ABSTRACT
OBJECTIVE: Disruption of the epithelial barrier plays an essential role in developing eosinophilic oesophagitis (EoE), a disease defined by type 2 helper T cell (Th2)-mediated food-associated and aeroallergen-associated chronic inflammation. Although an increased expression of interleukin (IL)-20 subfamily members, IL-19, IL-20 and IL-24, in Th2-mediated diseases has been reported, their function in EoE remains unknown. DESIGN: Combining transcriptomic, proteomic and functional analyses, we studied the importance of the IL-20 subfamily for EoE using patient-derived oesophageal three-dimensional models and an EoE mouse model. RESULTS: Patients with active EoE have increased expression of IL-20 subfamily cytokines in the oesophagus and serum. In patient-derived oesophageal organoids stimulated with IL-20 cytokines, RNA sequencing and mass spectrometry revealed a downregulation of genes and proteins forming the cornified envelope, including filaggrins. On the contrary, abrogation of IL-20 subfamily signalling in Il20R2 -/- animals resulted in attenuated experimental EoE reflected by reduced eosinophil infiltration, lower Th2 cytokine expression and preserved expression of filaggrins in the oesophagus. Mechanistically, these observations were mediated by the mitogen-activated protein kinase (MAPK); extracellular-signal regulated kinases (ERK)1/2) pathway. Its blockade prevented epithelial barrier impairment in patient-derived air-liquid interface cultures stimulated with IL-20 cytokines and attenuated experimental EoE in mice. CONCLUSION: Our findings reveal a previously unknown regulatory role of the IL-20 subfamily for oesophageal barrier function in the context of EoE. We propose that aberrant IL-20 subfamily signalling disturbs the oesophageal epithelial barrier integrity and promotes EoE development. Our study suggests that specific targeting of the IL-20 subfamily signalling pathway may present a novel strategy for the treatment of EoE.
Subject(s)
Eosinophilic Esophagitis , Animals , Mice , Cytokines/metabolism , Filaggrin Proteins , Interleukins/pharmacology , Interleukins/metabolism , Proteomics , HumansABSTRACT
BACKGROUND: Subjectively perceived results of treatment will be in the center of defining treatment success on the way to value-based and patient-centered health care. Patient-reported outcome measures (PROMs) serve as an instrument to measure treatment success. In inflammatory bowel disease (IBD), measuring treatment success from a patient's point of view is performed with the validated IBD-Control questionnaire. Because the IBD-Control questionnaire has not been published in German yet, the translation and validation of the IBD-Control in the German-speaking part of Switzerland was necessary before use. METHODS: We have translated the English original version of the IBD-Control questionnaire into German in a state-of-the-art procedure of "forward-backward translation" and validated the translated IBD-Control questionnaire with 154 patients with Crohn's disease or with ulcerative colitis. RESULTS: Professional health care and translation experts have contributed to the translation of the IBD-Control into German. The IBD-Control-D is an accepted questionnaire. Spearmans Rho showed high consistency between the IBD-Control-8-Subscore and the IBD-Control-VAS-Score (r=0.632). The disease activity in the past 6 months highly correlated with the IBD-8 subscore (r=0.640) as well as with the IBD-Control-VAS-Score (r=0.622). The IBD-Control-8-Subscore highly correlated with the Harvey Bradshaw Index (r=-0.620) and the partial Mayo Score (r=-0.679), as well as the IBD-Control-VAS-Score with the Harvey Bradshaw Index (r=-0.484) and the Mayo Score (r=-0.435), showing sufficient construct validity. The result is the German version of the IBD-Control, the IBD-Control-D, published here. CONCLUSION: The original English version is a valid instrument, and its use has proven to be a suitable instrument in German-speaking areas to make the subjective feeling of illness and treatment outcome measurable.
