Will the Real MS please Stand up!

Stys PK, Zamponi GW, van Minnen J, Geurts JJ. Will the real multiple sclerosis please stand up? Nat Rev Neurosci. 2012;13:507-14.

Multiple sclerosis (MS) is considered to be an autoimmune, inflammatory disease of the CNS. In most patients, the disease follows a relapsing–remitting course and is characterized by dynamic inflammatory demyelinating lesions in the CNS. Although on the surface MS may appear consistent with a primary autoimmune disease, questions have been raised as to whether inflammation and/or autoimmunity are really at the root of the disease, and it has been proposed that MS might in fact be a degenerative disorder. We argue that MS may be an ‘immunological convolution’ between an underlying primary degenerative disorder and the host’s aberrant immune response. To better understand this disease, we might need to consider non-inflammatory primary progressive MS as the ‘real’ MS, with inflammatory forms reflecting secondary, albeit very important, reactions.

Traditionally, multiple sclerosis (MS) has been considered to be an autoimmune disease in which dysregulated auto-reactive T cells in the periphery cross into the CNS and, together with macrophages and B cells, proceed to destroy various CNS elements. The resulting inflammatory reaction, which typically follows a relapsing–remitting clinical course in the initial stages, causes further demyelination and tissue injury. Such an ‘outside-in’ model is being challenged by a competing view that argues that the initial malfunction occurs within the CNS, similarly to other neurodegenerative disorders. This alternative, ‘inside-out’ model argues that a primary cytodegeneration (possibly focused on the oligodendrocyte–myelin complex) is the initial event, and by releasing highly antigenic constituents, secondarily promotes an autoimmune and inflammatory response in the predisposed host, possibly further driving degeneration.  Some people think that the inflammatory response just comes in to clear the debris up in some form of “protective immunity” This review suggests that MS is a neurodegenerative disease underlying whose clinical course is influenced by relapses. 

The “outside-in” of myelin basic protein induced autoimmunity is probably a load of guff that has been perpetuated by Fundamentalist Immunologists fixated on some form of EAE. These people have brain-washed the masses with their ideas that largely do not fit many of the realities of MS.

We at Team G have not paid a lot of attention to these myopic ramblings for well over a decade, in fact never paid much attention, and are surprised that a review really needs to reinforce this view. All you have to do is look at MS and read!

There is much evidence to suggest that there is a neurodegenerative process occurring early in MS because we can see this from grey matter and white matter shrinkage. Likewise if you look at MS tissue with ongoing myelin loss there are very few lymphocytes in sight. However, you have to take into account the response to therapy that tells us what inflammation does on balance.

Will the potent DMT influence the rate of progression? I think it will if you start early enough., but will it be enough..only time will tell..the experiment is in motion?

The evidence for MBP-based autoimmunity is weak and if you kill oligodendrocytes you do not get autoimmunity in mice or man!. This review focusses on oligodendrdrocyte loss as part of the cytodegeneration (cell degeneration) as the start of the problem but one also needs to accomodate neurodegeneration (nerve degeneration also). It is part of a jigsaw that we still need to unravel further.

If the inside-out model is the correct one, a key question that arises is: what are the potential underlying mechanisms that trigger progressive cytodegeneration? It is suggested in the manuscript that it is some metabolic disorder. Alternatively could it be a virus? or bacteria? or could it be actually autoimmunity or could it be all of the above?

The answer to the latter could still be yes but not in the worn-out myelin basic protein CD4 T cell way of thinking but in a inside-outside-inside way of thinking……confused?..So am I, but we will put some meat on this idea in another post.

However, the take home-message here is Wakey, Wakey, you can not just think about immunology and autoimmunity in a bubble and expect to see the whole MS story.

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  • My thoughts exactly. Reading the article it would seem to be a case of NS Sherlock! The more this is highlighted hopefully the blinkers may fall from the eyes of some of our more rigid colleagues.

  • Impression I get is that lots of people keep throwing up lots of promising ideas about lots of things. All these ideas are floating around but they don't settle into any clear pattern.

    Even fundamental questions like what sort of disease MS is are not settled ('we might need to consider non-inflammatory primary progressive MS as the 'real' MS …. )

    That's why the Charcot project is so promising. If the viral idea turns out to be correct it could cut through all the clutter and lead to something solid

  • Ideas…lead to an hypothesis and you try test they hypothesis…if it is correct you have a treatment. If not you re-formulate the hypothesis and start again.

    Therefore until there is a cast-iron treatment that works then this will be an on going process.

    It takes time and an open-mind to get a clear pattern

    The Charcot project again is aimed at testing an idea, but with a diferent slant from the same-old, same old. However, if the virus is just the trigger then timing of your anti-viral delivery is key.

    Unfortunately nothing is straight forward.

  • That second chart, which I think is descriptive of the inside out theory really resonates with me. I can see over my whole life that there has been progression, then I had my CIS of Pars Planitis then over ten years later my diagnosis.

    I can still feel things moving on Tysabri which scares me, but at least things are way more stable with less of the inflammatory components of the disease.

    This is related to your previous post today which would sort of describe the activity of the underlying disease process. I didn't fully grok it, but it seemed to be talking about non-lesion related activity which I suspect is real and is an idea suggested by the increased lesion counts found by higher strength MRIs. I suspect with a perfect MRI we would see activity all over the brain.

    Is that idea suspected by most people studying MS?

  • Therefore the idea that we "transition" into secondary progression makes no sense. Is that what you're saying?

