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The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronic Trypanosoma brucei infection.
Quintana, Juan F; Sinton, Matthew C; Chandrasegaran, Praveena; Kumar Dubey, Lalit; Ogunsola, John; Al Samman, Moumen; Haley, Michael; McConnell, Gail; Kuispond Swar, Nono-Raymond; Ngoyi, Dieudonné Mumba; Bending, David; de Lecea, Luis; MacLeod, Annette; Mabbott, Neil A.
Afiliación
  • Quintana JF; Lydia Becker Institute of Immunology and Inflammation, University of Manchester, United Kingdom.
  • Sinton MC; Division of Immunology, Immunity to Infection and Health, Manchester Academic Health Science Centre, University of Manchester, United Kingdom.
  • Chandrasegaran P; School of Biodiversity, One Health, Veterinary Medicine (SBOHVM), College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow United Kingdom.
  • Kumar Dubey L; Lydia Becker Institute of Immunology and Inflammation, University of Manchester, United Kingdom.
  • Ogunsola J; Division of Cardiovascular Sciences, University of Manchester, United Kingdom.
  • Al Samman M; School of Biodiversity, One Health, Veterinary Medicine (SBOHVM), College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow United Kingdom.
  • Haley M; Queen Mary University of London, London, United Kingdom.
  • McConnell G; School of Biodiversity, One Health, Veterinary Medicine (SBOHVM), College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow United Kingdom.
  • Kuispond Swar NR; School of Biodiversity, One Health, Veterinary Medicine (SBOHVM), College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow United Kingdom.
  • Ngoyi DM; Lydia Becker Institute of Immunology and Inflammation, University of Manchester, United Kingdom.
  • Bending D; Division of Immunology, Immunity to Infection and Health, Manchester Academic Health Science Centre, University of Manchester, United Kingdom.
  • de Lecea L; Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), University of Strathclyde, Glasgow, United Kingdom.
  • MacLeod A; Department of Parasitology, National Institute of Biomedical Research, Kinshasa, Democratic Republic of the Congo.
  • Mabbott NA; Department of Parasitology, National Institute of Biomedical Research, Kinshasa, Democratic Republic of the Congo.
PLoS Biol ; 21(11): e3002389, 2023 Nov.
Article en En | MEDLINE | ID: mdl-37983289
The meningeal space is a critical brain structure providing immunosurveillance for the central nervous system (CNS), but the impact of infections on the meningeal immune landscape is far from being fully understood. The extracellular protozoan parasite Trypanosoma brucei, 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 T. brucei 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+ fibroblastic reticular cells, CD21/35+ follicular dendritic cells (FDCs), CXCR5+ PD1+ T follicular helper-like phenotype, GL7+ CD95+ 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 LTß 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 T. brucei in the CNS, as suramin treatment before the onset of the CNS stage prevented the accumulation of GL7+ CD95+ GC-like B cells and brain-specific autoantibody deposition. Taken together, our data provide evidence that the meningeal immune response during chronic T. brucei 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.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Trypanosoma brucei brucei / Tripanosomiasis Africana Límite: Animals / Humans Idioma: En Revista: PLoS Biol Asunto de la revista: BIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Reino Unido

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Trypanosoma brucei brucei / Tripanosomiasis Africana Límite: Animals / Humans Idioma: En Revista: PLoS Biol Asunto de la revista: BIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Reino Unido