The Inside Outers have it…

Traka M, Podojil JR, McCarthy DP, Miller SD, Popko B. Oligodendrocyte death results in immune-mediated CNS demyelination. Nat Neurosci. 2016;19(1):65-74.

Although multiple sclerosis is a common neurological disorder, the origin of the autoimmune response against myelin, which is the characteristic feature of the disease, remains unclear. To investigate whether oligodendrocyte death could cause this autoimmune response, we examined the oligodendrocyte ablation Plp1-CreER(T);ROSA26-eGFP-DTA (DTA) mouse model. Approximately 30 weeks after recovering from oligodendrocyte loss and demyelination, DTA mice develop a fatal secondary disease characterized by extensive myelin and axonal loss. Strikingly, late-onset disease was associated with increased numbers of T lymphocytes in the CNS and myelin oligodendrocyte glycoprotein (MOG)-specific T cells in lymphoid organs. Transfer of T cells derived from DTA mice to naive recipients resulted in neurological defects that correlated with CNS white matter inflammation. Furthermore, immune tolerization against MOG ameliorated symptoms. Overall, these data indicate that oligodendrocyte death is sufficient to trigger an adaptive autoimmune response against myelin, suggesting that a similar process can occur in the pathogenesis of multiple sclerosis.

If MS is an autoimmune disease, how does it get started?

People who follow EAE say it is an “outside-In” problem where an immune response is generated in the periphery and then it enters the brain/spinal cord to cause the problems. 

However some pathologists see a problem with the oligodendrocyte first in the absence of infiltrate and so they say this is nonsense it is an “inside-out” issue.

They say conditions in the brain cause the initial immune response to enter the brain.

So what do you do think?

It seems like an major deal for some.

So a number of groups decided that they would kill off oligodendrocytes in transgenic mice and if the inside-out brigade is right, then it would cause autoimmunity.

That was the plan, but reality was that this caused nothing; nada. 
So the outside-in brigade could feel smug. 

However the problem there was it did not quite fit with the pathology. So this data says it is only once you do the right experiment that you may get an answer.

It was shown here and previously that if you kill oligodendrocytes then you get neurological problems becuase you are causing demyelination. 

We know that demyelination and dysmyelinated (not myelinated properly) eventually cause nerve death and neurological problems. 

So the right experiment to show the “inside-out” approach is when you leave your mice sitting in the animal house for a long time after the demyelinating event and then they found that autoimmunity developed. 

So the inside-out model is a goer. 

But does this idea mean that the autoimmune response is then generated within the brain. Some of the inside-outers may think this is the case and show prolierfation in the brain, so I will never say never but…..

Personally I don’t buy this.

Sure it seems logical that the problem in MS is initiated in the brain, but is it logical that an immune response is generated in the brain, when we have evolved the lymph gland system to do just that and a brain system not to do that. I think this idea is bonkers. 

It is an inside-outside-in. We know that there is a drainage system from the brain to lymph glands and it is the lymph glands where naive T cells are made to home to, they don’t home to the brain. There they become sensitized and then the memory-effector cells enter the blood and home into tissues including the brain and if they see their target again they can cause inflammation. 

They take cells from the lymph gland and transfer then into another animal and they get disease…we know this can happen because you can take myelin reactive cells from normal animals and make then
transfer disease.

They show they can tolerise the autoimmunity away by blocking MOG35-55 specific T cells, using an approach that is peptide specific, they block autoimmunity developing in the  transgenic mice. 

This is interesting because when we and others looked MOG35-55 was not the dominant antigen in MOG.

Novel pathogenic epitopes of myelin oligodendrocyte glycoprotein induce experimental autoimmune encephalomyelitis in C57BL/6 mice. Delarasse C, Smith P, Baker D, Amor S.Immunology. 2013;140(4):456-64

Shetty A, Gupta SG, Varrin-Doyer M, Weber MS, Prod’homme T, Molnarfi N, Ji N, Nelson PA, Patarroyo JC, Schulze-Topphoff U, Fogal SE, Forsthuber T, Sobel RA, Bernard CC, Slavin AJ,Zamvil SS.Immunodominant T-cell epitopes of MOG reside in its transmembrane and cytoplasmic domains in EAE. Neurol Neuroimmunol Neuroinflamm. 2014 4;1(2):e22.

