Doing the Hokey Cokey to work out what starts MS:-)


Sing to the Hokey Cokey. (Not sure (click here) it can be you exercise for the day:-). You put the dodgey ideas in, you throw the logic out, in out, in out, you shake it all about, you do the “Frontiers” con job (Appoint editors to get their mates to publish in a Froniers journal at $2-3,000 a time….Ker-ching, Ker-Ching) and flip-flop all around and thats what’s its all about….Oh oh the mousey BS…….Oh Oh the mousey BS…..Oh Oh the mousey BS and that’s what’s its all about.

What causes MS is a question and if you are interested you can follow the editorial and click on series of paper Editorial: “Inside-Out” vs “Outside-In” Paradigms in Multiple Sclerosis Aetiopathogenesis Luchicchi et al. 2021. Front Cell Neurosci. 2021; 15: 666529.

You need a model to work out what is going on, so the real MS can stand up? I have no problem with making new models to get at this question, but if there is an MS prodrome where disease starts a few years before disease onset, looking at established MS may not give you the answer. However, you can use your old models, but you just have to use them differently, to examine nerve damage that is not dependent on the peripheral (outside of the brain) immune system

Diagrams from Titus et al. 2021

You have the immune response being generated in lymph glands, possibly due to a viral induce trigger and then the immune response enters the central nervous system and this is called the outside-in therory. However this wasn’t working notably for progressive MS and also there was the pathology case of the person who died shortly after an attack with areas of oligodendrocyte damage in the relative absence of lymphocytes. Some question if this was NMO not MS, However, it prompted the idea that the problem in MS starts in the brain and the immune system is called in “the inside out” theory.

Then some people said the immune response was “protective autoimmunity”.

Some people bought the idea.

However, my take for that idea was……… What is the reposnse to immunotherapy?

Block the entry of the immune response into the CNS and there is benefit in relapsing and progressive MS, so the balance shows the immunity is damaging not ptotective. The original idea doesn’t fit the data in MS. However the problem for the inside-out brigade was they didn’t know that there was direct drainage pathway from the brain to the lymph glands. So if the problem starts in the brain they can drain into the lymph glands and stimulate the immue response to enter the CNS so inside-outside-in. The immune system response is always going to be generetated on the outside, becuase that is where immune responses are generated. Why evolve a system that is geared for this to occur in lymph glands then throw the idea away when there is no good data to suggest it is generated inside the CNS. You don’t see the massive expansion of cells that you see in lymph glands when an immune response is first generated. The lymph gland swells about 5 times its size when this happens. This is why you get swollen glands. Does this happen to the brain?

Histologically you can find evidence for oligodendrocyte death in the absence of lymphocytes, but do you need them to be next to the dead oligodendrocyte to think that the white blood cell killed the oligodendrocyte.

In this example it looks like the white blood cells (Blue blobs) are are the centre of the loss of myelin (brown stain = myelin) but do a section on the black line, there is not a lymphocyte in sight next to the oligodendrocyte loss. You think I joke but the cause of the nerve death in the brain could be due to immune attack of the spinal cord. Cut the roots and the leaves die.

However we know about pre-active lesions where a sick looking oligodendrocyte is present and surrounded by microglia. This is the effect on the “inside” but response to therapy says the relapse is a bad thing and it is caused by the immune system entering the CNS i.e. “Outside in”. However the question remains can you get the oligodendrocytes damaged lesion without the inflamatory lesion somewhere in the CNS. In the EAE model you know the answer and the first event is “outside in” leading to the neurodegeneration.

