Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease

Paolo Biancheri, Antonio Di Sabatino, Maria Rescigno, Paolo Giuffrida, Giulia Fornasa, Aikaterini Tsilingiri, Sylvia L F Pender, Cinzia Papadia, Eleanor Wood, Alessandra Pasini, Cristina Ubezio, Alessandro Vanoli, Alastair Forbes, Thomas T. MacDonald, Gino R Corazza

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: The short isoform of thymic stromal lymphopoietin (TSLP), a cytokine constitutively expressed by epithelial cells, is crucial in preserving immune tolerance in the gut. TSLP deficiency has been implicated in sustaining intestinal damage in Crohn's disease. We explored mucosal TSLP expression and function in refractory and uncomplicated coeliac disease (CD), a T-cell-mediated enteropathy induced by gluten in genetically susceptible individuals.

DESIGN: TSLP isoforms-long and short-and receptors-TSLPR and interleukin (IL)-7Rα-were assessed by immunofluorescence, immunoblotting and qRT-PCR in the duodenum of untreated, treated, potential and refractory patients with CD. The ability of the serine protease furin or CD biopsy supernatants to cleave TSLP was evaluated by immunoblotting. The production of interferon (IFN)-γ and IL-8 by untreated CD biopsies cultured ex vivo with TSLP isoforms was also assessed.

RESULTS: Mucosal TSLP, but not TSLPR and IL-7Rα, was reduced in untreated CD and refractory CD in comparison to treated CD, potential CD and controls. Transcripts of both TSLP isoforms were decreased in active CD mucosa. Furin, which was overexpressed in active CD biopsies, was able to cleave TSLP in vitro. Accordingly, refractory and untreated CD supernatants showed higher TSLP-degrading capacity in comparison to treated CD and control supernatants. In our ex vivo model, both TSLP isoforms significantly downregulated IFN-γ and IL-8 production by untreated CD biopsies.

CONCLUSIONS: Reduced mucosal TSLP expression may contribute to intestinal damage in refractory and untreated CD. Further studies are needed to verify whether restoring TSLP might be therapeutically useful especially in refractory patients with CD.

Original languageEnglish
Pages (from-to)1670-80
Number of pages11
JournalGut
Volume65
Issue number10
DOIs
Publication statusPublished - Oct 2016

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Celiac Disease
Mucous Membrane
Protein Isoforms
Furin
Biopsy
thymic stromal lymphopoietin
Interleukin-8
Immunoblotting
Interferons
Interleukin Receptors
Immune Tolerance
Interleukins
Serine Proteases
Duodenum
Crohn Disease
Fluorescent Antibody Technique

Keywords

  • Journal Article

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Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease. / Biancheri, Paolo; Di Sabatino, Antonio; Rescigno, Maria; Giuffrida, Paolo; Fornasa, Giulia; Tsilingiri, Aikaterini; Pender, Sylvia L F; Papadia, Cinzia; Wood, Eleanor; Pasini, Alessandra; Ubezio, Cristina; Vanoli, Alessandro; Forbes, Alastair; MacDonald, Thomas T.; Corazza, Gino R.

In: Gut, Vol. 65, No. 10, 10.2016, p. 1670-80.

Research output: Contribution to journalArticle

Biancheri, Paolo ; Di Sabatino, Antonio ; Rescigno, Maria ; Giuffrida, Paolo ; Fornasa, Giulia ; Tsilingiri, Aikaterini ; Pender, Sylvia L F ; Papadia, Cinzia ; Wood, Eleanor ; Pasini, Alessandra ; Ubezio, Cristina ; Vanoli, Alessandro ; Forbes, Alastair ; MacDonald, Thomas T. ; Corazza, Gino R. / Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease. In: Gut. 2016 ; Vol. 65, No. 10. pp. 1670-80.
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abstract = "OBJECTIVE: The short isoform of thymic stromal lymphopoietin (TSLP), a cytokine constitutively expressed by epithelial cells, is crucial in preserving immune tolerance in the gut. TSLP deficiency has been implicated in sustaining intestinal damage in Crohn's disease. We explored mucosal TSLP expression and function in refractory and uncomplicated coeliac disease (CD), a T-cell-mediated enteropathy induced by gluten in genetically susceptible individuals.DESIGN: TSLP isoforms-long and short-and receptors-TSLPR and interleukin (IL)-7Rα-were assessed by immunofluorescence, immunoblotting and qRT-PCR in the duodenum of untreated, treated, potential and refractory patients with CD. The ability of the serine protease furin or CD biopsy supernatants to cleave TSLP was evaluated by immunoblotting. The production of interferon (IFN)-γ and IL-8 by untreated CD biopsies cultured ex vivo with TSLP isoforms was also assessed.RESULTS: Mucosal TSLP, but not TSLPR and IL-7Rα, was reduced in untreated CD and refractory CD in comparison to treated CD, potential CD and controls. Transcripts of both TSLP isoforms were decreased in active CD mucosa. Furin, which was overexpressed in active CD biopsies, was able to cleave TSLP in vitro. Accordingly, refractory and untreated CD supernatants showed higher TSLP-degrading capacity in comparison to treated CD and control supernatants. In our ex vivo model, both TSLP isoforms significantly downregulated IFN-γ and IL-8 production by untreated CD biopsies.CONCLUSIONS: Reduced mucosal TSLP expression may contribute to intestinal damage in refractory and untreated CD. Further studies are needed to verify whether restoring TSLP might be therapeutically useful especially in refractory patients with CD.",
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T1 - Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease

