Human MS becomes EAE again, as its T cells that springs out in twin studies

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In the new era of preprint papers you can put your stuff online, even before it is reviewed.

Todays offering looks at twins, one with MS and one without an MS diagnosis. However when they look at the twin without a diagnosis, they find MRI features that they think could be early MS. These people are in what we call the prodromal phase. In this study they look at the immune component and conclude that T cells hold the key to determining whether MS features occur or not.

The looked at 43 pairs of twins, 22 untreated, 14 on beta interferon, 4 on natalizumab and 3 on glatiramer acetate. Evident of inflammation occured in 10/43 twins. They looked for MS associated signatures in these samples and found them in T cells, notably effector and activated CD4 and CD8 T cells, and not total B cells . This supports the view that MS is orchestrated by antigen-driven T cells.

This was replicated in another population of early MS but there was no impact of MS on peripheral B cell traits, which the y think contradicts the role of B cells, although it is possible that cells not detectably modified by MS can still participate in MS.

Sadly B memory cells never got a mention. Does ths mean that they were not really analysed or that they are unimportant? I guess we will never know unless the reviewer reads this post and asks the question:-( However, time and time again we see studies that only look at T cells, when they could look, report and shut me up:-)

So here we are T cells are king, in an apparently unbiased look. This is all nice science, but I suppose you may ask is, “What is new here?” The authors thought T cells were king before they did this work and they think the same after this study. It does not really move us further forward about knowing what those T cells do. No doubt we will soon see the study where they sequence the T cell receptors of every cell and make the receptors and hunt for specificity, but until then the question I have to ask is why have the T cell specific therapies not done a better job?

Response to therapy is surely the most important experiment in humans and is worth more than T cell rhetoric. That this study cannot explain the response to B cell therapy tends to suggest they are missing something.

So let’s all shout It’s behind you:-)

Gerdes, Lisa Ann and Janoschka, Claudia and Eveslage, Maria and Mannig, Bianca and Wirth, Timo and Schulte-Mecklenbeck, Andreas and Lauks, Sarah and Glau, Laura and Groß, Catharina C. and Tolosa, Eva and Flierl-Hecht, Andrea and Ertl-Wagner, Birgit and Barkhof, Frederik and Meuth, Sven G. and Kümpfel, Tania and Wiendl, Heinz and Hohlfeld, Reinhard and Klotz, Luisa, Immune Signatures of Prodromal Multiple Sclerosis in Monozygotic Twins (September 3, 2019). IMMUNITY-D-19-00879. Available atSRN: https://ssrn.com/abstract=3447318 or http://dx.doi.org/10.2139/ssrn.3447318

ABSTRACT The tremendous heterogeneity of the human population presents a major obstacle in understanding how autoimmune diseases like Multiple Sclerosis (MS) contribute to variations in human peripheral immune signatures. To minimize heterogeneity, we investigated a unique cohort of monozygotic twin pairs who were clinically discordant for MS. Notably, a subgroup of the clinically healthy twins exhibited signs of subclinical, prodromal MS. Comprehensive immune phenotyping revealed that in the overall cohort, the immune signatures of MS-affected and unaffected co-twins were remarkably similar. Twinship alone contributed 68% of the immune variation, whereas age, sex and MS together only Immune signatures of MS in twins 2 contributed 8%. However, distinct traits in CD4+ and CD8+ effector T cell populations emerged when we focused on the subgroup with prodromal MS. These early-disease immune traits were confirmed in a second independent cohort of untreated early relapsingremitting MS patients. Early involvement of effector T cell subsets points to a key role of T cells in MS disease initiation.

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13 comments

  • That flow-panel! Just. Wow.

    Most interesting finding: Figure 3D: B cells have the highest proportion of unexplained variance due to “other” factors (Not age, sex, MS or twinship).

    Still unclear to me: How well are IGHV/IGKV/IGLV genetic polymorphism risk contribution mapped in MS? Are they even investigated in the IMSGC studies due to multiple polymorphisms?

    • Hi Rune,
      Hope you are well, I guess you realise I don’t know enough to answer your questions. I must admit I get abit overwhelmed with the heat maps and often wonder what do they really mean?
      What do you make of Figure S3B?

      • All good! Recently published follow-up to idiotope paper doi: 10.3390/ijms20194843

        S3B really is a methodological thing. They use linear mixed models and need to account for the fact that different subpopulations depend on each other. Thus they calculated the dependency correlations.

        For instance: population “activated Monocytes” has almost 1 (blue) correlation with “monocytes” because the first is a direct subpopulation of the other.
        On the other hand, Treg subset correlate poorly (red) with Th17.

        It’s not really a finding, but rather a way to be transparent about their method.

  • A few comments:
    ” they find MRI features that they think could be early MS” do they mean RIS? Because pathophysiologically RIS is MS, then they compare MS with MS?
    This study might support that MS starts with B cells, that are affected by environment (EBV?) which then trigger T cells, affected by genetics, that then expand and cause MS, thus more T cells in quantity. Take away the B cells and nothing triggers the T cells to cause disease. This study was clearly designed to look at T cells, if one wants to look at B cells the study design should be different and environment should be taken into account.

    Also, no specific memory T cell treatment has been tried. The anti-cd4 antibody treatment depleted naive T cells or is there another specific T cell treatment that did not work?

