ECTRIMS 2021: Autoimmunity to Myelin. Is it a Red Herring?

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For many many years we have been fed a diet of MS is an autoimmune disease of T cell reactivity to myelin basic protein. This has been lapped up by researchers and with any dissenting voices their papers are destined to the impact factor nothing bin. However, there is only one problem with this idea and that is good evidence. Myelin basic protein is easy to make and is water soluble and easy to get T cell responses to it so its importance grew and grew.

Importantly trials to tolerize against this protein have been done and done again and they have consistently failed and one trial seemed to make disease worse but caused a peripheral nerve disease. MS is supposed to be a CNS disease

When scientists looked in a none/less-biased way, T cell responses to myelin basic protein did not appear and again we get the same answer here.

M Bronge et al. P336 – T cell reactivity screening reveals four novel CNS autoantigens in multiple sclerosis

Introduction: The autoantigen repertoire in multiple sclerosis (MS) remains largely uncharacterised, but is of central importance for understanding disease induction and progression mechanisms and for development of antigen-specific immunotolerance therapies.
Objectives: To perform a large unbiased screening of T cell reactivity against CNS-expressed proteins and to verify and characterise MS-specific immune responses in independent cohorts.
Aim: To identify novel T cell autoantigens in MS.
Methods: Using a novel in vitro method of direct antigen delivery via 1µm beads coated with a library of proteins from the Human Protein Atlas, we screened for T cell autoreactivity against 63 CNS-expressed proteins in a FluoroSpot assay using a cohort of natalizumab treated persons with MS (MS-nat, n=16) (These would have the disease causing cells trapped in the blood) and matched healthy controls (HC, n=9). Hits were verified in two separate cohorts: one with MS-nat (n=61), HCs (n=28) and one with MS-untreated (n=31), HCs (n=20), and persons with other neurological disease (n=19). Autoreactive cells were analysed using flow cytometry and encephalitogenicity of the autoantigens was examined via immunisation of SJL/J and DBA/1 mice.
Results: Four screened CNS proteins, Fatty acid binding protein 7 (FABP7), Prokineticin-2 (PROK2), Reticulon-3 (RTN3), and Synaptosomal associated protein 91kDa (SNAP91) elicited higher IFNγ, IL-22 and/or IL-17A responses in MS-nat compared to HCs. Higher IFNγ responses were verified for all antigens in MS-untreated (p=0.0118, p=0.001, p=0.0002, and p=0.0162 for FABP7, PROK2, RTN3, and SNAP91 respectively), and for PROK2 and RTN3 in MS-nat (p=0.001 and p=0.005). Increased IL-17A and IL-22 responses were also observed in MS-nat. Reactivity to more than one autoantigen was shown to be MS-selective. Autoreactive T cells were predominantly but not solely CD4+, expressed GM-CSF and, while dependent on HLA-DR, were present both in DRB1*15:01 positive and negative subjects. Immunisation in two mouse strains induced heterogeneous immune responses and immunohistochemistry revealed significant CNS leukocyte infiltration in response to all autoantigens.
Conclusion: The present study represents one of the largest systematic efforts in the search for MS autoantigens and identifies four novel T cell targets in MS: FABP7, PROK2, RTN3 and SNAP91. It demonstrates the heterogeneity and individual autoreactive profiles amongst patients and highlights targets for future diagnostic tools and immunomodulatory therapies in MS.

So the major point here is where is myelin basic protein and the answer is nowhere to be found. Where are these molecules found?

One asks why would MS be a oligodendrocyte related disease if these are important. In this study they immunize mice and get EAE but as long as the antigen is expressed somewhere in the CNS, whether it is on astrocytes, nerves or oligodendrocytes you can get EAE, if it expressed outside of the CNS you can get disease there too.

However can you get T cell responses to myelin…Sure if oligodendrocytes get damaged they will release their contents, some finds it way into dendritic cells/macrophages/B cells and gets presented to T cells…so the autoreactivity could be secondary rather than the primary problem

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

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MouseDoctor

18 comments

  • Of course the immune system is in play in MS. And causes lesions etc.

    However I believe there are changes in the brain years, before MS is diagnosed. Is this caused by the immune system? Or some sort of toxicity or dysfunction.

