Oligodendrocytes become antigen presenting cells

Now we have Th1 and Th2, then came M1 and M2 for macrophages, then we got A1 and A2 for astrocytes as the lab wanted some naming-fame and now we have different oligodendrocytes. Is this O1 and O2 for Good and the bad guys?

Falcão AM, van Bruggen D, Marques S, Meijer M, Jäkel S, Agirre E, Samudyata, Floriddia EM, Vanichkina DP, Ffrench-Constant C, Williams A, Guerreiro-Cacais AO, Castelo-Branco G. Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis.
Nat Med. 2018. doi: 10.1038/s41591-018-0236-y. [Epub ahead of print].

Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. 

We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. 

Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. 

Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. 

Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS.

I think it is not really O1 and O2, but O macrophage as the oligodendrocytes are reported to have the functions of antigen presenting cells. This is all well and dandy but….

The first question we should ask is….why?

The immune system has evolved over many years to have specific functions. In the 1980s we went over this, over and over again and it was found that a Wellington Boot that expressed MHC class II could present antigens to T cells.  OK I’m being a bit flippant, but you know where I am coming from.

There was study upon study. Ask MD2. He showed you could get endothelium to express MHC antigens. His work was repeated about 15 years later…without being cited…but the result was “So what.”

I would say that oligodendrocytes are not specialized for this activity and when people looked with electronmicropscopy it was indicated that the cells expresssing the MHC class II were not astrocytes, nerves, oligodendrocytes, endothelial cells in most cases but microglial-like cells. 

The Brain is full of microglial cells capable of engulfing  stuff and presenting antigens. Why do we need antigen presenting oligodendrocytes? Will someone come along in twenty years and say hey Microglia make myelin? If they do will we take notice?

In this study they look at single cells and the message they make.

In this study they look at the gene products and suggest that oligodendrocytes make MHC class I and MHC class II and so T cell MS is back on…and CD8  and CD4 could be doing the killing.

Phew say a million and one T cell biologists, their work is back in the spot light again.

Will it be repeated as surely it has to be….A quick look on http://www.brainseq2 and you find it. e.g HLA-A and HLA-DRA

But, we have been there before 🙁

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  • The immune system – as you surely know 😉 – is a vastly complicated thing that began its evolution even before mammal-like reptiles evolved. There are bound to be many areas of research to try to unravel it, and this is to be welcomed, if it eventually leads to a more refined therapy than the current slledgehammer drugs.

    But then, maybe researchers like Dr Peter Stys' team have a better idea:


    • This is a study asking question where MS starts is it "inside" or "outside" of the brain. The EAEers say "Outside-In" This paper says "Inside out"

      I say wake up and smell the roses people this is science hocum.

      MS starts outside the brain…yep it is when sperm meets egg thats when your genetics are cast, then your environment continues to roll that dice.
      Brain drainage pathways have been found that allows the brain protein out.
      However, you just have to look at MS and you see that the uninfiltrated normal appearing white matter is not normal, so why waste a "decade" thinking about it. Mouse neuroinflammation is not MS.

      Anyway a mouse was made where they injure the oligodedrocyte myelin first
      and they got inflammation. By hey inflammation means remove infection and repair.

      They got some lesions and they resemble MS, which is really hard to believe as mouse pathology rarely looks like MS. I wonder if this appraoch would work in the rat, but cuprizone doesnt work in rats.

      I don't have access to paper at monment so maybe I will post on this.
      Anyway this paper was published in P-nas in May.

      "An inhibitor of peptidyl arginine deiminases (PADs), enzymes that alter myelin structure and correlate with MS lesion severity, mitigated pathology even when administered only during the myelin-altering phase"

      They say "This does not prove that human MS advances in the same way, but provides compelling evidence that MS could also begin this way.”

      What about response to therap.

    • Just had a look at the Stys paper…again…and I don't know what MS they have looked at, but what ever I have looked at, it doesn't look like that shown in the P-nas paper.

      Furthermore, they don't even show that they have demyelination. Sure there is no luxol fast blue staining, but with the mega infiltrate they have, I will be surprised if there are any nerves present so perhaps not exactly MS.

