Organized meningeal immune cell infiltrates are suggested to play an important role in cortical grey matter pathology in the
multiple sclerosis brain, but the mechanisms involved are as yet unresolved.
Lymphotoxin-alpha plays a key role in lymphoid organ development and cellular cytotoxicity in the immune system and its expression is increased in the CSF of naïve and progressive
multiple sclerosis patients and post-mortem meningeal tissue. Here we show that persistently increased levels of
lymphotoxin-alpha in the cerebral meninges can give rise to lymphoid-like structures and underlying
multiple sclerosis-like cortical pathology. Stereotaxic
injections of recombinant
lymphotoxin-alpha into the rat meninges led to acute meningeal
inflammation and subpial
demyelination that resolved after 28 days, with
demyelination being dependent on prior subclinical immunization with
myelin oligodendrocyte glycoprotein. Injection of a
lymphotoxin-alpha lentiviral vector into the cortical meningeal space, to produce chronic localized overexpression of the
cytokine, induced extensive lymphoid-like immune cell aggregates, maintained over 3 months, including T-cell rich zones containing podoplanin + fibroblastic reticular stromal cells and B-cell rich zones with a network of follicular dendritic cells, together with expression of lymphoid
chemokines and their receptors. Extensive microglial and astroglial activation, subpial
demyelination and marked neuronal loss occurred in the underlying cortical parenchyma. Whereas subpial
demyelination was partially dependent on previous
myelin oligodendrocyte glycoprotein immunization, the neuronal loss was present irrespective of immunization.
Conditioned medium from LTĪ± treated microglia was able to induce a reactive phenotype in astrocytes. Our results show that chronic
lymphotoxin-alpha overexpression alone is sufficient to induce formation of meningeal lymphoid-like structures and subsequent neurodegeneration, similar to that seen in the progressive
multiple sclerosis brain.