Mice full of human cells react well to myelin antigens

M

Attenuated immune control of Epstein-Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA-DR15.Zdimerova H, Murer A, Engelmann C, Raykova A, Deng Y, Gujer C, Rühl J, McHugh D, Caduff N, Naghavian R, Pezzino G, Capaul R, Zbinden A, Ferlazzo G, Lünemann JD, Martin R, Chatterjee B, Münz C.Eur J Immunol. 2020 Sep 19. doi: 10.1002/eji.202048655. Online ahead of print

Immune responses to Epstein-Barr virus (EBV) infection synergize with the main genetic risk factor HLA-DRB1*15:01 (HLA-DR15) to increase the likelihood to develop the autoimmune disease multiple sclerosis (MS) at least sevenfold. In order to gain insights into this synergy, we investigated HLA-DR15 positive human immune compartments after reconstitution in immune-compromised mice (humanized mice) with and without EBV infection. We detected elevated activation of both CD4+ and CD8+ T cells in HLA-DR15 donor-reconstituted humanized mice at steady state, even when compared to immune compartments carrying HLA-DRB1*04:01 (HLA-DR4), which is associated with other autoimmune diseases. Increased CD8+ T cell expansion and activation was also observed in HLA-DR15 donor-reconstituted humanized mice after EBV infection. Despite this higher immune activation, EBV viral loads were less well controlled in the context of HLA-DR15. Indeed, HLA-DR15-restricted CD4+ T cell clones recognized EBV-transformed B cell lines less efficiently and demonstrated cross-reactivity toward allogeneic target cells and one MS autoantigen. These findings suggest that EBV as one of the main environmental risk factors and HLA-DR15 as the main genetic risk factor for MS synergize by priming hyperreactive T-cell compartments, which then control the viral infection less efficiently and contain cross-reactive CD4+ T cell clones.

You have mice and they can be generated so that they are immune deficient. You can park human cells in them and start to ask questions that you may not be able to do in humans. They looked at 3500 mice spanning 6 years of reconstitution experiments, but they only looked at T cells…3500 missed opportunitities?

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MouseDoctor

5 comments

  • Why would you only look at T cells when you have the mice and could also look at B cells at the same time…. Why … Why?
    Didn’t we already know “ These findings suggest that EBV as one of the main environmental risk factors and HLA-DR15 as the main genetic risk factor for MS synergize by priming hyperreactive T-cell compartments, which then control the viral infection less efficiently and contain cross-reactive CD4+ T cell clones.”
    What we need to know is how? And why?

    • Yes, MD noted that in the conclusion. Seems there’s a general stagnation in research in terms of creativity and innovation as not to challenge norms. While new discoveries are built on the shoulders of giants, we also face the risk of tunnel vision. This is not strictly MS related however I do believe that the assumption that MS is a chronic autoimmune disease really narrows opportunities for research. A simple we don’t know yet is somewhat scary and reassuring at the same time.

  • Being as EBV is accumulating stronger upon stronger evidence as being the cause of multiple sclerosis what can i do as a patient to help accelerate trials that target EBV ?

    What can we do to gain the attention of people or to gain media attention or any other way to help gain attention and momentum in this line of ms research ?

  • I personally don’t doubt that T-cells have a huge responsibility in MS. I myself having been diagnosed at age 14 (40 yrs ago 1981) with TYPE 1 Diabetes and then fighting with multiple nerve issues until finally being diagnosed with MS in 2015 (though my first HUGE symptom hitting in 2001). So yes, in my mind, T cells are a big player. But what is the other player triggering it…. I had Mono in 1984/1985

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