Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis, 2024, Olivia G. Thomas et al

Abstract
Background
Epstein-Barr virus (EBV) is a likely prerequisite for multiple sclerosis (MS) but the underlying mechanisms are unknown. We investigated antibody and T cell responses to EBV in persons with MS (pwMS), healthy EBV-seropositive controls (HC) and post-infectious mononucleosis (POST-IM) individuals up to 6 months after disease resolution. The ability of EBV-specific T cell responses to target antigens from the central nervous system (CNS) was also investigated.

Methods
Untreated persons with relapsing-remitting MS, POST-IM individuals and HC were, as far as possible, matched for gender, age and HLA-DRB1*15:01. EBV load was determined by qPCR, and IgG responses to key EBV antigens were determined by ELISA, immunofluorescence and Western blot, and tetanus toxoid antibody responses by multiplex bead array. EBV-specific T cell responses were determined ex vivo by intracellular cytokine staining (ICS) and cross-reactivity of in vitro-expanded responses probed against 9 novel Modified Vaccinia Ankara (MVA) viruses expressing candidate CNS autoantigens.

Results
EBV load in peripheral blood mononuclear cells (PBMC) was unchanged in pwMS compared to HC. Serologically, while tetanus toxoid responses were unchanged between groups, IgG responses to EBNA1 and virus capsid antigen (VCA) were significantly elevated (EBNA1 p = 0.0079, VCA p = 0.0298) but, importantly, IgG responses to EBNA2 and the EBNA3 family antigens were also more frequently detected in pwMS (EBNA2 p = 0.042 and EBNA3 p = 0.005). In ex vivo assays, T cell responses to autologous EBV-transformed B cells and to EBNA1 were largely unchanged numerically, but significantly increased IL-2 production was observed in response to certain stimuli in pwMS. EBV-specific polyclonal T cell lines from both MS and HC showed high levels of autoantigen recognition by ICS, and several neuronal proteins emerged as common targets including MOG, MBP, PLP and MOBP.

Discussion
Elevated serum EBV-specific antibody responses in the MS group were found to extend beyond EBNA1, suggesting a larger dysregulation of EBV-specific antibody responses than previously recognised. Differences in T cell responses to EBV were more difficult to discern, however stimulating EBV-expanded polyclonal T cell lines with 9 candidate CNS autoantigens revealed a high level of autoreactivity and indicate a far-reaching ability of the virus-induced T cell compartment to damage the CNS.

Author summary
Previous infection with Epstein-Barr virus (EBV) is likely required for multiple sclerosis (MS) which occurs when the immune system damages the brain. How EBV contributes to this process is unknown, but some research suggests that immune responses to EBV may react to proteins in the brain that mimic virus proteins.

We investigated T-cell and antibody responses to EBV in people with MS (pwMS) and, as controls, people persistently infected with EBV who acquired the virus either silently or symptomatically. pwMS had more frequent antibody responses to several viral proteins, including EBNA1, EBNA2, EBNA3A, EBNA3B and VCA, but their EBV viral load was similar. T cell responses to EBV-transformed B-cells and EBNA1 were only slightly different in pwMS compared to controls. However, T-cell lines from pwMS and healthy individuals, established using each person’s own EBV-infected B-cell line, could also respond to multiple brain proteins. T-cell responses to myelin oligodendrocyte glycoprotein (MOG) were particularly common and we isolated T-cells that cross-recognised MOG and EBNA1.

Our findings suggest that adaptive immune responses to EBV–which would normally fight EBV infection–are dysregulated in MS and can also target multiple proteins in the brain, indicating their likely involvement in disease.

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The first statement of the paper is already wrong as it appears that EBV is not a prerequisite for MS, rather than being the strongest identified risk factor.

Getting the first statement wrong never conveys trust in the work one is doing...

I'm surprised they only looked at the antibody response to EBV and in that sense didn't have the same measure of control that for example Ascherios paper had.