    • I would agree with you that they are describing RIS they apparetly did MRI ad there was talk of CSF. So yep you are right early in onset verses later.
      Yes on the B cell trigger point too, a possibility.
      Yes the study was designed to look at T cells so agree too.

      Are you trying to get me to say this is a fancy but rubbish study?

      When you say anti-CD4 targetted naive T cells that is not really correct. Yes I agree naive cells appeared to be more sensitive but the antibody clearly depletes primed CD45RO T cells and this is also offset by homeostatic proliferation of surviving CD45R0 cells (https://www.ncbi.nlm.nih.gov/pubmed/9151795). However, this more limited effect on memory cells is the escape clause when it comes t reponse to therapy. There was a small effect on the MS. As we have shown 60% depletion of CD4 may not be sufficient. Anti-IL17, IL12, IL-23 have not been great. But maybe we should try a depletion CD27 cells to take out memory T and B cells do you have ideas of how to take out memory cells. Fingolimod seems to work but it is relatively insensitive on effector memory cells which are the subset of cells entering the CNS. How would you get rid of memory T cells?

      • Bmt

        Immune cells

        Median leukocyte (WBC) count measured by an automated hematology analyzer reached a nadir of 20/μl on day 5. On day 7, it was 50/μl, and virtually all leukocytes were mononuclear cells (MNCs). By flow cytometry, median 75.6% of the MNCs were monocytes, 19.5% NK cells, 0.6% T cells, and 0.2% B cells.

        Innate immune cell (neutrophil, monocyte, and NK cell) counts returned to the normal range by 1 month posttransplant. B cell counts recovered by 6 months posttransplant. Memory B cell counts recovered more slowly than naïve B cell counts. This may be because naïve B cells only differentiated into memory B cells after encountering their cognate antigens. Dendritic cell counts recovered by 6 months posttransplant. T cells showed the slowest recovery—CD8 T cell counts were borderline low at 6 and 12 months and returned back to normal by 2 years, and CD4 T cell counts reached borderline low normal levels only at 2 years posttransplant (Fig. 1).

        T cell recovery was studied in detail (Figs. 2 and ​and3).3). Peripheral expansion, assessed by the percentage of Ki67+ (proliferating) T cells, was robust early posttransplant, particularly for CD8 T cells. At 1 month posttransplant, median 10% CD4 T cells and 35% CD8 T cells were Ki67+ (normal ≤ 3%). The difference in the percentage of Ki67+ cells among CD4 vs. CD8 T cells at 1 month was statistically significant (P = 0.01). The difference was important as memory/effector CD8 T cell counts recovered to normal within 1 month posttransplant whereas memory/effector CD4 T cell counts remained low for at least 2 years (Fig. 2). The relative insufficiency of the peripheral expansion of CD4 T cells could be due not only to decreased proliferation (compared to that of CD8 T cells) but also shorter survival. Indirect evidence for a contribution of the latter mechanism is that abnormally high numbers of CD28− CD4 T cells were generated in the first several months posttransplant (Fig. 2). CD28− T cells have short telomeres and thus presumed short life span [23,24].

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956741/

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956741/figure/F1/?report=objectonly

        Blast from the Past…Memory B cells depleted by HSCT

        By MouseDoctor
        May 21, 2017

        Massive overshoot of B cells, due to mature B cell over population, that masks a major deletion of memory B cells. CD4 T cells disappear for over 2 years , CD8 are down for 8 months. Black bars 5th and 95th percentile of health and dotted line is the medium of health. No reports of autoimmunity in the report. Does this say anything, but the memory B cells were down

        https://multiple-sclerosis-research.org/2017/05/blast-from-the-past-memory-b-cells-depleted-by-hsct/

      • I agree, I think what I am trying to say that the experiment was not setup to test the B cells. This on the other hand is a very nice study in particular since it is a twin study, it could be very informative. I would advice the authors to sort memory B cells and analyze epigenetics in two groups: monozygotic twins discordant for MS, one with the disease and one with not.
        I still think the evidence is lacking to say that the anti-cd4 trial confirms its not T cells, for example Ifn-gamma producing T cells were not affected., maybe they downregulate cd4.
        Hmm, how to take away the memory b cells, perhaps give gilenya a couple of weeks so that naive and central memory stay in lymph nodes and then use anti-cd4, take away all the effector memory from the blood and stop gilenya, difficult…
        Also I am not really sure from the studies if its central or effector memory T cells that cause inflammation. Perhaps its central becoming effector just before inflammation, otherwise fingolimod would not work?
        Same goes for B cells, switched or unswitched?

        • Seems it’s nothing to do with T regs.
          Sustained reduction of the frequency of CD4+CD25+ Treg was observed during treatment. Anti-CD25 antibody treatment led to evidence of impaired in vivo Treg proliferation and impaired ex vivo Treg suppression. Inflammatory MS activity was substantially reduced with treatment despite reduction of circulating Treg, and there was no correlation between changes in the frequency of Treg and changes in brain inflammatory activity. However, new-onset inflammatory disease, notably dermatitis, was also observed in a number of subjects during treatment.

          • But MD2: CD25 is also widely regarded as a T cell activation marker, with slower kinetics than CD154 or CD69.

            Thus you could argue that study simply prohibited T cell activation and it doesn’t really say anything about Treg effects on MS.

          • Of course the memory B cell population expresses CD25 and you know how keen we are on memory B cells and MS 😉

        • Maybe the gamma interferon producing T cells were CD8

          How to take away the memory B cells. give us £20,000 and we will have the tool made.

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