  • rmforall said…

    "Very close, very close…how about a blood circulating toxin that penetrates into the middle layer of blood vessels…" THEN THE USUAL STUFF (DELETED AS USUAL) ABOUT METHANOL/FORMALEHYDE"

    A toxin- who knows? but if you read the other post these early pre active lesions do not centre on blood vessels.

    However looking at Grey matter lesions you could convince yourself that the causative agent is a soluble factor that could be bathing the brain…..could it be a toxin a virus or an antibody or cytokine. The latter could evoke the "inside out" idea triggering and "outside in" phenomenon but having nothing to do directly with T cells.

  • "I suspect with a perfect MRI we would see activity all over the brain".

    There are clearly things going on in the so called "normal appearing white matter and grey matter that are not picked up with conventional MRI".

    These can be seen by histology and may never be picked up by MRI because the way it detects things and its lack of good resolution.

    MRI detects movement and of charged particles in relation to a magnetic field that is switchd on and off so it is not surprising that the hisstological correlates of MRI is wooley.

  • "I can still feel things moving on Tysabri which scares me",

    We know that tysabri is not 100% active so it may not stop all things going on.

    I am not a clinician but from talking to people it seems that progression can and does occur in some people taking tysabri.

    The question that is now being addressed is whether tysabri will change the slope of the development of progression. There is reason to think it should, but the question remains is there a different mechanism of progression lurking below. The other question is if you start treatment early enough what happens then?

    Is there a different mechanism of progression lurking below. I think at some point the answer to that is yes and even based on simple animal autoimmune studies we can see this phenonmenon.

    Even from the first attack there is some progressive changes but as time goes on and damage accumulates then this progressive element is easier to spot. However if we treat early and aggressively we do not see the clinical progression, if we start later we do.

    I think this suggests that it is best to start treatment of MS as early as possible and would argue that we should aim to deliver a nerve/cell protector also as a combination.

    Although to date the immune modulators have not had much impact on progressive MS, and this stage of disease may respond to nerve protectors, I still think it is likely that we need immune modulators as well even in progression.

    I would suggest that there are two processes occuring and the (auto)immune element can shape the course of an underlying grumbling damaging disease.

    I think alot of the answers should be found studying the pathology of MS, where the gold dust may come from a few informative cases, such as what happens in the brain of someone who is on potent immunosuppression and then accidentally dies unrelated to their MS. What is going on then? Maybe that can tell us about what progrssion is. Is it a problem with demyelination? is it a problem of a microglial response? Is it still a problem of oligodendrocytes?

  • That we "transition" into secondary progression makes no sense.

    This transition in to secondary progression is a clinical definition about how you recover and worsen, and how you compensenate neurologically in response to MS. Progression may occr when this compensation mechnism is exhausted or reaches a threshold level of damage

    However there may be no difference in what is occuring inside the brain as it is part of a continum. I think relapses and the events occuring in response to this will influence where you are in that continum

    A definition of disease stage becomes important however if and when it impacts on the potential treatment options.

  • Now that all human tissues can be grown and studied in the laboratory, it will be easy to show the conversion of methanol via the ADH1 enzyme into formaldehyde within the cells, and the protective effects of low levels of ethanol — this is the key idea to share with many ambitious researchers. A single study could within weeks achieve extremely important results with a modest effort by any qualified team.

  • so this follows Corthals paper that shows disordered lipid metabolism can initiate degeneration and subsequent inflammation – how interesting that this would all back up swank and Jelneks work…
    Typical story – new idea comes up, is rubbished and then actually we agree they were right all along.
    Certainly there is no evidence that says they are wrong..

  • "A single study could within weeks achieve extremely important results with a modest effort by any qualified team"

    Therefore rmforall, get off you backside and go and do this!!!!..

    You claim to be a scientist/researcher. Do some science rather than preaching!!!!.

    I am sure you can find a lab near you that will indulge you, to help you on your quest.

    We have heard you view, enough is enough, it really has become a stuck record….and I know you are old enough to understand the pre CD age.How many times must I ask!

    Your post has slipped through as the Google filter has been putting you in Spam, so even a machine has got bored with you and is sticking your monosubject comments in the bin.

    If you have something to say on any other subject fine…but methanol and formaldehyde is not such a subject.

  • rmforrall said

    In all common decency, why not allow my brief courteous relevant, perhaps totally misinformed, post, and see what our competent community does — why the prejudiced censorship, disallowing any debate? ….Then DELETED

    Sorry this is ADVERTISING

    If people want to look through your posts they can find this mentioned EVER time you post!!!.

    If someone gave a plug for "Mein Kampf" ever time they posted or "Gone with the Wind" for that matter you would find it irriating

    While Science sleeps cost more than Mein Kampf on Kindle. This is advertising and this is why your posts go in spam… STOP IT

  • rmforall said…

    Hey, look again, please reconsider your sincere blanket negative assessment of my posts:

    I am not a trained, experienced, qualified scientist or researcher.

    I am not a manipulative, profit oriented scammer or manipulator.

    I am a decent intelligent citizen, serving as a volunteer information activist on the Net since January 1999,


    providing long,conscientious, careful, fair, civil, detailed reviews of mainstream medical research, specifically in the area of aspartame methanol formaldehyde toxicity.


    On this forum, I have found almost every week recent research that his paradigm is relevant to — in which case I do my best as a medical research layman to present pertinent aspects of his work.


    This is a contribution that deserves to be honored, not suppressed or libeled, if our forum is to explore leads, that if useful, are new keys for treating, preventing, and doing productive research on multiple sclerosis.


  • Dear rmforall
    Whilst I will not question your intellectual ability, I do question your ability to read and assimilate.

    If you have intelligence you will stop wasting my time, with this endless lobbying



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