Autoimmunity in MS…It occurs

A

As you know I am a useless speller and often don’t check the posts until after they go live…Why?

It is too much of pain if I am doing it by phone and with predictive texting who knows what it sometimes does. Also being slightly dyslexic there are some words, which I spell wrong over an over again like “soory” and “comming” and some times it is names like “Micheal” which is a bummer when my friend’s Mike has michael in their email address. ProfK knows what its like to get his name spelled wrong i..e, e..i…I know its “ie” its Ssssssshmeeerer, but that doesn’t stop it being wrong.

So what happens when you see you have a BartsMS post…you click your altmetric to see what “gushing” comments you are going to get about your last ace paper. You expect “this is wonderful” blah blah blah “the cure of the week” and then you arrive and get a shock. An online journal club from hell. Then to cap it all you get the SH1 spellin and their name wrong too. Ultimate insult.

Now it is just my rubbish spellin, usually but Prof Franklinstein has been spelt wrong for ten years (However, I didn’t go round stitching mice together) and whilst you may think my Goshing is destuctive, it is not really. It is maybe making a constructive point. It may just a vehicle to report one of our past papers…Because folks……part of our public engagement remit is to discuss what we do. I don’t do vitamin D and fry black swans….that is ProfGs baby. He can talk about that when he gets his course written that was dumped on him due to COVID-19:-(.

Now you may want to know that I can edit what I wrote we can correct the spellin, so I can flip-flop more that Borris Johnson in a pair of sandals and generally if I upset someone I just remove it. It saves on the aggro. But it does mean I can’t go to Saudia Arabia as the person I upset there may be connected:-).

So to be competitive I thought I would tease someone about their new paper in PeeNas, yes it the Proceedings from the National Academy of Science USA. This is where there is a front door for publication of papers and there is a back door for access to publication for the members. I wonder if this member entered via the back door?

What does it say…Well the idea that MS is a disease caused by autoimmunity to myelin basic protein is a pile of old bo***cks

For many years we have been viewing MS an autoimmunity to myelin basic protein (MBP). This was caused by T cells. MBP was easy to make and it dissolved in water and so we could get T cells to proliferate…they could induce EAE and therefore we have it MS is an autoimmune disease of MBP…Only one problem…Yep you guessed it….Data.

The data just doesn’t support this idea as treatment to inhibit MBP autoimmunity has been a bust over, and over again, MBP is expressed outside of the central nervous system and as we know CD4 Th17 aren’t what we should be looking at 🙂

Now we look in the body of people with MS and we find antibodies to CNS proteins because yes folks there is autoimmunity occurring in multiple sclerosis. You can have the antibodies from MS and inject them into the brain of animals and they cause neurological problems.

When you destroy a nerve and oligodencrocytes bits of cellular protein are going to escape out of the CNS and they can make antibodies to be produced. Hence things like anti-neurofilament ,which is normally a protein inside the cell gets liberated and you can start to make an antibody response

They looked to see what antibodies reacted to

You can see a few people with MS (in green at the top) make alot of red and some don’t make much red and only blue. This means some people with MS do not make antibodies to the myelin antigens. However you can see the few people with abit of red. They make antibodies to all sorts of things and so it tell us that using single proteins to block autoimmunity is never going to work, unless it can not specifically suppressthe responses to lots of different antigens. If that happens if you suppressed the responses to to those that fight infection you could have a problem. Some have reactivity to aquaporin 4 that may suggest they are not MS but NMO

In the paper it says ” Even in individuals with a strong antibody response in MS, a single dominant antigen does not emerge from explorations of adaptive immunity”. “While the data confirm broadly elevated anti-myelin autoantibody levels in plasma of MS patients, the levels of significance were not high enough to serve as a clinical biomarker for MS”.

Alpha B crystallin (CryAB) was a favourite of the authors and the biology seemed nice but when it came to the trial…it was never going to work because tolerance to peptides/proteins does not work well enough in sensitized individuals unless you deplete the white bllod cells first…We told this to the investigator…They knew best and it would be hard to do a combination study…trial failed…company is no more…..and the idea is on the maggot pile never to be touched again! Doing the easy trial never works!

