Abstract
Subpial demyelination is a specific hallmark of multiple sclerosis 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-myelin oligodendrocyte glycoprotein 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 experimental autoimmune encephalomyelitis 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.
Highlights
Subpial cortical gray matter demyelination [1, 2] is a specific feature of multiple sclerosis (MS) pathology [3]
The goals of the current study were to ascertain the impact of meningeal tertiary lymphoid tissue (TLT) formation on pathology in the underlying cortex in adoptive transfer (A/T) SJL/J EAE and to determine the impact of timed modulation of leukocyte entry into the brain on immunological and pathological correlates of clinical disease
We found that adoptive transfer of PLP-primed T cells resulted in the formation of meningeal TLTs that are associated with a gradient of demyelination and microglia/macrophage accumulation as well as the degradation of the glial limitans and oxidative injury in the subpial cortex, reproducing some aspects of the pathology seen in MS patients with acute [18] and progressive disease [5]
Summary
Subpial cortical gray matter demyelination [1, 2] is a specific feature of multiple sclerosis (MS) pathology [3]. Only a limited number of animal models can mimic subpial cortical demyelination, and in these particular models, cortical demyelination is not associated with aggregates of meningeal immune cells [20, 21]. This does not reflect the human MS scenario, where cortical pathology is clearly associated with meningeal inflammation [4,5,6, 15,16,17]
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