    If EBV is the driver of MS in some way, Is MS not a chronic viral infection? Rather than auto immune driven disease

    • Totally agree with you. For some reason people with MS can’t properly control EBV which has got into the CNS. Cells must be dying or under stress and the consequence is that the immune system (firstly the innate system and then the peripheral immune system) gets involved causing more damage. Proper anti-virals (that address EBV) will provide the answer as to what MS is (as you say, a chronic viral infection). The case studies of HAART have provided a glimpse of what anti-virals can do. Prof G knows this – he’s hinted at it several times. But until effective anti-viral appear the researchers (all) will keep on doing research trying to find the antigen, trying to fathom out if it’s B cell or T cell driven etc. I wonder if ECTRIMS 2021 will shed any new light on the role of EBV in MS?

      • I remember the doctor David Weldon that made his wife well/better of MS by a mix of antibiotics as if bacteria is the problem (metronidazole). I know anticiotics have been tested, but not worked for others. But interesting anyway. dr Weldon use diets, togehter with treatment and used a lot of different things (coctail) as I remember.

        I know antibiotics do not work on virus 🙂

        My son had HSCT and got ofcourse a lot of antivirus after the treatment….

        If EBV is the reason for so many diseases, maybe a vaccine is in its place? (involved in 7 autoimmune diseases?)

    • but 95% of all people have had EBV. Just a few get MS.
      maybe children should hav vaccines? against EBV? if we beleive EBV is the cause of MS and a lot of other diseases. Because they beleive EBV also causes other conditions.

      • But 100 percent of people with MS have EBV antibodies.

        Maybe genetic factors and environmental factors allow EBV to be uncontrolled in the body? Infecting b-cells that become auto immune and immortal

        Or does EBV effect how oligodendrocytes function?

        EBV vaccines don’t exist yet and are under development. I’m sure there will be one one day but maybe 10 or more years away.

        I’m not an expert btw but I don’t believe MS is simply auto immune. Where’s the anti gen?

        What’s happening to the brain years before a lesion appears?

        • I apparently don’t have EBV antibodies. My father on the other hand was very unwell with EBV… All in the genes (somehow) has always been my theory. My father does not have any form of MS.
          I will always know and believe that our genes are what we are – I know people who live the most unhealthy of lifestyles that have been hit by EBV and they have no illness or MS…. I hope I will be alive when the genetic research proves this! x

          • You may need to be immortal then. You can have an identical twin with identical genes and they have a 75% chance they wont get MS, it is a genes environment thing, we know of 400 genes there will be as many more, they all have miniscle influence on susceptibility…sure they will predispose you to MS. However, they are largely normal variants and non of the variants are absolutely necessary…so yes it is in the genes but this is not going to give you the answer. HLA-DRB1*1501 is a common MS gene it is very common in Northern Europeans it does not give us a solution, then there are many single gene conditions sickle cell thalesaemia we have known about the genes for 50 years, Huntingtons disease likewise there is not a simple solution…I actually there is but I wont go there. Manybe the genes point to EBV as HLA-DR*1501 associates with viral load.

          • to mouse doctor- is it a difference between male twins or female twins? x crormosome – i have read that difference in twins may be because of which x cromosome is active ( the medical expression i do not know)
            for females epigenetick them could be om interest?

          • they have loked for epogentic effects between twins if my memoroty serves me right and nothing found yet

        • yes, and it does not meet the requirements to be an autoimmun disease (only 2 og 4 criterias, but the neurologist says since it reacts on immunsuppressive medication it must be autoimmune, i ask a lot of docotor about thing 🙂 ). And there has been for a long time theories of Inside out (not autoimmun) and outside in (autoimmun) due to findings on autopsies.

  • Nice post

    Question: If natalizumab trapped the disease causing cells in the blood

    Why the “Higher IFNγ responses were verified for all antigens in MS-untreated and PROK2 and RTN3 in MS-nat

    Should` nt be equal for both groups?

    Natalizumab does more than trap cells in the blood?

