Mousey study to make ProfG happy….It’s all EBV or is it?


A christmas present for ProfG…It’s EBV….But am I BoJo and about to Steal the Crombo Joy away from him

Márquez AC, Shanina I, Horwitz MS. Multiple Sclerosis-Like Symptoms in Mice Are Driven by Latent γHerpesvirus-68 Infected B Cells. Front Immunol. 2020 Nov 19;11:584297.

Multiple sclerosis (MS) is caused by a combination of genetic and environmental factors. It is believed that previous infection with Epstein Barr Virus (EBV) plays an important role in the development of MS. Previously, we developed a murine model where latent infection with gamma herpesvirus 68 (γHV-68), a murine homolog to EBV, enhanced the symptoms of experimental autoimmune encephalomyelitis (EAE), resulting in disease that more closely resembles MS in humans. Here, we explored the conditions that were necessary for EAE enhancement. We showed that latently infected CD19+IgD B cells were capable of enhancing EAE symptoms when transferred from mice previously infected with γHV-68 into uninfected mice. We also observed a prevention of enhancement when B cells were depleted before infection. However, depletion after the establishment of latency only partially reduced EAE. This indicated the existence of a mechanism where B cells play an important role as antigen presenting cells (APCs) prior to EAE induction for the priming of Th1 cells. It is possible that these signals persist even after B cell depletion, strongly suggesting a paracrine signaling modulation of non-B cell APCs. These results strongly support the concept that EBV contributes to the development of autoimmunity and highlights the need for a vaccine against EBV that could limit or prevent multiple sclerosis development.

The message is pretty clear but does the data passs the “smack you in the eye” test?

Did one mouse die? A change over two days and you stop the experiment

think….I’m sorry to say

Scary Mommy

Although the text says a lot on the effects on the disease, I am sorry to say the effects are so very little that I find it hard to put this in my memory vault of data. I will wait until someone else replicates this

However the paper re-inforces our view that CD20 depletion does very little in mice….as suggested by our stuff. This is becuase the mice have a T cell mediated disease.

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  • But how do you explain the result in Figure 3B with the B-cell depletion experiment? Doesn’t that result pass your “smack in the eye” test? You say that the EAE mouse model is primarily a T-cell-mediated disease. Why does B-cell depletion just prior to EAE induction have an effect on the EAE score?

    The authors also don’t describe randomization of mice into different treatment groups and any blinding of the EAE scorers, which may allow an opportunity for biased scoring.

    • How do I explain….Simple…It’s biological variability compare the control group from each experiment in 1B,2B, 3B etc they are all over the place. The slope of 1a is inbetween the two slopes in 3B. Now if you read Matsushita T, Yanaba K, Bouaziz JD, Fujimoto M, Tedder TF.J Clin Invest. 2008 Oct;118(10):3420-30. and the original description of anti-CD20 it makes EAE worse. Cyclophophamide at this time point depletes B cells and EAE can be worse. People argue it affects regulatory B cells.

      Smack you in the eye test…Not passed…They end up in exactly the same place that one gets there a day or two earlier…so to sorry to say “So what”…it is biologically meaningless. If you get treated with anti-CD20 and you relapse at month 3 verses month 3.15 you are still getting disease and it is a treatment fail. A T cell depleter in the same experiment as 3B and there is no EAE. So grade O. We are having to split hairs of 3.0 verse 3.15 B cell depletion. The chances of this replicating in another lab is not high and translating into human is probably low. The histology show not much difference

      P.S. The statistical analysis is wrong you can’t do Student T tests on this type of data…end of story. It says Five independent experiments 20 to 25 mice/group I dont think that this means a total of a 100-125 mice in total, I think 5 experiments of 4-5 per group with an n=4 you are going to be lucky to get a p <0.05 so 5 underpowered experiments is not like doing one properly. N = 6-12 in two experiments suggests experiment of 3 verses 6....You start to think What colour are the Y fronts at this point

      • I agree that the description of the experiments is inadequate and makes it difficult to confidently conclude anything based on the data presented. I had missed the 6 to 24 mice/group in figure 1. Seems a bit asymmetric.

        All models are models. So could the conclusion of this publication be that the gammaHV-68-infected B cells with EAE induction is an unconvincing model of MS disease in humans? Or do problems with the data and statistics lead you to conclude nothing?

        • The conclusions sound confident and the problem is this is what gets remembered not the data that was used to generate the statement. Its ait likte the salt causes MS animal work…It has been rolled out in to a clinical trial…the endpoint is the TH17 response but I predict we wont see any effect on lesions load. In years past I would have tried to reproduce the work, but I am more jaded and have been burned enough time to be more sceptical.

          What do I conclude and do? I do nothing but I log it….and then wait for other people to replicate it. Animal models are always nocked. However, the reason I commented on this paper is because of the confidence of the conclusions. As to data with statistics etc about 50-90% of papers in Nature, Science cells do it wrong, but this robotic we do the experiment three times with n=5/group is something people get trained to do and accept.

  • Hopefully we can get a human-EBV study which am sure would really help research to better understanding and pinpointing the pathogenesis of MS. However, if it does work out, could we see different types of MS? i.e. autoimmune MS, EBV MS and so on.

  • I read that vaccine development is becoming easier and quicker because of the covid research – so is this likely to make an EBV vaccine a possibility?

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