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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