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



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.



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.



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.
First Department of Internal Medicine, St Matteo Hospital, University of Pavia, Pavia, Italy Centre for Immunobiology, Barts and the London School of Medicine and Dentistry, London, UK.
Paolo
P
Biancheri
First Department of Internal Medicine, St Matteo Hospital, University of Pavia, Pavia, Italy.
Antonio
A
Di Sabatino
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
Maria
M
Rescigno
First Department of Internal Medicine, St Matteo Hospital, University of Pavia, Pavia, Italy Centre for Immunobiology, Barts and the London School of Medicine and Dentistry, London, UK.
Paolo
P
Giuffrida
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
Giulia
G
Fornasa
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
Katerina
K
Tsilingiri
Faculty of Medicine, University of Southampton, Southampton, UK.
Sylvia L F
SL
Pender
Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich Medical School, University of East Anglia, Norwich, UK.
Cinzia
C
Papadia
Academic Department of Medical and Surgical Gastroenterology, Homerton University Hospital, London, UK.
Eleanor
E
Wood
First Department of Internal Medicine, St Matteo Hospital, University of Pavia, Pavia, Italy.
Alessandra
A
Pasini
First Department of Internal Medicine, St Matteo Hospital, University of Pavia, Pavia, Italy.
Cristina
C
Ubezio
Department of Molecular Medicine, St Matteo Hospital, University of Pavia, Pavia, Italy.
Alessandro
A
Vanoli
Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich Medical School, University of East Anglia, Norwich, UK.
Alastair
A
Forbes
Centre for Immunobiology, Barts and the London School of Medicine and Dentistry, London, UK.
Thomas T
TT
MacDonald
First Department of Internal Medicine, St Matteo Hospital, University of Pavia, Pavia, Italy.
Gino R
GR
Corazza
D000328:Adult; D000368:Aged; D001706:Biopsy / Q000379:methods; D002446:Celiac Disease / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000737:chemistry / Q000378:metabolism; D004386:Duodenum / Q000276:immunology / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D045683:Furin / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D016209:Interleukin-8 / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms; D020395:Receptors, Interleukin-7 / Q000276:immunology*; D013223:Statistics as Topic; D013601:T-Lymphocytes / Q000276:immunology; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D016209:Interleukin-8; D020033:Protein Isoforms; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D045683:Furin; D000094632:Thymic Stromal Lymphopoietin
COELIAC DISEASE; GUT IMMUNOLOGY; MATRIX METALLOPROTEINASE; MUCOSAL IMMUNITY; SMALL INTESTINE