Autoimmunity developing after demyelination

Pathology studies suggest that oligodendrocytes are the target of the immune attack. So it was asked whether loss of oligodendrocytes could trigger autoimmune attack. This was done using a gene approach to kill oligodendrocytes and the conclusion was NO it did not.

Oligodendrocytes were killed using a transgene and animal showed neurological signs because they were demyelinated

Mathis C, Hindelang C, LeMeur M, Borrelli E.A transgenic mouse model for inducible and reversible dysmyelination. J Neurosci. 2000; 20(20):7698-705

It was then said that loss of oligodendrocytes did not induce autoimmunity.

Primary oligodendrocyte death does not elicit anti-CNS immunity.
Locatelli G, Wörtge S, Buch T, Ingold B, Frommer F, Sobottka B, Krüger M, Karram K, Bühlmann C, Bechmann I, Heppner FL, Waisman A, Becher B. Nat Neurosci. 2012;15(4):543-50
    They made a genetically-engineered mouse where the myelin-forming cells called oligodendrocytes make a target for the diptheria toxin which in normal mice would do nothing, but in these genetically engineered mice it causes the destruction of the oligodendrocytes
  1. Dr Locatelli came to the blog to say "I'm the first one saying that mouse models are unlikely to model MS (especially RR MS) since we know so little about it" and we wished him well in his new career as surely he " won't be working on mouse MS models anymore, as he thinks they are no good"
  2. In the critique we said "Well if you kill oligodendrocytes you get demyelination and animals (and presumably humans) develop neurological sysmptoms as a consequence of demyelination. Indeed in this study the mice actually died and this is perhaps a problem as this down-hill spiral (of about 2-3 weeks) may have been too quick for a proper destructive autoimmune response to develop. This takes time in animals and humans. They did try and reduced the amount of toxin to limit the amount of nerve damage and did this over months and still no MS-like disease. The researchers were looking mainly in the brain for the autoimmune response, when the autoimmune response may accumulate first in the spinal cord of mice" 

    Importantly we said  "However, the problem of getting experiments that essentially do not work as planned could mean that rather than the idea being wrong, the wrong experimental design was used". 

So it turns out these words ring true as we know have a YES answer to this question

Traka M, Podojil JR, McCarthy DP, Miller SD, Popko B.
Oligodendrocyte death results in immune-mediated CNS demyelination. Nat Neurosci. 2015. doi: 10.1038/nn.4193. [Epub ahead of print]

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-CreERT;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.

So here they transiently kill the oligodendrocytes with a different method and about 7-8months later there is a fatal neurological disease and this was associated with T cells in the brain and T cells reactive against a myelin protein are found and these transfered disease, so the demyelinating event has led to T cell autoimmunity, Is this how MS starts?

The symptomatologyis not your typical EAE, have a look at the videos.