Increased production of interleukin-21, but not interleukin-17A,in the small intestine characterizes pediatric celiac disease |
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Institution: | 1. Division of Gastroenterology and Nutrition, Laboratory of Pediatrics, Erasmus Medical Center–Sophia Children''s Hospital, Rotterdam, The Netherlands;2. Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands;3. Department of Pediatrics, Maasstad Hospital, Rotterdam, The Netherlands;4. Department of Pediatric Gastroenterology, Erasmus Medical Center–Sophia Children''s Hospital, Rotterdam, The Netherlands;5. 5Present address: Department of Pathology, Reinier de Graaf Gasthuis, Delft, The Netherlands |
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Abstract: | Celiac disease (CD) is caused by inflammatory CD4+ T-cell responses to dietary gluten. It is unclear whether interleukin (IL)-21 and IL-17A contribute to CD onset and lesion severity; therefore, we investigated IL-21 and IL-17A expression in biopsies from pediatric CD patients with different histopathological scores. High numbers of IL-21-producing cells were observed in pediatric CD lesions, even Marsh 1–2 lesions, whereas increased numbers of IL-17 secreting cells were not observed. Intraepithelial lymphocytes, CD4+ T cells and also neutrophils secreted IL-21. Flow cytometry of lamina propria cells revealed a large population of IL-21- and interferon-γ (IFN-γ)-secreting CD3+ T cells that did not secrete IL-17A. Adult CD patient biopsies also contained high numbers of IL-21-positive cells; however, enhanced numbers of IL-17-positive cells were observed in a small subgroup of patients with severe lesions. As duodenal tissue damage increases contact with microbe-associated molecular patterns, we hypothesized that microbial sensing by Toll-like receptors (TLRs) modulates T cell–derived cytokine secretion. Costimulation with TLR3 ligands during polyclonal T-cell activation significantly increased IL-21 secretion, whereas TLR2 ligands selectively enhanced IL-17A. These results demonstrate that an IL-17A-independent increase in IL-21 production by CD4+ T cells is characteristic of pediatric CD. We hypothesize that incidental IL-17 secretion is caused by tissue damage rather than gluten-specific responses. |
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