So T cell proliferation tells us little about what is the important pathogen..but hey we know that too…did you?

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  • So the correct question would be: what makes the oligodendrocytes die?

    Then there was also evidence that the progressive MS and RRMS are the same disease, as result of the death of oligodendrocytes generate autoimmunity?

  • Posts like this are why I read this blog first thing each day.

    Can someone tell me please; what is the life cycle of the oligodendrocytes? Do I have the same oligodendrocyte cells that I was born with? Are they replaced etc.

    How does EBV fit into the inside Outer model?

    • Aidan,

      I asked myself the same questions, I remembered the theory of Dr. Peter Stys, University of Calgary, Alberta in Canada, who says that degeneration occurs first and autoimmunity is due to play myelin in the CNS that triggers the innate immune system and that in turn acina peripheral immune cells. He even says that the form "original, pure" MS is Primary Progressive.

      Now virus leading to death of oligodendrocytes for example?
      The JC virus, for example, infects and kills oligodendrocytes.
      EBV could go causing a "slow death" of oligodendrocytes?

      Yesterday I commented on the unrelated blogger comments this month a case study of a 11 year old boy who developed a severe viral encephalitis, very similar to MS, and died. The boy underwent a stem cell transplant, and died a month and a half after treatment. The presence of virus, in which case the coronavirus was just came to be detected by at autopsy more refined methods which detect molecules emitted by certain viruses.

  • 1. More evidence in journal article that supports "inside out" hypothesis:

    The study, “Structural Transition in Myelin Membrane as Initiator of Multiple Sclerosis,” was published in the Journal of the American Chemical Society (JACS)

    2. Why are many researchers so convinced that there is an autoimmune process causing progression? Is it possible that a demyelinated axon will just go through process of adding Na and Ca channels and eventually trigger apoptosis anyways in absence of an immune response? The lack of efficacy of current immunotherapies (alemtuzumab, Tysabri, Gilenya, CRABs) in progressive MS and the lack of T and B cells on pathology specimens in the atrophied grey matter in autopsies of MS patient brains would support this, wouldn't it?

  • As a PPMSer, to whom "relapses" have been a largely alien concept, the theory of inside-outside (or inside-outside-inside) makes a lot more sense, intuitively speaking.

    Such studies are more coal to my fires of scepticism that "outside DMTs" are ever going to be the ultimate panacea, certainly not for PPMS. We need to find the trigger, the beginning, and stop the neurodegeneration / oligodendrocyte death.

    Of course, this is not a "scientific opinion". This is just the personal conviction of one PPMSer. (And I have yet to read anything on this blog or elsewhere to sway that conviction much.)

  • There are some other interesting ideas as well.

    Last year some research occurred in mice where a single drop of blood in the CNS set off an immune response. This did not make a whole lot of sense to me. Several months later I had some twitter dialog with a brain surgeon who told me that in TIA and stroke immune responses can and do happen. The talk also involved CCVSI towards forward blood pressure and lack of proper discharge from the CNS may result in small TIA issues which may set off an immune response. He said it may well explain that some people appear to have exacerbation relief from the procedure. He also said it would be more complex than what is commonly discussed re: the mechanisms believed associated with this procedure.

    Then, there is the research finding last year at University of Western Virginia related to linkage between the CNS and the peripheral immune system. Both considered for years to be independent of one another and may well be interlinked.

    Thus perhaps its not in or out but in reality both. People with MS are said to have a weaker T-Regulatory system .vs. healthy people. Some say with Alemtuzumab it appears that over years the T-Reg comes back stronger.

    Perhaps there are many trigger points to a hypersensitive immune system. Other conditions where the immune system attacks healthy body tissues "logically" would be related yet, it appears never do the research minds meet in this?

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