| Autor: |
Costes LMM; Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, 3000 CA, The Netherlands., Lindenbergh-Kortleve DJ; Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, 3000 CA, The Netherlands., van Berkel LA; Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, 3000 CA, The Netherlands., Veenbergen S; Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, 3000 CA, The Netherlands., Raatgeep HRC; Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, 3000 CA, The Netherlands., Simons-Oosterhuis Y; Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, 3000 CA, The Netherlands., van Haaften DH; Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, 3000 CA, The Netherlands., Karrich JJ; Department of Hematology, Erasmus University Medical Center, Rotterdam, 3000 CA, The Netherlands., Escher JC; Department of Pediatric Gastroenterology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands., Groeneweg M; Department of Pediatrics, Maasstad Hospital, Rotterdam, 3079 DZ, The Netherlands., Clausen BE; Institute for Molecular Medicine, University Medical Center of Johannes Gutenberg University, Mainz, 55131, Germany., Cupedo T; Department of Hematology, Erasmus University Medical Center, Rotterdam, 3000 CA, The Netherlands., Samsom JN; Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, 3000 CA, The Netherlands. j.samsom@erasmusmc.nl. |
| Abstrakt: |
Breach of tolerance to gluten leads to the chronic small intestinal enteropathy celiac disease. A key event in celiac disease development is gluten-dependent infiltration of activated cytotoxic intraepithelial lymphocytes (IELs), which cytolyze epithelial cells causing crypt hyperplasia and villous atrophy. The mechanisms leading to gluten-dependent small intestinal IEL infiltration and activation remain elusive. We have demonstrated that under homeostatic conditions in mice, gluten drives the differentiation of anti-inflammatory T cells producing large amounts of the immunosuppressive cytokine interleukin-10 (IL-10). Here we addressed whether this dominant IL-10 axis prevents gluten-dependent infiltration of activated cytotoxic IEL and subsequent small intestinal enteropathy. We demonstrate that IL-10 regulation prevents gluten-induced cytotoxic inflammatory IEL infiltration. In particular, IL-10 suppresses gluten-induced accumulation of a specialized population of cytotoxic CD4 + CD8αα + IEL (CD4 + CTL) expressing Tbx21, Ifng, and Il21, and a disparate non-cytolytic CD4 + CD8α - IEL population expressing Il17a, Il21, and Il10. Concomitantly, IL-10 suppresses gluten-dependent small intestinal epithelial hyperproliferation and upregulation of stress-induced molecules on epithelial cells. Remarkably, frequencies of granzyme B + CD4 + CD8α + IEL are increased in pediatric celiac disease patient biopsies. These findings demonstrate that IL-10 is pivotal to prevent gluten-induced small intestinal inflammation and epithelial damage, and imply that CD4 + CTL are potential new players into these processes. |
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