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

Abstract

ObjectiveThe 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.DesignTSLP 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.ResultsMucosal 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.ConclusionsReduced 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.

Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma

“…However, a propensity to form amphipathic helices combined with a high isoelectric point (pI) of 11.1 would support its presumed function as antimicrobial peptide6366. sfTSLP may also exhibit anti-inflammatory properties6465 and may mediate immune tolerance in the gut67.…”

Epithelial cell–derived cytokines: more than just signaling the alarm

“…In humans, a short isoform appears to be expressed in basal conditions, whereas a longer isoform is induced by inflammatory stimuli (12). Cleavage of human TSLP by serine proteases may also regulate TSLP protein levels or function, although it is unclear whether a similar regulatory mechanism exists in mice (13,14). TSLP genetic variants and high levels of TSLP expression have been linked to atopic diseases such as AD, asthma, allergic rhinoconjunctivitis, and EoE (15).…”

Thymic stromal lymphopoietin levels are increased in patients with celiac disease

“…Biancheri et al showed a reduced mucosal TSLP expression in refractory and untreated CD, whereas Sziksz et al revealed a higher mucosal TSLP expression in patients with newly diagnosed CD [16,17]. Furthermore, previous studies showed elevated serum TSLP levels in patients with atopic dermatitis and asthma [24,18].…”

“…Biancheri et al demonstrated that TSLPR and IL-7Rα were expressed in CD mucosa, and mRNA levels of both long (lTSLP) and short TSLP (shTSLP) isoforms were reduced in CD compared with the control group [16]. Sziksz et al determined a higher mucosal expression of TSLP in patients with newly diagnosed CD than in CD patients under a gluten-free diet (GFD) and controls [17].…”