Saturday, 12 May 2018

Mirror Mirror on the wall, what is the greatest cause of all?

This is a chant that we have been saying to ourselves for years as we try to understand what is the cause of MS.

In this study we are told that it is myelin, altered myelin.  

New concept?

But is it really..as we know dysmyelinated mutants get neurological problems.


A molecular pathway through which biochemically altered myelin triggers autoimmune demyelination in mouse. (A) With intact myelin, immune boost (IB) alone had little effect. (B) In stark contrast, an abbreviated, subdemyelinating cuprizone (CPZ) treatment induced a subtle biochemical myelinopathy [likely including citrullinated MBP (citMBP)] that, when followed by IB, secondarily triggered severe inflammatory demyelination. Such lesions are populated by citrullinated myelin-reactive innate [macrophages/microglia (Mφ/M)] and adaptive (T lymphocytes) immune cells, that drive severe demyelination and secondary and bystander axonal degeneration. (C) Paradoxically, IB administered after an overtly demyelinating 3-wk course of CPZ, with associated clearance of myelin antigens, had no effect. Only the combination of subtle biochemical myelin pathology together with appropriately timed immune stimulation, triggered brisk inflammatory demyelinating lesions similar to those found in MS.

Caprariello AV, Rogers JA, Morgan ML, Hoghooghi V, Plemel JR, Koebel A, Tsutsui S, Dunn JF, Kotra LP, Ousman SS, Wee Yong V, Stys PK. Biochemically altered myelin triggers autoimmune demyelination.Proc Natl Acad Sci U S A. 2018 May 4. pii: 201721115.
Although immune attack against central nervous system (CNS) myelin is a central feature of multiple 
sclerosis (MS), its root cause is unresolved. In this report, we provide direct evidence that subtle biochemical modifications to brain myelin elicit pathological immune responses with radiological and histological properties similar to MS lesions. A subtle myelinopathy induced by abbreviated cuprizone treatment, coupled with subsequent immune stimulation, resulted in lesions of inflammatory demyelination. The degree of myelin injury dictated the resulting immune response; biochemical damage that was too limited or too extensive failed to trigger overt pathology. 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. Moreover, cultured splenocytes were reactive against donor myelin isolates, a response that was substantially muted when splenocytes were exposed to myelin from donors treated with PAD inhibitors. By showing that a primary biochemical myelinopathy can trigger secondary pathological inflammation, "cuprizone autoimmune encephalitis" potentially reconciles conflicting theories about MS pathogenesis and provides a strong rationale for investigating myelin as a primary target for early, preventative therapy.


In this study they say "Conventional views hold that dysregulated immune attacks against myelin, a fatty substance which ensheathes and supports axons in the central nervous system (CNS), cause the characteristic focal lesions of inflammatory demyelination. However, neither the immune triggers nor their targets have been identified, and despite potent immune-modulating therapies, for most patients the progression to disability remains inevitable".

The notion that unchecked immune attacks on myelin from the “outside in” has been countered by the argument that pathology of CNS myelin precedes and triggers inflammatory demyelination from the “inside out”.  

This is based on some pathological observations of damage in the seeming absence of active inflammation. 

Now, I have no problem with this possibility that the central problem in MS starts in the brain so can be "inside out", however immune responses have no need to be generated in the brain. In my opinion they are probably always generated in lymph glands because this is where there is the machinery for this to occur. So the inflammation is always going to be "outside in". 

In the inside-out pathology there are always a few immune cells detected and who said it needs an immune cell anywhere near the damage for the damage to be immune-mediated. This could be done by a soluble molecule or perhaps lack of a soluble or other molecule, such as oxygen. So you can have damage caused by the immune system without significant numbers of immune cells being present. Pigeon-holing concepts make you blinkered.

This concept of "inside out" and "outside in" is EAEologist-babble and ignores the finding that there are unconventional lymph gland pathways from the CNS to the lymph glands. This may allow for the "inside-out-inside" approach and it could fit all views.

