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The extracellular protozoan parasite <jats:italic>Trypanosoma brucei<\/jats:italic>, which causes human African trypanosomiasis (HAT) or sleeping sickness, accumulates in the meningeal spaces, ultimately inducing severe meningitis and resulting in death if left untreated. Thus, sleeping sickness represents an attractive model to study immunological dynamics in the meninges during infection. Here, by combining single-cell transcriptomics and mass cytometry by time-of-flight (CyTOF) with in vivo interventions, we found that chronic <jats:italic>T<\/jats:italic>. <jats:italic>brucei<\/jats:italic> infection triggers the development of ectopic lymphoid aggregates (ELAs) in the murine meninges. These infection-induced ELAs were defined by the presence of ER-TR7<jats:sup>+<\/jats:sup> fibroblastic reticular cells, CD21\/35<jats:sup>+<\/jats:sup> follicular dendritic cells (FDCs), CXCR5<jats:sup>+<\/jats:sup> PD1<jats:sup>+<\/jats:sup> T follicular helper-like phenotype, GL7<jats:sup>+<\/jats:sup> CD95<jats:sup>+<\/jats:sup> GC-like B cells, and plasmablasts\/plasma cells. Furthermore, the B cells found in the infected meninges produced high-affinity autoantibodies able to recognise mouse brain antigens, in a process dependent on LT\u03b2 signalling. A mid-throughput screening identified several host factors recognised by these autoantibodies, including myelin basic protein (MBP), coinciding with cortical demyelination and brain pathology. In humans, we identified the presence of autoreactive IgG antibodies in the cerebrospinal fluid (CSF) of second stage HAT patients that recognised human brain lysates and MBP, consistent with our findings in experimental infections. Lastly, we found that the pathological B cell responses we observed in the meninges required the presence of <jats:italic>T<\/jats:italic>. <jats:italic>brucei<\/jats:italic> in the CNS, as suramin treatment before the onset of the CNS stage prevented the accumulation of GL7<jats:sup>+<\/jats:sup> CD95<jats:sup>+<\/jats:sup> GC-like B cells and brain-specific autoantibody deposition. Taken together, our data provide evidence that the meningeal immune response during chronic <jats:italic>T<\/jats:italic>. <jats:italic>brucei<\/jats:italic> infection results in the acquisition of lymphoid tissue-like properties, broadening our understanding of meningeal immunity in the context of chronic infections. These findings have wider implications for understanding the mechanisms underlying the formation ELAs during chronic inflammation resulting in autoimmunity in mice and humans, as observed in other autoimmune neurodegenerative disorders, including neuropsychiatric lupus and multiple sclerosis.<\/jats:p>","DOI":"10.1371\/journal.pbio.3002389","type":"journal-article","created":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T18:43:30Z","timestamp":1700505810000},"page":"e3002389","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronic Trypanosoma brucei infection"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5092-5576","authenticated-orcid":true,"given":"Juan 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