Transcriptomic profiling of the acute mucosal response to local food injections in adults with eosinophilic esophagitis

Mirelle T.A. Kleuskens; Maria L. Haasnoot; Johan Garssen; Albert J. Bredenoord; Betty C.A.M. van Esch; Frank A. Redegeld

doi:10.1016/j.jaci.2023.10.027

Transcriptomic profiling of the acute mucosal response to local food injections in adults with eosinophilic esophagitis

Mirelle T.A. Kleuskens, Maria L. Haasnoot, Johan Garssen, Albert J. Bredenoord, Betty C.A.M. van Esch^*, Frank A. Redegeld^*

^*Corresponding author for this work

Slotervaart Hospital

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: Exposure of the esophageal mucosa to food allergens can cause acute mucosal responses in patients with eosinophilic esophagitis (EoE), but the underlying local immune mechanisms driving these acute responses are not well understood. Objective: We sought to gain insight into the early transcriptomic changes that occur during an acute mucosal response to food allergens in EoE. Methods: Bulk RNA sequencing was performed on esophageal biopsy specimens from adult patients with EoE (n = 5) collected before and 20 minutes after intramucosal injection of various food extracts in the esophagus. Baseline biopsy specimens from control subjects without EoE (n = 5) were also included. Results: At baseline, the transcriptome of the patients with EoE showed increased expression of genes related to an EoE signature. After local food injection, we identified 40 genes with a potential role in the early immune response to food allergens (most notably CEBPB, IL1B, TNFSF18, PHLDA2, and SLC15A3). These 40 genes were enriched in processes related to immune activation, such as the acute-phase response, cellular responses to external stimuli, and cell population proliferation. TNFSF18 (also called GITRL), a member of the TNF superfamily that is best studied for its costimulatory effect on T cells, was the most dysregulated early EoE gene, showing a 12-fold increase compared with baseline and an 18-fold increase compared with a negative visual response. Further experiments showed that the esophageal epithelium may be an important source of TNFSF18 in EoE, which was rapidly induced by costimulating esophageal epithelial cells with the EoE-relevant cytokines IL-13 and TNF-α. Conclusions: Our data provide unprecedented insight into the transcriptomic changes that mediate the acute mucosal immune response to food allergens in EoE and suggest that TNFSF18 may be an important effector molecule in this response.

Original language	English
Pages (from-to)	780-792
Number of pages	13
Journal	Journal of Allergy and Clinical Immunology
Volume	153
Issue number	3
Early online date	14 Nov 2023
DOIs	https://doi.org/10.1016/j.jaci.2023.10.027
Publication status	Published - Mar 2024

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Funding

This research is funded within the Partnership between the Dutch Research Council (NWO) domain Applied and Engineered Sciences and Danone Nutricia Research , with additional financial support from Topsector Agri and Food, project number 16495 with the acronym LOIRE. A.J.B. is supported by Vidi grant 91718300 from NWO. This research is funded within the Partnership between the Dutch Research Council (NWO) domain Applied and Engineered Sciences and Danone Nutricia Research, with additional financial support from Topsector Agri and Food, project number 16495 with the acronym LOIRE. A.J.B. is supported by Vidi grant 91718300 from NWO.Disclosure of potential conflict of interest: A. J. Bredenoord received research funding from Norgine, Thelial, SST and received speaker and/or consulting fees from Laborie, Medtronic, Dr. Falk Pharma, Alimentiv, Sanofi, Regeneron, and AstraZeneca (all unrelated to this work). J. Garssen and B. C. A. M. van Esch are partly employed by Danone Nutricia Research. The rest of the authors declare that they have no relevant conflicts of interest.

Funders	Funder number
Topsector Agri and Food	16495, 91718300
AstraZeneca
Danone Nutricia Research
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Keywords

Acute response
eosinophilic esophagitis
esophagus
food challenge
GITRL
RNA sequencing
TNFSF18

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Cite this

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title = "Transcriptomic profiling of the acute mucosal response to local food injections in adults with eosinophilic esophagitis",

abstract = "Background: Exposure of the esophageal mucosa to food allergens can cause acute mucosal responses in patients with eosinophilic esophagitis (EoE), but the underlying local immune mechanisms driving these acute responses are not well understood. Objective: We sought to gain insight into the early transcriptomic changes that occur during an acute mucosal response to food allergens in EoE. Methods: Bulk RNA sequencing was performed on esophageal biopsy specimens from adult patients with EoE (n = 5) collected before and 20 minutes after intramucosal injection of various food extracts in the esophagus. Baseline biopsy specimens from control subjects without EoE (n = 5) were also included. Results: At baseline, the transcriptome of the patients with EoE showed increased expression of genes related to an EoE signature. After local food injection, we identified 40 genes with a potential role in the early immune response to food allergens (most notably CEBPB, IL1B, TNFSF18, PHLDA2, and SLC15A3). These 40 genes were enriched in processes related to immune activation, such as the acute-phase response, cellular responses to external stimuli, and cell population proliferation. TNFSF18 (also called GITRL), a member of the TNF superfamily that is best studied for its costimulatory effect on T cells, was the most dysregulated early EoE gene, showing a 12-fold increase compared with baseline and an 18-fold increase compared with a negative visual response. Further experiments showed that the esophageal epithelium may be an important source of TNFSF18 in EoE, which was rapidly induced by costimulating esophageal epithelial cells with the EoE-relevant cytokines IL-13 and TNF-α. Conclusions: Our data provide unprecedented insight into the transcriptomic changes that mediate the acute mucosal immune response to food allergens in EoE and suggest that TNFSF18 may be an important effector molecule in this response.",

