An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy

Autores
Vereertbrugghen, Alexia; Pizzano, Manuela; Sabbione, Florencia; Keitelman, Irene Angélica; Shiromizu, Carolina Maiumi; Vera Aguilar, Douglas; Fuentes, Federico; de Paiva, Cintia S.; Giordano, Mirta Nilda; Trevani, Analía Silvina; Galletti, Jeremías Gastón
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Proper sight is not possible without a smooth, transparent cornea, which is highly exposed to environmental threats. The abundant corneal nerves are interspersed with epithelial cells in the anterior corneal surface and are instrumental to corneal integrity and immunoregulation. Conversely, corneal neuropathy is commonly observed in some immune-mediated corneal disorders but not in others, and its pathogenesis is poorly understood. Here we hypothesized that the type of adaptive immune response may influence the development of corneal neuropathy. To test this, we first immunized OT-II mice with different adjuvants that favor T helper (Th)1 or Th2 responses. Both Th1-skewed mice (measured by interferon-γ production) and Th2-skewed (measured by interleukin-4 production) developed comparable ocular surface inflammation and conjunctival CD4+ T cell recruitment but no appreciable corneal epithelial changes upon repeated local antigenic challenge. Th1-skewed mice showed decreased corneal mechanical sensitivity and altered corneal nerve morphology (signs of corneal neuropathy) upon antigenic challenge. However, Th2-skewed mice also developed milder corneal neuropathy immediately after immunization and independently of ocular challenge, suggestive of adjuvant-induced neurotoxicity. All these findings were confirmed in wild-type mice. To circumvent unwanted neurotoxicity, CD4+ T cells from immunized mice were adoptively transferred to T cell-deficient mice. In this setup, only Th1-transferred mice developed corneal neuropathy upon antigenic challenge. To further delineate the contribution of each profile, CD4+ T cells were polarized in vitro to either Th1, Th2, or Th17 cells and transferred to T cell-deficient mice. Upon local antigenic challenge, all groups had commensurate conjunctival CD4+ T cell recruitment and macroscopic ocular inflammation. However, none of the groups developed corneal epithelial changes and only Th1-transferred mice showed signs of corneal neuropathy. Altogether, the data show that corneal nerves, as opposed to corneal epithelial cells, are sensitive to immune-driven damage mediated by Th1 CD4+ T cells in the absence of other pathogenic factors. These findings have potential therapeutic implications for ocular surface disorders.
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: 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: Shiromizu, Carolina Maiumi. 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. Academia Nacional de Medicina de Buenos Aires; 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: de Paiva, Cintia S.. Cullen Eye Institute; Estados Unidos
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: 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
CD4 T CELLS
CORNEAL NERVES
IMMUNOPATHOLOGY
NEUROPATHY
TH1 RESPONSE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/227982
Acceder
id CONICETDig_271446ab23e3d6d91fb50e51ac92ec09
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathyVereertbrugghen, AlexiaPizzano, ManuelaSabbione, FlorenciaKeitelman, Irene AngélicaShiromizu, Carolina MaiumiVera Aguilar, DouglasFuentes, Federicode Paiva, Cintia S.Giordano, Mirta NildaTrevani, Analía SilvinaGalletti, Jeremías GastónCD4 T CELLSCORNEAL NERVESIMMUNOPATHOLOGYNEUROPATHYTH1 RESPONSEhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Proper sight is not possible without a smooth, transparent cornea, which is highly exposed to environmental threats. The abundant corneal nerves are interspersed with epithelial cells in the anterior corneal surface and are instrumental to corneal integrity and immunoregulation. Conversely, corneal neuropathy is commonly observed in some immune-mediated corneal disorders but not in others, and its pathogenesis is poorly understood. Here we hypothesized that the type of adaptive immune response may influence the development of corneal