    Obrigado

    Higher IFNγ responses were verified for all antigens in MS-untreated

  • This is the most interesting I have read in a long time. One knows that MS do not meet all 4 requirements for beeig an autoimmune disease. My son got MS as 20 years old, he used Gilenya that did not work. After that he had HSCT that did not work. He now was convinced by his doctor to use mavenclad that will get him cured the doctor kind of implied.
    I have read about inside out and outside in theories (the last is autoimmunity), and I have asked neurologist if it could be possible that his MS not is autoimmune since the best treatment did fail. And I have asked if there are different diseases, but same outcome, where myelin is damaged.
    I read that autopsy showed that myelin was damaged from within and not from outside (autoimmunity). Some norwegian doctors even wrota an article where they asket if MS was mitochondrial mediated, so obviously last question not asked or last answer not answered.

  • Please let me be blunt. In my humble opinion, the concept of autoimmunity is the biggest crock of shit that modern medicine has foisted upon society. And the use of mice, which don’t get MS, and almost maniacal fixation on EAE, which is an allergic response to a foreign protein introduced into those mice, has consistently led researchers into brick walls.

    It should be clear by now that the problem with most “autoimmune” diseases does not lie with the immune system, but rather within the cells that are the target of the immune system. Recent research has consistently found that those cells are producing proteins or other compounds that identify them as hostile to the body. This is most likely caused by a combination of environmental and genetic factors.

    Thus, the immune system is simply doing its job, trying to eradicate what has been flagged as hostile invaders. MS research needs to start focusing on just what is happening within the cells of the CNS that are being destroyed by the activated immune response. Likewise, diabetes researchers need to look at what’s going on in beta cells – an area of investigation that is already gaining steam. Same thing goes for those looking into lupus, rheumatoid arthritis, etc.

    There was a recent article in Scientific American that delves into these “new” theories. They aren’t really new, of course, since MS was long thought to be infectious in origin, before the autoimmune idea took hold in the 80s.

    My own neurologist, who has his own state-of-the-art research labs, recently did an in-depth analysis of my spinal fluid. He found over a dozen proteins and molecules that shouldn’t be in there, for which he has no explanation. None. No idea what they mean, no idea whether came from, no idea how to combat them. And this as I find myself slipping ever closer to quadriplegia.

    Yes, drugs that target the immune system are effective in mediating the amount of relapses and the creation of new lesions, but they do nothing at all towards curing the disease. Great for pharmaceutical companies and their investors, ultimately bad for the end users of their products. Especially those of us suffering from progressive disease, still subject to the hideous ravages of this horrendous scourge without any real hope of shelter from the storm…

    • Interesting.
      Celiac disease is autoimmune. There we KNOW THERE is a protein, and if you take away the protein, you take away the disease reaction. We have doctors in Norway that think the same as you. And they also are conserned about gut bacteria and leaky gut and how things can enter the blood system. But they do not really work with autoimmune diseases, not neccessarily neurologists but other specialists, but treat a lot of them on other issues, and see improvmenets by focusing on gut bacteria.

      In norway they study results og the proteins in CNS, and ask the quiestions these days if MS is autoimmune. https://www.nature.com/articles/s41598-021-82388-w

      they think the problem is lack of proteins that take part in rebuilding.

      from the article I read;

      The researchers started by examining the protein analyzes with the aim of mapping the protein pattern that is common to MS patients, both those with and those without elevated inflammation in the central nervous system.

      – These analyzes gave clear answers. The MS patients in both groups had low levels of proteins that are important for developing and rebuilding the nerve cells, Ellen Mosleth explains.

      Contrary to what has been thought so far, that MS is due to degradation, the new results point to inadequate renewal.

      The researchers concentrated on those patients who had no signs of inflammation. There were far fewer of the proteins that contribute to the development and reconstruction of the central nervous system in patients who had the first signs of MS compared with healthy controls.

      – Today, medicine is given that reduces the inflammation in the central nervous system. These drugs will continue to be important, but the development of new drugs must also focus on measures that stimulate the renewal of the nervous system. Many of the proteins that were identified are linked to vitamins and minerals. A follow-up of this is important, says Kjell Morten Myhr, head of department and professor of neurology at the University of Bergen, and chief physician at the Department of Neurology at Haukeland University Hospital.

      He is supported by his colleague Christian Vedeler, who adds that a new course in MS research can now be staked out.

    • Unrelated to this post, I simply want to say that it’s nice to see you on this site again WK.
      Only a few days ago it went through my mind you hadn’t responded to a post in quite some time and I was wondering how you are.

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