So the problem is there seems to be no consistent myelin antigen that is found in these studies and there never is going to be, we have been looking for fifty years and the same lack of consistency arises. Sure you can find reactivity to myelin in some people, but not all respond to MBP and again in this study you can see they are reactive to all sorts of things.

However MD2 hit upon a reason where it does not matter what those B cells are reactive to. Oligoclonal bands in multiple sclerosis; Functional significance and therapeutic implications. Does the specificity matter?Pryce G, Baker D.Mult Scler Relat Disord. 2018 Oct;25:131-137. 

See the vehicle of the post is not about them it is about us:-)

They say the identification of individuals with active antibody responses may help stratify those who may benefit most from B cell targeted therapeutics”. Is this going to be true?

Time will tell, but I think the treatment failure for relapses is less than 50% for CD20 treatment. Was it these people who made a or did’nt make an antibody response. Should be easily testable…..A quick trip to San Franscico or a visit to their friends in Kaiser to get samples from the people treated with rituximab, ocrelizumab etc who failed… Easy project.

In this study the arrays used alot of peptides, many pathogenic antibodies do not see linear short peptide sequences but 3D structures,what was missed or where we led down the garden pathway. Maybe DrAngry could make some of the globodies as it could be a simple technology…currently adapted to covid-19 it could be adapted to myelin antigens so lets be crystal clear who had this idea:-). Maybe Prof. SteinMAN can whittle it down to a few candidates and let us know. We can stand on his shoulders (a passtime in Catalonia) and make new science

The problem is the person at the top is in for a fall as barcelona found out when they met Bayern Munich 🙂

Autoantibodies against central nervous system antigens in a subset of B cell-dominant multiple sclerosis patients.Kuerten S, Lanz TV, Lingampalli N, Lahey LJ, Kleinschnitz C, Mäurer M, Schroeter M, Braune S, Ziemssen T, Ho PP, Robinson WH, Steinman L.Proc Natl Acad Sci U S A. 2020 Aug 18:202011249. doi: 10.1073/pnas.2011249117.

Significance

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). B cells play a key role in MS immunopathology, as demonstrated by the success of B cell-directed therapies; however, the target antigen of MS remains unknown. Using a combination of ELISpot-based prescreening of peripheral blood mononuclear cells followed by investigation of antibody specificity with a CNS antigen array, we identified a population of MS patients characterized by a highly active B cell response. These individuals with MS, who have active B cell responses, exhibited heterogeneous interindividual anti-CNS antibody responses, although the antigenic specificity of the antibodies remained stable over time for each individual

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), with characteristic inflammatory lesions and demyelination. The clinical benefit of cell-depleting therapies targeting CD20 has emphasized the role of B cells and autoantibodies in MS pathogenesis. We previously introduced an enzyme-linked immunospot spot (ELISpot)-based assay to measure CNS antigen-specific B cells in the blood of MS patients and demonstrated its usefulness as a predictive biomarker for disease activity in measuring the successful outcome of disease-modifying therapies (DMTs). Here we used a planar protein array to investigate CNS-reactive antibodies in the serum of MS patients as well as in B cell culture supernatants after polyclonal stimulation. Anti-CNS antibody reactivity was evident in the sera of the MS cohort, and the antibodies bound a heterogeneous set of molecules, including myelin, axonal cytoskeleton, and ion channel antigens, in individual patients. Immunoglobulin reactivity in supernatants of stimulated B cells was directed against a broad range of CNS antigens. A group of MS patients with a highly active B cell component was identified by the ELISpot assay. Those antibody reactivities remained stable over time. These assays with protein arrays identify MS patients with a highly active B cell population with antibodies directed against a swathe of CNS proteins.

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MouseDoctor

11 comments

  • I am curious, with your dyslexia how do you manage to do what you do with all the chemistry names/formulas etc? I have images of exploding labs with miss spelt experiments. Maybe it’s similar to people stuttering whilst speaking but not when singing? I hope you don’t mind me asking and you are not offended.

