated immune responses among MS patients compared to controls, with a series of statistical analyses applied to determine the reliability and significance of these findings.

Elevated antibody responses to Epstein-Barr virus linked to increased risk of multiple sclerosis