      Sure I sound like Mister Grumpy…Look what else I wrote on this one


      Maybe they should do some reading rather than have a debate for a decade about a trivia (in they way it is being thought about), we know blocking cells arriving in the CNS offers benefit..its called response to therapy.

    • I don't know, I think you may be completely in the right, then again, maybe you're not. At any rate, I am very glad that researchers like Stys are looking for other avenues to tackle progressive disease, because there is certainly nothing available right now that I see as offering a desirable potential benefit:harm ratio for my slow PPMS. If I'm honest, with respect, I feel you are too firmly bolted to your anti-inflammatory ideas. But what do I know.

      We should focus more on finding therapeutic targets for the non-inflammatory damage in MS – Commentary:

    • clap trap. The fact that they suggest that the issues with progression are non-inflammatory shows that they have never looked or understood what lesions are in progressive MS. The are inflammatory, but not adaptive immune inflammatory..

      "Will the right MS stand up"

      It stood up twenty years ago, you just have to stop the lemming mentality.

    • Abit of bedtime reading

      Turned Inside Out: Will Myelin-Protective Therapies Become the Next-Generation Anti-Inflammatories? DNA Cell Biol. 2018 Nov 21. doi: 10.1089/dna.2018.4496. [Epub ahead of print] Caprariello AV1, Stys PK.

    • Many thanks MD – that is very interesting indeed.

      No MD2 – it's about balance, honesty, owning up to the unknowns. But being stubborn, I quite often prefer not listening to anybody anyway, whether I trust them or not. So ignore me. 🙂

  • Re 'it was found that a Wellington Boot that expressed MHC class II could present antigens to T cells.' MD this makes me laugh every time you say it! Good way of teaching immunology 😉

  • "maybe researchers like Dr Peter Stys' team have a better idea:"

    Well he got this right.

    "Most of the science and treatment for MS has been targeted at the immune system, and while anti-inflammatory medications can be very effective, they have very limited benefit in the later progressive stages of the disease when most disability happens.”

    • anti-inflammatory medications can be very effective, they have very limited benefit in the later progressive stage..

      Were is the evidence for this? The inflammatory response of progressive MS has not really been targeted. Virtually all MS driugs fail to target the CNS in any meaning full way and they do not target microglail inflammation. Therefore I beg to disagree

    • Where is the evidence that *current* anti-inflammatories do anything but delay progression by a few years in some people? At least Stys et al have been asking what might be the trigger of the inflammatory mushroom cloud, instead of acting as another dismal cog in the pharma-driven anti-inflammatory promotion machine.

    • Hey Wiring, why do you think they have the cushy ECTRIMS meeting every year at beautiful cities throughout Europe? What comes out? More of the same I'm afraid.

    • "At least Stys et al have been asking what might be the trigger of the inflammatory mushroom cloud, instead of acting as another dismal cog in the pharma-driven anti-inflammatory promotion machine".

      Each to their own!

      P.S. The Cushy ECTRIMS meeting each year is to educate your non-MS specialist neuros in the way of MS.

  • Educate the non-MS neurons in the way of MS. The pharma companys’ line I suppose. Keeps the wheels greased for the future gen.

    • Each year Doctors need to get CME (Continuing medical education) points. This shows that they are keeping up to date. Yes they do get fed a pharma diet because they are prescribing phara food, however it does not have to be the pharma line. Indeed i am presenting this week to Spanish Neurologists "How do MS drugs really work" no pharma has seen my slides, no pharma has dictated the content and I have made them all myself.

    • Thanks but shame it is probably a load of rubbish.

      Antigen presentation by brain endothelial cells was done to death in the 1980s ask MD2.

      Ill have a read wonder if they quote MD2s work

    • Have read it, an artefact.

      Mouse endothelial cells do not express significant amounts of MHC class ii in vivo…end of story…..a wellington boot experiment.

      To suggest all T cells entering the CNS are myelin specific is dreaming and does not fit the extensive reality in ms or biology. The substantial history on this subject is ignored.

      Look at the RNA seq data above endothelial cells a.negative.for class II.

      Who reviews this stuff….Their mates I suspect..Ugh:-(

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