You can use EAE as the “outside in model” which is mediated by CD4 T cells, but perhaps lacks translational ability as CD20-depletion really doesn’t work in mouse EAE and evidence for myelin autoimmunity in humans is lacking. However memory B cells present myelin antigens to T cells. Harp CT, Ireland S, Davis LS, Remington G, Cassidy B, Cravens PD, Stuve O, Lovett-Racke AE, Eagar TN, Greenberg BM, Racke MK, Cowell LG, Karandikar NJ, Frohman EM, Monson NL. Memory B cells from a subset of treatment-naïve relapsing-remitting multiple sclerosis patients elicit CD4(+) T-cell proliferation and IFN-γ production in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Eur J Immunol. 2010 Oct;40(10):2942-56

However the cuprizone model generated in mice is suggested to be a model to support the “inside-out”. You kill the oligodendrocyte but you don’t get the immune response entering CNS because cuprizone afffects the immune system. However this uses an “outside-in” oligodendrocyte toxin. It is a model of transient demyelination…you don’t have to do anything and it repairs. The view presented is that this is a great model but this model is again a mouse specific problem as cuprizone doesn’t cause demyelination in rats and monkeys. So it is not without its problems. It is a model. It can only give the right answer if you ask the right question.

However, EAE is questionsed because:

  1. CD8 are the predominant immune cells but in EAE CD4 T cells predominate. However, there are CD8-dominant EAE variants. I have also seen this view questioned by pathologists.
  2. Lesions in EAE predominate in spinal cord in EAE, whereas MS occurs in the brain, but monkey EAE has plenty of lesions in the brain and mice dont have alot of white matter in the brain.
  3. There is a limited overlap of proteins and genes identified as being involved in EAE and MS…but surely MHC is the most important gene in both. We have found 400 MS genes, but most of those do not have a defined unequivical role in MS. What proteins are involved in MS..myelin basic protein…yer right. This is like pushing the Ugly sisters foot in Cinderellas shoe to get something to fit.
  4. Fourth, when ablation of the immune system in MS patients was followed by autologous haematopoietic stem cell transplantation, a reduction in the autoimmune response was observed but disease progression continued. Here I have to point out this is a time related effect and in reality this is no different between EAE and MS, if you don,t stop relapses early enough, progression occurs many EAE models however this takes most than 2 weeks to be seen.

The cuprizone model shows us that if you have demyelinated nerves they are vulnerale to death. This occurs in EAE, this occurs in myelin mutants. You just have to look hard enough.

In this series of papers Sen et al. 2021 asked “For how long can these marked differences between EAE and MS be ignored before we question the merit of accepting a correlation between an acute, peripherally-induced immune response and central demyelination (as seen in EAE) as an effective model for the pathoaetiology of MS?” “The almost overwhelming focus on EAE has thus allowed the “tail to wag the mouse” rather than the more realistic circumstance in which effect follows cause. In this scenario, MS (unlike EAE) is not a disease that is initially mediated by the T-cells trafficking from the periphery but is caused by another mechanism, namely “degeneration of oligodendrocytes”.

Yes we should focus of stopping these demyeliniating, neurodegenerative oligodendrocyte damaging lesions. We could give you a long list of potential remedies but if we are going to do this in the clinic, we need to stop the damaging, peripheral inflammation as well.

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  • Probably not relevant but a few years before I had an obvious Ms episode I developed swollen gland behind my ear which was never investigated could this have been due to my MS?

  • A systemic autoimmune attack across the BBB (as in ADEM, NMO, CRION, characteristically involves the optic nerves bilaterally. ( as expected, outside-in). Simultaneous bilateral ON virtually rules out MS, MS ON is characteristically unilateral.(? inside out). Even second attacks in these conditions follow the same pattern.

    In addition to this clinical observation, where primary MS lesions have been reliably described ( Gay F, Brain 120, 1997: Barnet and Prineas Ann Neurol 2004.) lesions this stage are not associated with a break down in the BBB and show few if any inflammatory cells.

    Once the lesions are established of course, it is inevitable that there will be two way pathological events.

    Slippery fish, MS. As usual. B….r (rude word).

    You know what I think. (Gay F. Bacterial transportable toxins of the nasopharyngeal microbiota in MS. Nose to brain direct. Rev Neurologique (Paris0 2019. Oct 16). Inside out.

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