Unstable EBV latency drives inflammation in multiple sclerosis patient derived spontaneous B cells
Soldan S. et al. (Research Square) DOI: 10.21203/rs.3.rs-2398872/v1
EBV is the strongest environmental factor associated with MS and recent data showed that EBV-infection could be triggering MS disease (Bjornevik et al. Science. 2022). Among the mechanisms underlying MS development, infection and activation of autoreactive B cells, molecular mimicry between EBV and CNS proteins, and suboptimal control of EBV infection by T cells have been proposed. In this preprint Soldan et al. use spontaneous (i.e. without de novo EBV infection) lymphoblastoid cell lines (SLCLs) derived from peripheral blood mononuclear cell (PBMC) cultures from multiple sclerosis patients and healthy controls to investigate host-virus interactions in B cells.
They observed that EBV enter a replicative lytic cycle preferentially in pwMS with active disease activity. The EBV lytic cycle was also associated with inflammation that may result from the activation of tumor necrosis factor (TNF) and/or interferon signalling pathways. Importantly, authors used tenofovir alafenamide, an antiviral that targets EBV replication, to demonstrate that the reduction of EBV lytic gene expression also decreased EBV-associated inflammation in SLCLs. The authors also proposed that the entry of EBV in lytic cycle might result from the differential binding of EBV nuclear protein EBNA1 to regions of the viral origin of replication between patients with MS and healthy controls.
Increasing the number of SLCLs derived from healthy controls (n=2) would strengthen the results presented.
As 3 out of 4 SLCLs derived from MS patients with active ‘died off’ after 32 weeks of culture, it would be important to mention when the different experiments were performed and verify whether SLCL characteristics (phenotype, gene expression) may vary with time of culture.
Similarly, whether the mixed-lymphocyte reaction (MLR) experiments were performed with the last surviving SLCLs should be mentioned. These experiments would benefit from an increased number of SLCL, and the addition of cell lines derived from patients with stable disease.
This preprint show that the EBV infection is associated with higher entry to lytic cycle in spontaneous lymphoblastic cell lines derived from patients with MS. It provides some evidence of that EBV intrinsic properties, such as EBNA1-mediated latency, is altered in patient with MS. These results are in line with the recent observation of skewed T-cell responses toward lytic EBV antigens in patients with MS (Schneider-Hohendorf et al. J Exp Med. 2022), and support the involvement of EBV in MS disease development.
Reviewed by Nicolas Ruffin as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.
The author declares no conflict of interests in relation to their involvement in the review.