AU - Biancheri, Paolo

AU - Di Sabatino, Antonio

AU - Rescigno, Maria

AU - Giuffrida, Paolo

AU - Fornasa, Giulia

AU - Tsilingiri, Aikaterini

AU - Pender, Sylvia L F

AU - Papadia, Cinzia

AU - Wood, Eleanor

AU - Pasini, Alessandra

AU - Ubezio, Cristina

AU - Vanoli, Alessandro

AU - Forbes, Alastair

AU - MacDonald, Thomas T.

AU - Corazza, Gino R

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PY - 2016/10

Y1 - 2016/10

N2 - OBJECTIVE: The short isoform of thymic stromal lymphopoietin (TSLP), a cytokine constitutively expressed by epithelial cells, is crucial in preserving immune tolerance in the gut. TSLP deficiency has been implicated in sustaining intestinal damage in Crohn's disease. We explored mucosal TSLP expression and function in refractory and uncomplicated coeliac disease (CD), a T-cell-mediated enteropathy induced by gluten in genetically susceptible individuals.DESIGN: TSLP isoforms-long and short-and receptors-TSLPR and interleukin (IL)-7Rα-were assessed by immunofluorescence, immunoblotting and qRT-PCR in the duodenum of untreated, treated, potential and refractory patients with CD. The ability of the serine protease furin or CD biopsy supernatants to cleave TSLP was evaluated by immunoblotting. The production of interferon (IFN)-γ and IL-8 by untreated CD biopsies cultured ex vivo with TSLP isoforms was also assessed.RESULTS: Mucosal TSLP, but not TSLPR and IL-7Rα, was reduced in untreated CD and refractory CD in comparison to treated CD, potential CD and controls. Transcripts of both TSLP isoforms were decreased in active CD mucosa. Furin, which was overexpressed in active CD biopsies, was able to cleave TSLP in vitro. Accordingly, refractory and untreated CD supernatants showed higher TSLP-degrading capacity in comparison to treated CD and control supernatants. In our ex vivo model, both TSLP isoforms significantly downregulated IFN-γ and IL-8 production by untreated CD biopsies.CONCLUSIONS: Reduced mucosal TSLP expression may contribute to intestinal damage in refractory and untreated CD. Further studies are needed to verify whether restoring TSLP might be therapeutically useful especially in refractory patients with CD.

AB - OBJECTIVE: The short isoform of thymic stromal lymphopoietin (TSLP), a cytokine constitutively expressed by epithelial cells, is crucial in preserving immune tolerance in the gut. TSLP deficiency has been implicated in sustaining intestinal damage in Crohn's disease. We explored mucosal TSLP expression and function in refractory and uncomplicated coeliac disease (CD), a T-cell-mediated enteropathy induced by gluten in genetically susceptible individuals.DESIGN: TSLP isoforms-long and short-and receptors-TSLPR and interleukin (IL)-7Rα-were assessed by immunofluorescence, immunoblotting and qRT-PCR in the duodenum of untreated, treated, potential and refractory patients with CD. The ability of the serine protease furin or CD biopsy supernatants to cleave TSLP was evaluated by immunoblotting. The production of interferon (IFN)-γ and IL-8 by untreated CD biopsies cultured ex vivo with TSLP isoforms was also assessed.RESULTS: Mucosal TSLP, but not TSLPR and IL-7Rα, was reduced in untreated CD and refractory CD in comparison to treated CD, potential CD and controls. Transcripts of both TSLP isoforms were decreased in active CD mucosa. Furin, which was overexpressed in active CD biopsies, was able to cleave TSLP in vitro. Accordingly, refractory and untreated CD supernatants showed higher TSLP-degrading capacity in comparison to treated CD and control supernatants. In our ex vivo model, both TSLP isoforms significantly downregulated IFN-γ and IL-8 production by untreated CD biopsies.CONCLUSIONS: Reduced mucosal TSLP expression may contribute to intestinal damage in refractory and untreated CD. Further studies are needed to verify whether restoring TSLP might be therapeutically useful especially in refractory patients with CD.

KW - Journal Article

U2 - 10.1136/gutjnl-2014-308876

DO - 10.1136/gutjnl-2014-308876

M3 - Article

C2 - 26342013

VL - 65

SP - 1670

EP - 1680

JO - Gut

JF - Gut

SN - 0017-5749

IS - 10

ER -