    • It is relatively mild, but thinking about it, I was rather rubbish at organic chemistry, but in reality I don’t bother with the formulas unless I have to work out the molecular weight then I know oxygen = 16, carbon = 12 etc. I read a chemical formula and no lights go on, but I also know there are many ways to name a compound. I work with a chemist and they get excited when they sees a structure, it is simply another language and you know how badly the English deal with foreign languages. The compounds all have codes so when you read 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol it doesn’t mean any thing to me when I worked with it and it was called FTY720 that was its code, you may know of it as fingolimod or gilenya.

  • So does that mean those who are doing well on Ocrevus, as in zero relapses and zero new lesions, are likely to be the ones with the highly active B cell component and that´s why Ocrevus works? Been on Ocrevus since 2017 and have not had a relapse or new lesion. Prior to that, Copaxone and Gilenya with 2 relapses a year and new lesions.

    • Unlikely, since it appears that only a limited subset pwMS express these antibodies whereas anti-CD20 therapies are much more broadly effective.

  • Very interesting post and I have read your paper as well. I have some questions:
    1- Will BTKi influence or kill plasma cells? Many papers say it doesn’t. What is the truth?
    2- Merck data report some plasma cells depletion with cladribine (slides presented at ean2020). Could it be sufficient and explain the Rejdak paper? Would a higher dose make sense?
    3- Have you thought about injecting free-Fc dimer from IgG into mouse brain to see what happens? If mouse get EAE or something MS like disease we would know that it is due to Fc and that antibodies specificity is not required. Fc is quite easy to obtain from a given antibody.
    4- how did Dr Franklin stitched two mice together without immune rejections?

    I think that antibodies may also simply stick to brain tissue due to hydrophobicity of the brain surface like a reverse phase interaction 🙂 . If the brain is full with lipids it should have a fairly hydrophobic surface. Your chemistry colleague may inform further if needed. At that point you can have all the types of immune activation given that the antibody is stuck in a geometrically convenient way (Fc exposed). No specificity required, just plasma cells producing random antibodies.

    • 1. Won’t know till you try.
      2. Yes,you’re right there are some data regarding potential reduction/depletion of oligoclonal bands with cladribine. This needs to be followed up.
      3. Not sure that would tell you anything, it certainly wouldn’t trigger EAE. In a chronic model such as ours, it could potentially produce a worsening of neurodegeneration as there are already populations of activated microglia primed to be triggered by Fc but it’s a loooon experiment and i’m not getting any younger 😉
      4. The mice are an inbred strain and so genetically identical so perfectly matched and therefore no immune reactions/rejections or blood matching problems.

      • I have developed a bias against oligoclonal bands… you may have understood it now 😀

        The idea is to verify if Fc alone can induce disease in animals subjected are subject to MS-like disease without prior sensitization.
        The presence of Fc in the CNS would activate the immune system to attack but without pointing to a defined target so if we see damage this would mean that any immune response established in the CNS can cause and maintain MS.

        What do you think of common marmoset as a model for such kind of experiments? Would it be able to tell something more with respect to mice?

        About you not getting younger… on average every three posts on this blog you lose a kilo so you will live longer 😉
        PhD students or post-docs to do the study?

      • Lolll

        Because of the dramatic success of B-cell–
        depleting antibodies in limiting multiple sclerosis
        lesion formation and clinical disease activity,
        there is renewed attention on the role of B cells.36
        It has long been known that the CSF of most
        patients with multiple sclerosis harbors unique
        antibodies (oligoclonal bands) that are produced
        within the CNS. There is evidence that the antibody-
        producing function of B-lineage cells is
        important in some multiple sclerosis lesions.7
        However, because of the rapidity of the clinical
        response to B-cell depletion (as early as 8 to 12
        weeks), even before the reduction of circulating
        immunoglobulin, it seems more likely that other
        functions of B cells, including antigen presentation
        to helper T cells and cytokine production, are
        more relevant.

        Multiple Sclerosis
        Daniel S. Reich, M.D., Ph.D., Claudia F. Lucchinetti, M.D.,
        and Peter A. Calabresi, M.D.

        N Engl J Med 2018;378:169-80.
        DOI: 10.1056/NEJMra1401483

        If you’re going through hell, keep going.

        Winston Churchill
        🙂

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