What causes demyelination of the cortex creating grey matter lesions. Well in this study there is no difference to what causes demyelination in the spinal cord…It’s T cells, T cells, T cells.
Cortical lesions have been associated with cog fog and so if you get rid of them surely that is great for progression.
Siponimod is the new mod on the block and now we get data suggesting it stops Th17 from accumulating in the brain and stops them causing cortical lesions, so siponimod should be good for Cog Fog. This is shown here.
The study was done blinded but we are not told how the experiment was randomised, although they were randomised, so is by chance that the animals destined to get the drug developed disease 2 days after those destined to get dummy drug as it seems the experiment is flawed.
Why because there should be no differencece between the blue line (nothing) and the black line (nothing) up to day 8. But you can see they have long since split and the blue animals developed disease 2 days earlier. By day 8 you can see which animals had lost weight…give them nothing and they get sick, and those that haven’ lost weight.
I think brain involvement in EAE does not really reflect the paralysis seen in EAE as this is probably largely a spinal cord problem, I think if you are going to to look at the influence of brain lesions my guess is that you should be looking at behavioural tests rather than mobility tests.
But I guess we can ask, is surely you can do these experiments in humans, you can give them siponimod, you can see cortical lessions with scanners and you have perform cognitive tests.
Siponimod therapy implicates Th17 cells in a preclinical model of subpial cortical injury.Ward LA, Lee DS, Sharma A, Wang A, Naouar I, Ma XI, Pikor N, Nuesslein-Hildesheim B, Ramaglia V, Gommerman JL. JCI Insight. 2019 Dec 10. pii: 132522. doi: 10.1172/jci.insight.132522. [Epub ahead of print]
Subpial demyelination (demyelination around the CNS surface) is a specific hallmark of multiple sclerosis (MS) and a correlate of disease progression. Although the mechanism(s) that mediate pathogenesis in the subpial compartment remain unclear, it has been speculated that inflammation in the overlying meninges may be associated with subpial injury. Here we show that adoptive transfer of proteolipid protein-primed Th17 cells into SJL/J recipient mice induces subpial demyelination associated with microglial/macrophage activation, disruption of the glial limitans and evidence of an oxidative stress response. This pathology was topologically associated with foci of immune cells in the meninges and occurred in the absence of measurable anti-MOG IgM or IgG antibodies. To test the role of brain-infiltrating leukocytes on subpial injury, we modulated sphingosine 1-phosphate (S1P) receptor1,5 activity with BAF312 (siponimod) treatment. Administration of BAF312, even after adoptively transferred T cells had entered the brain, significantly ameliorated clinical EAE and diminished subpial pathology, concomitant with a selective reduction in the capacity of transferred T cells to make Th17 cytokines. We conclude that sustained subpial cortical injury is associated with the capacity for brain-resident T cells to produce Th17 cytokines, and this pathological process occurs in an S1P receptor1,5-dependent manner.