Why are experts important?
In the so-called post-truth era experts are derided and ignored. Not at Barts-MS.
Last Friday we held a lock-in to review and discuss our EBV research programme and bring in expertise from outside our group. We were fortunate to have card-carrying EBV experts, oncologists, B-cell biologists and protein and antibody experts around the table. A central plank of the EBV hypothesis of MS has been built on the B-cell data, i.e. memory B-cells is one of the likely treatment targets for licensed DMTs and it just so happens to be the cell that EBV uses as its home. EBV hijacks the B-cell’s machinery and is so doing is likely to tip the balance towards autoimmunity. The dogma in the field is EBV is a B-cell tropic virus. I was therefore very surprised to hear new evidence which shows EBV also infects T-cells and therefore is likely to have an impact on T-cell biology. At the moment it is only the EBV type 2 that has been shown in infect T-cells, but this observation is likely to apply to the type 1 virus as well.
What does this mean for MS? I am not sure, but it has potential implications for how we target EBV in people with established MS; that is if EBV is the treatment target. At the very least it challenges some of our thinking about how we treat MS. For example, if we need to eliminate EBV to cure MS we probably have to target other compartments, including the T-cell compartment, and not just the B-cell and plasma cell compartments. T-cells may act as a reservoir for persistent EBV infection. This may explain why combined T- and B-cell depleters (non-selective immune reconstitution therapies), although riskier in the short-term, seem to have the edge over B-cell depleters when it comes to end-organ damage markers (brain volume loss) and confirmed disability improvement (CDI). NIRTs have also been described to eliminate EBV from the body in a small number of patients, which has not been described for B-cell depleters. It also means that we will need to build in components to our research programme that also focuses on T-cells as a potential mediator of EBV’s effects on the immune system.
Why are experts important? Experts teach you things you don’t know. Experts have the time and background knowledge to do the necessary deep thinking on their subject, which is required to challenge the prevailing dogma. I would like to thank the experts who came to our lock-in last Friday; you have changed my worldview on EBV.
Coleman et al. Epstein-Barr Virus Type 2 Infects T Cells in Healthy Kenyan Children. J Infect Dis. 2017 Sep 15;216(6):670-677.
BACKGROUND: The 2 strains of Epstein-Barr virus (EBV), EBV type 1 (EBV-1) and EBV-2, differ in latency genes, suggesting that they use distinct mechanisms to establish latency. We previously reported that EBV-2 infects T cells in vitro. In this study, we tested the possibility that EBV-2 infects T cells in vivo.
METHODS: Purified T-cell fractions isolated from children positive for EBV-1 or EBV-2 and their mothers were examined for the presence of EBV and for EBV type.
RESULTS: We detected EBV-2 in all T-cell samples obtained from EBV-2-infected children at 12 months of age, with some children retaining EBV-2-positive T cells through 24 months of age, suggesting that EBV-2 persists in T cells. We were unable to detect EBV-2 in T-cell samples from mothers but could detect EBV-2 in samples of their breast milk and saliva.
CONCLUSIONS: These data suggest that EBV-2 uses T cells as an additional latency reservoir but that, over time, the frequency of infected T cells may drop below detectable levels. Alternatively, EBV-2 may establish a prolonged transient infection in the T-cell compartment. Collectively, these novel findings demonstrate that EBV-2 infects T cells in vivo and suggest EBV-2 may use the T-cell compartment to establish latency.