Increased production of interleukin-21, but not interleukin-17A, in the small intestine characterizes pediatric celiac disease

• Published in: Mucosal immunology Vol. 6; no. 6; pp. 1202 - 1213
• Main Authors: van Leeuwen, M A, Lindenbergh-Kortleve, D J, Raatgeep, H C, de Ruiter, L F, de Krijger, R R, Groeneweg, M, Escher, J C, Samsom, J N
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-11-2013; Elsevier Limited
• Subjects: 631/250/127/1213; 631/250/249/1313/1357; 631/250/347; 692/700/1720; Adult; Allergology; Antibodies; Biomedical and Life Sciences; Biomedicine; CD4-Positive T-Lymphocytes - immunology; Celiac Disease - immunology; Cell Separation; Cells, Cultured; Child; Disease Progression; Flow Cytometry; Gastroenterology; Glutens - immunology; Humans; Immunology; Interleukin-17 - genetics; Interleukin-17 - metabolism; Interleukins - genetics; Interleukins - metabolism; Intestine, Small - pathology; Lymphocyte Activation; Mucous Membrane - immunology; Mucous Membrane - pathology; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 3 - metabolism; Up-Regulation
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2013.19

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.