They hypothesize "that the characteristic T lesions reflects but the tip of a pathological iceberg, i.e., the later manifestation of an insidious precursory myelinopathy with secondary autoimmunity. Proof of principle in an animal model that a subtle myelinopathy triggers autoimmune inflammation and therefore represents a proximate driver of inflammatory demyelination, and claim that this would represent a major advance in the field". 

However, with a bit of reading, you soon see that it has long been known that dysmyelination mutants eventually get nerve damage as seen with Jimpy and Shiverer mice etc and some of the myelin gene knockout mice. Therefore, altered myelin can cause damage. Likewise there have been other studies where viral attack of the brain, have lead to subsequent autoimmunity.

However, the problem is...Does this, or other, pathway(s) have any real relevance to MS? It is just an idea.

In this study they start with altered myelin which is triggered by giving a toxin that affects oligodendrocytes and add an inflammatory stimulus and they get lesions, just like you get in MS. However, these are just like you get in EAE and viral encephalitis, but is this pathway relevant to MS?. I don't know? It is one more model.

In this study they look at biochemically altered myelin notably of myelin basic protein, a major myelin constituent that influences its compaction. 

So the next question is MBP relevant to autoimmunity in MS?

MBP is used and researched as it is an easy to purify and is water soluble myelin component, allowing T cell immunologistst to do studies in test tubes. However, MBP is found in both the peripheral and central nervous system and MS is more localised to the central nervous system. This would suggest perhaps that it is not a good target antigen. Healthy and people with MS both respond to MBP. Therefore again suggesting that it is not a very good candidate. Attempts to block immune responsiveness to myelin basic protein has universally failed (although there are other explanations), so is this relevant to MS?. It is just another model?

In this study they give 2 weeks of cuprizone a copper-based toxin of mouse oligodendrocytes in some brain regions. Usually it takes 5 weeks to cause demyelination so this is the start of changes, they then give Freund's adjuvant and pertussis toxin (without antigen). These are used to make EAE when they contain myelin or other part of nervous tissue. What are they doing here, it is difficult to say, but the pertussis toxin (toxin from whooping cough) cause white blood cells to proliferate like crazy and may increase the chance that autoimmunity could develop. But it works best with only a short course of cuprizone.  

They looked at the histology and there was loss of luxol fast blue stain. This means loss of myelin, but is this secondary to being pushed out of the way by infiltrating lymphocytes or because the nerves were dying? 

They imply that nerves were dying, just like in mouse EAE. However, MS is a demyelinating issue. So again the question is posed. Does this have any relevance to the pathogenesis of MS? 

In this study they show that there is an immune response to altered myelin, called citrullated myelin. 

Citrullination or deimination is the conversion of the amino acid arginine in a protein into the amino acid citrulline.


There are plenty of studies in MS documenting citrullated myelin responses (CLICK). Is this the missing key bit of information...Maybe. 

You are going to need to design a treatment that incorporates this view and modifies the modified myelin and then we can see if it modifies MS. Will it work?

So there you have it "subclinical myelin perturbations accruing during an early prodromal convert underlying immune susceptibilities into self-myelin autoimmune attacks"


Then we get a "kangeroo-moment" where we jump to suggest that this leads to un-remitting myelin alterations and failures of MS treatments and progressive neurodegeneration.

The suggestion that " Unremitting biochemical myelin alterations, ongoing from the earliest stages of MS, could explain why even potent immune-modulating therapies fail to halt later-stage MS progression and ensuing disability; once autoimmune inflammation largely subsides, either with immune-modulating therapy or with age by immune senescence, the underlying progressive biochemical pathology of myelin continues unabated, leading to degeneration of axoglial elements and irreversible disability".

We know that nerve damage and inflammation is present from the prodrome (Radiologically isolated syndrome) to the end of MS. Is this captured in this model.

The authors say
"Although our data clearly demonstrate a causal link between myelin modifications and inflammatory demyelination in mouse, this link remains unresolved in humans". 


9 comments:

  1. What does the link between organophosphate exposure and Parkinson's and MS in humans say about MS pathology?

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  2. "once autoimmune inflammation largely subsides, either with immune-modulating therapy or with age by immune senescence, the underlying progressive biochemical pathology of myelin continues unabated, leading to degeneration of axoglial elements and irreversible disability"."