neuropathy. To test this, we first immunized OT-II mice with different adjuvants that favor T helper (Th)1 or Th2 responses. Both Th1-skewed mice (measured by interferon-γ production) and Th2-skewed (measured by interleukin-4 production) developed comparable ocular surface inflammation and conjunctival CD4+ T cell recruitment but no appreciable corneal epithelial changes upon repeated local antigenic challenge. Th1-skewed mice showed decreased corneal mechanical sensitivity and altered corneal nerve morphology (signs of corneal neuropathy) upon antigenic challenge. However, Th2-skewed mice also developed milder corneal neuropathy immediately after immunization and independently of ocular challenge, suggestive of adjuvant-induced neurotoxicity. All these findings were confirmed in wild-type mice. To circumvent unwanted neurotoxicity, CD4+ T cells from immunized mice were adoptively transferred to T cell-deficient mice. In this setup, only Th1-transferred mice developed corneal neuropathy upon antigenic challenge. To further delineate the contribution of each profile, CD4+ T cells were polarized in vitro to either Th1, Th2, or Th17 cells and transferred to T cell-deficient mice. Upon local antigenic challenge, all groups had commensurate conjunctival CD4+ T cell recruitment and macroscopic ocular inflammation. However, none of the groups developed corneal epithelial changes and only Th1-transferred mice showed signs of corneal neuropathy. Altogether, the data show that corneal nerves, as opposed to corneal epithelial cells, are sensitive to immune-driven damage mediated by Th1 CD4+ T cells in the absence of other pathogenic factors. These findings have potential therapeutic implications for ocular surface disorders.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: 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: Shiromizu, Carolina Maiumi. 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. Academia Nacional de Medicina de Buenos Aires; 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: de Paiva, Cintia S.. Cullen Eye Institute; Estados UnidosFil: 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: 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; ArgentinaBioMed Central2023-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/227982Vereertbrugghen, Alexia; Pizzano, Manuela; Sabbione, Florencia; Keitelman, Irene Angélica; Shiromizu, Carolina Maiumi; et al.; An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy; BioMed Central; Journal Of Neuroinflammation; 20; 1; 12-2023; 1-231742-2094CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-023-02800-2info:eu-repo/semantics/altIdentifier/doi/10.1186/s12974-023-02800-2info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:51:52Zoai:ri.conicet.gov.ar:11336/227982instacron: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:34982025-10-15 14:51:52.623CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy
title An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy
spellingShingle An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy
Vereertbrugghen, Alexia
CD4 T CELLS
CORNEAL NERVES
IMMUNOPATHOLOGY
NEUROPATHY
TH1 RESPONSE
title_short An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy
title_full An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy
title_fullStr An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy
title_full_unstemmed An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy
title_sort An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy
dc.creator.none.fl_str_mv Vereertbrugghen, Alexia
Pizzano, Manuela
Sabbione, Florencia
Keitelman, Irene Angélica
Shiromizu, Carolina Maiumi
Vera Aguilar, Douglas
Fuentes, Federico
de Paiva, Cintia S.
Giordano, Mirta Nilda
Trevani, Analía Silvina
Galletti, Jeremías Gastón
author Vereertbrugghen, Alexia
author_facet Vereertbrugghen, Alexia
Pizzano, Manuela
Sabbione, Florencia
Keitelman, Irene Angélica
Shiromizu, Carolina Maiumi
Vera Aguilar, Douglas
Fuentes, Federico
de Paiva, Cintia S.
Giordano, Mirta Nilda
Trevani, Analía Silvina
Galletti, Jeremías Gastón
author_role author
author2 Pizzano, Manuela
Sabbione, Florencia
Keitelman, Irene Angélica
Shiromizu, Carolina Maiumi
Vera Aguilar, Douglas
Fuentes, Federico
de Paiva, Cintia S.
