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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 na\u00efve 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 LT\u03b1 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.<\/jats:p>","DOI":"10.1093\/brain\/awac232","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T10:49:00Z","timestamp":1656672540000},"page":"4287-4307","source":"Crossref","is-referenced-by-count":42,"title":["Lymphotoxin-alpha expression in the meninges causes lymphoid tissue formation and neurodegeneration"],"prefix":"10.1093","volume":"145","author":[{"given":"Rachel E","family":"James Bates","sequence":"first","affiliation":[{"name":"Division of Neuroscience, Department of Brain Sciences, Imperial College London , Hammersmith Hospital Campus, London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor","family":"Browne","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Department of Brain Sciences, Imperial College London , Hammersmith Hospital Campus, London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee","family":"Schalks","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Department of Brain Sciences, Imperial College London , Hammersmith Hospital Campus, London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Department of Brain Sciences, Imperial College London , Hammersmith Hospital Campus, London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Tan","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Department of Brain Sciences, Imperial College London , Hammersmith Hospital Campus, London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puja","family":"Parekh","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Department of Brain Sciences, Imperial College London , Hammersmith Hospital Campus, London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8284-7763","authenticated-orcid":false,"given":"Roberta","family":"Magliozzi","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Department of Brain Sciences, Imperial College London , Hammersmith Hospital Campus, London , UK"},{"name":"Neurology Section, Department of Neurological and Movement Sciences, University of Verona , Verona 37134 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Neurology Section, Department of Neurological and Movement Sciences, University of Verona , Verona 37134 , 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Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,7,1]]},"reference":[{"key":"2022122116022842100_awac232-B1","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1093\/brain\/awh641","article-title":"Cortical demyelination and diffuse white matter injury in multiple sclerosis","volume":"128","author":"Kutzelnigg","year":"2005","journal-title":"Brain"},{"key":"2022122116022842100_awac232-B2","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/ana.21423","article-title":"Gray matter atrophy is related to long-term disability in multiple sclerosis","volume":"64","author":"Fisniku","year":"2008","journal-title":"Ann Neurol"},{"key":"2022122116022842100_awac232-B3","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s00401-011-0840-0","article-title":"The neuropathological basis of clinical progression in multiple 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