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.
As ever, I hope that treatment research will look beyond simply destroying immune system components, depleting cells.
Immunosuppressive / -destructive therapies terrify me.
We are thinking about trying to selectively target EBV.
Any comments on AtaraBio’s ATA188/ATA190 studies. I wonder if a small modification would target T-cells as well.
The atara grown T cells are EBV peptide specific and would recognize any cell which displays EBV associated peptides and respond accordingly. You shouldn’t need to modify them as the T cells are already activated (theoretically) antigen specific. B cells are better antigen presenting cells compared with T cells, but they still could present some antigens. Easy enough to test in the lab with some patient T cells, EBV peptides, and some functional assays for cytotoxicity. Fratricide does happen between T cells if there is antigen present.
But Atara are targeting lytic antigens for EBV I believe, and the paper doesn’t say whether the EBV infected T cells express lytic or the latent antigens.
The T-cell story needs more work to be done particularly in MSers.
As long as the cell expresses EBV antigen and they are presented on the surface in an MHC molecule AtaraBio’s cells should find and kill these cells. However, like all clever herpesviruses EBV has several tricks it uses to evade immune detection. The T-cell may be another niche/trick it uses as part of its evasion strategy.
Great Article Prof G. Glad to see u are making this blog ur priority again. Not that MD was doing a bad job. This article makes total sense. As big data analytics consultant. I look for patterns in data and b cell atrophy levels were screaming to me a 2nd or 3rd pathway of brain degeneration. Have you consider applying machine learning analytics to crack the nut of MS?
EBV can also infect NK cells. EBV causes a number of NK/T lymphomas. If you want to think about EBV and its complex effects on the immune system, you should also include this potential reservoir as well.
“Under ideal conditions, a human DNA enzyme called APOBEC3B is capable of mutating and killing EBV and KSHV as it invades and replicates inside the body. However, researchers discovered that both viruses are able to produce defense proteins—BORF2 and ORF61, respectively—that bind directly to the APOBEC3B enzyme. In doing so, APOBEC3B is unable to mutate and kill the viral DNA and is directed away from sites of virus replication.
Researchers used CRISPR/Cas9-mediated genome engineering to delete the EBV’s defense protein. Through that process, the human APOBEC3B enzyme was able to mutate the virus, rendering it harmless and unable to replicate in cells.
“We are already working hard to extend these results from cells to mice and other complex organisms,” said Harris.”
https://www.nature.com/articles/s41564-018-0284-6
https://medicalxpress.com/news/2018-11-strategy-cancers-tied-mono-disease.html?fbclid=IwAR1F0fHlxAk1WaXKXrA1H6B-xG0NrO9o4EpIUOuTh8pZ53yLQon3iMq5irU
At least this might make MD stop the war on T cells… 😉
It might..but first I have to see if I can get rid of the T cell and them I can pair them up B and T if it makes sense. The point is to challenge peole to think rather than simply accept dogma
Had this at 19 very painful took me months to get over it. I lost a dress size lived on complain for sometime
Diagnosed with MS after having my daughter at 28. My brother has past away from MS at 40. My Mother’s little sister 76 Gastro cancer killed her but she had problems like my brother and me after G.V.
Hi,
So I had Mono when I was 14 years old. MS diagnosed in 2010. AHSCT (CTX-ATG) done in 2014, with great results until 2018, when I have relapsed. I have just checked my EBV and I have Igg 171 u/ml and Igm <10 u/ml. I'm wondering if HSCT has erased my previous Igg memory and if so, have I get EBV again after HSCT?