Giordano, Mirta Nilda
Trevani, Analía Silvina
Galletti, Jeremías Gastón
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CD4 T CELLS
CORNEAL NERVES
IMMUNOPATHOLOGY
NEUROPATHY
TH1 RESPONSE
topic CD4 T CELLS
CORNEAL NERVES
IMMUNOPATHOLOGY
NEUROPATHY
TH1 RESPONSE
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Proper sight is not possible without a smooth, transparent cornea, which is highly exposed to environmental threats. The abundant corneal nerves are interspersed with epithelial cells in the anterior corneal surface and are instrumental to corneal integrity and immunoregulation. Conversely, corneal neuropathy is commonly observed in some immune-mediated corneal disorders but not in others, and its pathogenesis is poorly understood. Here we hypothesized that the type of adaptive immune response may influence the development of corneal neuropathy. To test this, we first immunized OT-II mice with different adjuvants that favor T helper (Th)1 or Th2 responses. Both Th1-skewed mice (measured by interferon-γ production) and Th2-skewed (measured by interleukin-4 production) developed comparable ocular surface inflammation and conjunctival CD4+ T cell recruitment but no appreciable corneal epithelial changes upon repeated local antigenic challenge. Th1-skewed mice showed decreased corneal mechanical sensitivity and altered corneal nerve morphology (signs of corneal neuropathy) upon antigenic challenge. However, Th2-skewed mice also developed milder corneal neuropathy immediately after immunization and independently of ocular challenge, suggestive of adjuvant-induced neurotoxicity. All these findings were confirmed in wild-type mice. To circumvent unwanted neurotoxicity, CD4+ T cells from immunized mice were adoptively transferred to T cell-deficient mice. In this setup, only Th1-transferred mice developed corneal neuropathy upon antigenic challenge. To further delineate the contribution of each profile, CD4+ T cells were polarized in vitro to either Th1, Th2, or Th17 cells and transferred to T cell-deficient mice. Upon local antigenic challenge, all groups had commensurate conjunctival CD4+ T cell recruitment and macroscopic ocular inflammation. However, none of the groups developed corneal epithelial changes and only Th1-transferred mice showed signs of corneal neuropathy. Altogether, the data show that corneal nerves, as opposed to corneal epithelial cells, are sensitive to immune-driven damage mediated by Th1 CD4+ T cells in the absence of other pathogenic factors. These findings have potential therapeutic implications for ocular surface disorders.
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: 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: Shiromizu, Carolina Maiumi. 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. Academia Nacional de Medicina de Buenos Aires; 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: de Paiva, Cintia S.. Cullen Eye Institute; Estados Unidos
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: 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 Proper sight is not possible without a smooth, transparent cornea, which is highly exposed to environmental threats. The abundant corneal nerves are interspersed with epithelial cells in the anterior corneal surface and are instrumental to corneal integrity and immunoregulation. Conversely, corneal neuropathy is commonly observed in some immune-mediated corneal disorders but not in others, and its pathogenesis is poorly understood. Here we hypothesized that the type of adaptive immune response may influence the development of corneal neuropathy. To test this, we first immunized OT-II mice with different adjuvants that favor T helper (Th)1 or Th2 responses. Both Th1-skewed mice (measured by interferon-γ production) and Th2-skewed (measured by interleukin-4 production) developed comparable ocular surface inflammation and conjunctival CD4+ T cell recruitment but no appreciable corneal epithelial changes upon repeated local antigenic challenge. Th1-skewed mice showed decreased corneal mechanical sensitivity and altered corneal nerve morphology (signs of corneal neuropathy) upon antigenic challenge. However, Th2-skewed mice also developed milder corneal neuropathy immediately after immunization and independently of ocular challenge, suggestive of adjuvant-induced neurotoxicity. All these findings were confirmed in wild-type mice. To circumvent unwanted neurotoxicity, CD4+ T cells from immunized mice were adoptively transferred to T cell-deficient mice. In this setup, only Th1-transferred mice developed corneal neuropathy upon antigenic challenge. To further delineate the contribution of each profile, CD4+ T cells were polarized in vitro to either Th1, Th2, or Th17 cells and transferred to T cell-deficient mice. Upon local antigenic challenge, all groups had commensurate conjunctival CD4+ T cell recruitment and macroscopic ocular inflammation. However, none of the groups developed corneal epithelial changes and only Th1-transferred mice showed signs of corneal neuropathy. Altogether, the data show that corneal nerves, as opposed to corneal epithelial cells, are sensitive to immune-driven damage mediated by Th1 CD4+ T cells in the absence of other pathogenic factors. These findings have potential therapeutic implications for ocular surface disorders.
publishDate 2023
dc.date.none.fl_str_mv 2023-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/227982
Vereertbrugghen, Alexia; Pizzano, Manuela; Sabbione, Florencia; Keitelman, Irene Angélica; Shiromizu, Carolina Maiumi; et al.; An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy; BioMed Central; Journal Of Neuroinflammation; 20; 1; 12-2023; 1-23
1742-2094
CONICET Digital
CONICET
url http://hdl.handle.net/11336/227982
identifier_str_mv Vereertbrugghen, Alexia; Pizzano, Manuela; Sabbione, Florencia; Keitelman, Irene Angélica; Shiromizu, Carolina Maiumi; et al.; An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy; BioMed Central; Journal Of Neuroinflammation; 20; 1; 12-2023; 1-23
1742-2094
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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publisher.none.fl_str_mv BioMed Central
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