keywords = "Acute response, eosinophilic esophagitis, esophagus, food challenge, GITRL, RNA sequencing, TNFSF18",

author = "Kleuskens, {Mirelle T.A.} and Haasnoot, {Maria L.} and Johan Garssen and Bredenoord, {Albert J.} and {van Esch}, {Betty C.A.M.} and Redegeld, {Frank A.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2024",

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doi = "10.1016/j.jaci.2023.10.027",

language = "English",

volume = "153",

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T1 - Transcriptomic profiling of the acute mucosal response to local food injections in adults with eosinophilic esophagitis

AU - Kleuskens, Mirelle T.A.

AU - Haasnoot, Maria L.

AU - Garssen, Johan

AU - Bredenoord, Albert J.

AU - van Esch, Betty C.A.M.

AU - Redegeld, Frank A.

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N2 - Background: Exposure of the esophageal mucosa to food allergens can cause acute mucosal responses in patients with eosinophilic esophagitis (EoE), but the underlying local immune mechanisms driving these acute responses are not well understood. Objective: We sought to gain insight into the early transcriptomic changes that occur during an acute mucosal response to food allergens in EoE. Methods: Bulk RNA sequencing was performed on esophageal biopsy specimens from adult patients with EoE (n = 5) collected before and 20 minutes after intramucosal injection of various food extracts in the esophagus. Baseline biopsy specimens from control subjects without EoE (n = 5) were also included. Results: At baseline, the transcriptome of the patients with EoE showed increased expression of genes related to an EoE signature. After local food injection, we identified 40 genes with a potential role in the early immune response to food allergens (most notably CEBPB, IL1B, TNFSF18, PHLDA2, and SLC15A3). These 40 genes were enriched in processes related to immune activation, such as the acute-phase response, cellular responses to external stimuli, and cell population proliferation. TNFSF18 (also called GITRL), a member of the TNF superfamily that is best studied for its costimulatory effect on T cells, was the most dysregulated early EoE gene, showing a 12-fold increase compared with baseline and an 18-fold increase compared with a negative visual response. Further experiments showed that the esophageal epithelium may be an important source of TNFSF18 in EoE, which was rapidly induced by costimulating esophageal epithelial cells with the EoE-relevant cytokines IL-13 and TNF-α. Conclusions: Our data provide unprecedented insight into the transcriptomic changes that mediate the acute mucosal immune response to food allergens in EoE and suggest that TNFSF18 may be an important effector molecule in this response.

AB - Background: Exposure of the esophageal mucosa to food allergens can cause acute mucosal responses in patients with eosinophilic esophagitis (EoE), but the underlying local immune mechanisms driving these acute responses are not well understood. Objective: We sought to gain insight into the early transcriptomic changes that occur during an acute mucosal response to food allergens in EoE. Methods: Bulk RNA sequencing was performed on esophageal biopsy specimens from adult patients with EoE (n = 5) collected before and 20 minutes after intramucosal injection of various food extracts in the esophagus. Baseline biopsy specimens from control subjects without EoE (n = 5) were also included. Results: At baseline, the transcriptome of the patients with EoE showed increased expression of genes related to an EoE signature. After local food injection, we identified 40 genes with a potential role in the early immune response to food allergens (most notably CEBPB, IL1B, TNFSF18, PHLDA2, and SLC15A3). These 40 genes were enriched in processes related to immune activation, such as the acute-phase response, cellular responses to external stimuli, and cell population proliferation. TNFSF18 (also called GITRL), a member of the TNF superfamily that is best studied for its costimulatory effect on T cells, was the most dysregulated early EoE gene, showing a 12-fold increase compared with baseline and an 18-fold increase compared with a negative visual response. Further experiments showed that the esophageal epithelium may be an important source of TNFSF18 in EoE, which was rapidly induced by costimulating esophageal epithelial cells with the EoE-relevant cytokines IL-13 and TNF-α. Conclusions: Our data provide unprecedented insight into the transcriptomic changes that mediate the acute mucosal immune response to food allergens in EoE and suggest that TNFSF18 may be an important effector molecule in this response.

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Transcriptomic profiling of the acute mucosal response to local food injections in adults with eosinophilic esophagitis

Abstract

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Keywords

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