title: Increased production of interleukin-21, but not interleukin-17A, in the small intestine characterizes pediatric celiac disease.
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.
authors.affiliation: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: van Leeuwen
authors.forename: D J
authors.initials: DJ
authors.lastname: Lindenbergh-Kortleve
authors.forename: H C
authors.initials: HC
authors.lastname: Raatgeep
authors.forename: L F
authors.initials: LF
authors.lastname: de Ruiter
authors.forename: R R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: M
authors.initials: M
authors.lastname: Groeneweg
authors.forename: J C
authors.initials: JC
authors.lastname: Escher
authors.forename: J N
authors.initials: JN
authors.lastname: Samsom
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002446:Celiac Disease / Q000276:immunology*; D002469:Cell Separation; D002478:Cells, Cultured; D002648:Child; D018450:Disease Progression; D005434:Flow Cytometry; D005983:Glutens / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D007421:Intestine, Small / Q000473:pathology; D008213:Lymphocyte Activation; D009092:Mucous Membrane / Q000276:immunology* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D015854:Up-Regulation; D000098546:Interleukin-21
chemical_list: D020381:Interleukin-17; D007378:Interleukins; C495342:TLR2 protein, human; C495344:TLR3 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D005983:Glutens; D000098546:Interleukin-21