CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model

Autores
Vereertbrugghen, Alexia; Pizzano, Manuela; Cernutto, Agostina; Sabbione, Florencia; Keitelman, Irene Angélica; Vera Aguilar, Douglas; Podhorzer, Ariel; Fuentes, Federico; Corral Vázquez, Celia; Guzman, Mauricio; Giordano, Mirta Nilda; Trevani, Analía Silvina; De Paiva, S. Cintia; Galletti, Jeremías Gastón
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Dry eye disease (DED) is characterized by a dysfunctional tear film in which the corneal epithelium and its abundant nerves are affected by ocular desiccation and inflammation. Although adaptive immunity and specifically CD4+ T cells play a role in DED pathogenesis, the exact contribution of these cells to corneal epithelial and neural damage remains undetermined. To address this, we explored the progression of a surgical DED model in wild-type (WT) and T cell-deficient mice. We observed that adaptive immune-deficient mice developed all aspects of DED comparably to WT mice except for the absence of functional and morphological corneal nerve changes, nerve damage-associated transcriptomic signature in the trigeminal ganglia, and sustained tear cytokine levels. Adoptive transfer of CD4+ T cells from WT DED mice to T cell-deficient mice reproduced corneal nerve damage but not epitheliopathy. Conversely, T cell-deficient mice reconstituted solely with naïve CD4+ T cells developed corneal nerve impairment and epitheliopathy upon DED induction, thus replicating the WT DED phenotype. Collectively, our data show that while corneal neuropathy is driven by CD4+ T cells in DED, corneal epithelial damage develops independently of the adaptive immune response. These findings have implications for T cell-targeting therapies currently in use for DED.
Fil: Vereertbrugghen, Alexia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Pizzano, Manuela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Cernutto, Agostina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Sabbione, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Keitelman, Irene Angélica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Vera Aguilar, Douglas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Podhorzer, Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Fuentes, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Corral Vázquez, Celia. Hospital del Mar Research Institute; España
Fil: Guzman, Mauricio. Hospital del Mar Research Institute; España
Fil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Trevani, Analía Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: De Paiva, S. Cintia. Baylor College Of Medicine. Department Of Ophthalmology. Ocular Surface Center; Estados Unidos
Fil: Galletti, Jeremías Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Materia
Corneal nerves
CD4 T cells
Neuropathy
Immunopathology
Autoimmunity
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/265359
Acceder
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network_name_str CONICET Digital (CONICET)
spelling CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye modelVereertbrugghen, AlexiaPizzano, ManuelaCernutto, AgostinaSabbione, FlorenciaKeitelman, Irene AngélicaVera Aguilar, DouglasPodhorzer, ArielFuentes, FedericoCorral Vázquez, CeliaGuzman, MauricioGiordano, Mirta NildaTrevani, Analía SilvinaDe Paiva, S. CintiaGalletti, Jeremías GastónCorneal nervesCD4 T cellsNeuropathyImmunopathologyAutoimmunityhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Dry eye disease (DED) is characterized by a dysfunctional tear film in which the corneal epithelium and its abundant nerves are affected by ocular desiccation and inflammation. Although adaptive immunity and specifically CD4+ T cells play a role in DED pathogenesis, the exact contribution of these cells to corneal epithelial and neural damage remains undetermined. To address this, we explored the progression of a surgical DED model in wild-type (WT) and T cell-deficient mice. We observed that adaptive immune-deficient mice developed all aspects of DED comparably to WT mice except for the absence of functional and morphological corneal nerve changes, nerve damage-associated transcriptomic signature in the trigeminal ganglia, and sustained tear cytokine levels. Adoptive transfer of CD4+ T cells from WT DED mice to T cell-deficient mice reproduced corneal nerve damage but not epitheliopathy. Conversely, T cell-deficient mice reconstituted solely with naïve CD4+ T cells developed corneal nerve impairment and epitheliopathy upon DED induction, thus replicating the WT DED phenotype. Collectively, our data show that while corneal neuropathy is driven by CD4+ T cells in DED, corneal epithelial damage develops independently of the adaptive immune response. These findings have implications for T cell-targeting therapies currently in use for DED.Fil: Vereertbrugghen, Alexia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Pizzano, Manuela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Cernutto, Agostina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Sabbione, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Keitelman, Irene Angélica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Vera Aguilar, Douglas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Podhorzer, Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Fuentes, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Corral Vázquez, Celia. Hospital del Mar Research Institute; EspañaFil: Guzman, Mauricio. Hospital del Mar Research Institute; EspañaFil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Trevani, Analía Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: De Paiva, S. Cintia. Baylor College Of Medicine. Department Of Ophthalmology. Ocular Surface Center; Estados UnidosFil: Galletti, Jeremías Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaNational Academy of Sciences2024-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/265359Vereertbrugghen, Alexia; Pizzano, Manuela; Cernutto, Agostina; Sabbione, Florencia; Keitelman, Irene Angélica; et al.; CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 121; 48; 11-2024; 1-120027-84242692-8205CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/doi/10.1073/pnas.2407648121info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.2407648121info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:52:56Zoai:ri.conicet.gov.ar:11336/265359instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:52:57.254CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model
title CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model
spellingShingle CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model
Vereertbrugghen, Alexia
Corneal nerves
CD4 T cells
Neuropathy
Immunopathology
Autoimmunity
title_short CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model
title_full CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model
title_fullStr CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model
title_full_unstemmed CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model
title_sort CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model
dc.creator.none.fl_str_mv Vereertbrugghen, Alexia
Pizzano, Manuela
Cernutto, Agostina
Sabbione, Florencia
Keitelman, Irene Angélica
Vera Aguilar, Douglas
Podhorzer, Ariel
Fuentes, Federico
Corral Vázquez, Celia
Guzman, Mauricio
Giordano, Mirta Nilda
Trevani, Analía Silvina
De Paiva, S. Cintia
Galletti, Jeremías Gastón
author Vereertbrugghen, Alexia
author_facet Vereertbrugghen, Alexia
Pizzano, Manuela
Cernutto, Agostina
Sabbione, Florencia
Keitelman, Irene Angélica
Vera Aguilar, Douglas
Podhorzer, Ariel
Fuentes, Federico
Corral Vázquez, Celia
Guzman, Mauricio
Giordano, Mirta Nilda
Trevani, Analía Silvina
De Paiva, S. Cintia
Galletti, Jeremías Gastón
author_role author
author2 Pizzano, Manuela
Cernutto, Agostina
Sabbione, Florencia
Keitelman, Irene Angélica
Vera Aguilar, Douglas
Podhorzer, Ariel
Fuentes, Federico
Corral Vázquez, Celia
Guzman, Mauricio
Giordano, Mirta Nilda
Trevani, Analía Silvina
De Paiva, S. Cintia
Galletti, Jeremías Gastón
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Corneal nerves
CD4 T cells
Neuropathy
Immunopathology
Autoimmunity
topic Corneal nerves
CD4 T cells
Neuropathy
Immunopathology
Autoimmunity
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Dry eye disease (DED) is characterized by a dysfunctional tear film in which the corneal epithelium and its abundant nerves are affected by ocular desiccation and inflammation. Although adaptive immunity and specifically CD4+ T cells play a role in DED pathogenesis, the exact contribution of these cells to corneal epithelial and neural damage remains undetermined. To address this, we explored the progression of a surgical DED model in wild-type (WT) and T cell-deficient mice. We observed that adaptive immune-deficient mice developed all aspects of DED comparably to WT mice except for the absence of functional and morphological corneal nerve changes, nerve damage-associated transcriptomic signature in the trigeminal ganglia, and sustained tear cytokine levels. Adoptive transfer of CD4+ T cells from WT DED mice to T cell-deficient mice reproduced corneal nerve damage but not epitheliopathy. Conversely, T cell-deficient mice reconstituted solely with naïve CD4+ T cells developed corneal nerve impairment and epitheliopathy upon DED induction, thus replicating the WT DED phenotype. Collectively, our data show that while corneal neuropathy is driven by CD4+ T cells in DED, corneal epithelial damage develops independently of the adaptive immune response. These findings have implications for T cell-targeting therapies currently in use for DED.
Fil: Vereertbrugghen, Alexia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Pizzano, Manuela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Cernutto, Agostina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Sabbione, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Keitelman, Irene Angélica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Vera Aguilar, Douglas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Podhorzer, Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Fuentes, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Corral Vázquez, Celia. Hospital del Mar Research Institute; España
Fil: Guzman, Mauricio. Hospital del Mar Research Institute; España
Fil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Trevani, Analía Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: De Paiva, S. Cintia. Baylor College Of Medicine. Department Of Ophthalmology. Ocular Surface Center; Estados Unidos
Fil: Galletti, Jeremías Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
description Dry eye disease (DED) is characterized by a dysfunctional tear film in which the corneal epithelium and its abundant nerves are affected by ocular desiccation and inflammation. Although adaptive immunity and specifically CD4+ T cells play a role in DED pathogenesis, the exact contribution of these cells to corneal epithelial and neural damage remains undetermined. To address this, we explored the progression of a surgical DED model in wild-type (WT) and T cell-deficient mice. We observed that adaptive immune-deficient mice developed all aspects of DED comparably to WT mice except for the absence of functional and morphological corneal nerve changes, nerve damage-associated transcriptomic signature in the trigeminal ganglia, and sustained tear cytokine levels. Adoptive transfer of CD4+ T cells from WT DED mice to T cell-deficient mice reproduced corneal nerve damage but not epitheliopathy. Conversely, T cell-deficient mice reconstituted solely with naïve CD4+ T cells developed corneal nerve impairment and epitheliopathy upon DED induction, thus replicating the WT DED phenotype. Collectively, our data show that while corneal neuropathy is driven by CD4+ T cells in DED, corneal epithelial damage develops independently of the adaptive immune response. These findings have implications for T cell-targeting therapies currently in use for DED.
publishDate 2024
dc.date.none.fl_str_mv 2024-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
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info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/265359
Vereertbrugghen, Alexia; Pizzano, Manuela; Cernutto, Agostina; Sabbione, Florencia; Keitelman, Irene Angélica; et al.; CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 121; 48; 11-2024; 1-12
0027-8424
2692-8205
CONICET Digital
CONICET
url http://hdl.handle.net/11336/265359
identifier_str_mv Vereertbrugghen, Alexia; Pizzano, Manuela; Cernutto, Agostina; Sabbione, Florencia; Keitelman, Irene Angélica; et al.; CD4 + T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 121; 48; 11-2024; 1-12
0027-8424
2692-8205
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
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repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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