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".