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These ectopic lymphoid aggregates, observed in the leptomeninges adjacent to so\u2010called \u201cType 3\u201d sub\u2010pial cortical lesions, are associated with more severe gray matter damage and worse clinical outcomes. Mouse models of MS that recapitulate TLS formation in the central nervous system (CNS) have provided critical insights into the mechanisms driving their development and maintenance. In these models of experimental autoimmune encephalomyelitis (EAE) initiation of TLS is facilitated by Th17 cells, which promote chronic inflammation via cytokines such as IL\u201017 and GM\u2010CSF. The cell surface expression of lymphotoxin\u2010\u03b1 and lymphotoxin\u2010\u03b2 heterotrimers (LT\u03b1\u03b2) on lymphocytes, including Th17 cells, elaborates the organization of ectopic lymphoid tissues via LT\u03b2R signaling on radio\u2010resistant stromal cells and resident fibroblasts. Ultimately a pro\u2010inflammatory environment characterized by cytokines such as IL\u201017 and GM\u2010CSF promotes the recruitment of neutrophils which produce proteases and chemokines that sustain a pro\u2010inflammatory milieu. Emerging EAE data suggest that disrupting TLS organization or targeting key pathways involved in their maintenance could represent promising strategies for modulating chronic CNS inflammation in MS. Understanding the cellular and molecular mechanisms regulating TLS dynamics is therefore critical for the development of therapies aimed at halting or reversing nonremitting MS disease.<\/jats:p>","DOI":"10.1111\/imr.70045","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T07:54:51Z","timestamp":1750924491000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Follicle on the Roof: Tertiary Lymphoid Structures in Central Nervous System Autoimmunity"],"prefix":"10.1111","volume":"332","author":[{"given":"Michelle","family":"Zuo","sequence":"first","affiliation":[{"name":"Department of Immunology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela A.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4576-6168","authenticated-orcid":false,"given":"Jennifer L.","family":"Gommerman","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/ANNUREV.IMMUNOL.26.021607.090257"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/35018581"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074\u20107613(01)00257\u20106"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.CYTOGFR.2014.02.002"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/S41568\u2010019\u20100144\u20106"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2018.01952"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI.INSIGHT.177555"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000004812"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2012.04.006"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2015.00657"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.4049\/JIMMUNOL.179.7.4929"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/NRRHEUM.2016.217"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2003.10.056"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/J.1750\u20103639.2004.TB00049.X"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/BRAIN\/AWM038"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.12.008"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/S41467\u2010018\u201007053\u20109"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/S41586\u2010025\u201009050\u20107"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/S12987\u2010020\u201000230\u20103"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.12.040"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/CNE.902510209"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010018\u20100213\u20102"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/SCIENCE.ABF9277"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/SCIENCE.ABF7844"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1124\/DMD.112.050344"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3171\/JNS.1986.65.3.0316"},{"key":"e_1_2_10_28_1","first-page":"111","article-title":"Interrelationships of the Pia Mater and the Perivascular (Virchow\u2010Robin) Spaces in the Human Cerebrum","volume":"170","author":"Zhang E. 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