    Yes..patients think they've beaten disease and neuros think
    they've cured it w/alemtuzumab when relapses go away..but no..sadly :(

    ReplyDelete
  3. Enough with the mouse studies, already! In the 15 years since my diagnosis, I've read countless research reports involving EAE and other mouse models of multiple sclerosis. Only an infinitesimal amount of these reports have ever proven to have any real relevance to the human MS population.

    The simple fact is this: mice don't get ms. You can inject them with myelin or other toxins and achieve something that kind of sort of looks like MS, but it's not ms. Then, it seems as if staring intently at the mice long enough or breathing on them shows some kind of benefit. Honestly, it's almost come to that level of ridiculousness.

    We must come up with better models of the disease to work on. The amount of time and money wasted on mouse studies is – given the the enormity of the impact of MS on those humans it attacks – obscene.

    Really, it's time to rethink our entire approach to MS research. Thus far the best we've come up with are treatments that profoundly suppress parts of the intricate human immune system, the long-term effects of which are a complete unknown. And these treatments do absolutely nothing towards effecting a cure.

    Given modern laboratory techniques, the rapid advances in computational power, the emergence of AI, and the vast body of knowledge accumulated by ms researchers and clinicians, one would think a coordinated, concerted effort to finally identify the cause or causes of the disease might finally bear fruit. Time spent fixated on mice with induced conditions that sort of resemble MS is, at this point, time wasted. And those of us forced to watch ourselves disappear by inches don't have that time to waste.

    Patients should be rising up against the status quo, but unfortunately most are too busy just trying to get through the day with some modicum of functionality and dignity left intact. MS has gone from medical backwater to one of the most profitable areas of medical practice in the last two decades. It's high time to cure the damn thing and send it back from whence it came. We now have the technology and basic understandings of the mechanisms to get this done, given the will. Coming up with an effective anti-EBV treatment would be a great first step…

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    Replies
    1. You can now virtually grow any organ in the dish. Including embryo size brain tissue. Why not grow miniature brains in dish and inject them with blood of a ms person and see what happens. No need to disect dead ms people anymore. Besides any efficacy seen in mouse is going to ne more pronpunced on account of being alot smaller. Where as human nevres are a lot longer!

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    2. Also MS patient is one of the richest patient community. We need a society run by MS patients and not the current corrupt ms society status quo. Start fund that is dedicated to cure and not treatment. Also boycott pharma that are fleecing money from patients. It's time for revolution but ms people need to put on their big boy pants!

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    3. A society run by MS patients... There are not only problems with pharma dominance, but factions within the MS patient population, driven not least by fear of this nasty disease. Those who believe in hitting hard and early with dangerous drugs, the HSCT mob, and those that think biotin and turmeric are the bee's knees. In my experience, people with MS seem very prone to entrenchment and I now avoid getting into discussion with others about treatments - I save discussions for my neurologist. I'm tired of being preached at about what amount to anecdotes and personal convictions.

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    4. Yes your right. Fear does make you take irrational stand. But ms affects all levels of society. Including scientists, doctors, even some Neuro. We need to have our voices heard to push for a cure. Pharma are no longer in the business of cure. Last cure found was 10 years ago. Unversities are no longer in the business of cure. All their funding cones from pharma. We need the best of MS population to step up And take control of our money to fund cures and reverse damage only. Mark my words 20 years from now we will still be discussing the black swan has arrived or we can now reduce relapses by 99.555 % while the damage continues. We have no other option. Let's free ourselves from our own shackles. MS has probably already been cured in some pharma lab and is locked away in some safe. Let's wake up and smell the coffee.

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  4. "Enough with the mouse studies"

    Someone asked specifically about this study.

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  5. Sorry, I just asked about this study in the open comments of the month of May/2018, and had not seen that MD posted on it.

    But not having the answer of what the real cause of MS would be and how it actually starts is disturbing.

    ReplyDelete

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