Gastroenterology

Gastroenterology

Volume 125, Issue 3, September 2003, Pages 730-745
Gastroenterology

On the cover
Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease☆

https://doi.org/10.1016/S0016-5085(03)01047-3Get rights and content

Abstract

Background & Aims: The mechanism of intraepithelial lymphocyte hyperplasia, a hallmark of celiac disease, is unknown. We have investigated the role of epithelium-derived interleukin (IL)-15 in the alterations of epithelial homeostasis in refractory celiac sprue, a privileged situation to study the first step of lymphoid transformation and the contribution of intraepithelial lymphocytes to villous atrophy in celiac disease. Methods: IL-15 expression was assessed in biopsy specimens and isolated enterocytes by combining immunohistochemistry, flow cytometry, and real-time quantitative polymerase chain reaction. The ability of IL-15 to induce growth and survival of clonal intraepithelial lymphocytes lacking surface CD3 and to induce their cytotoxicity and secretion of interferon gamma was tested using soluble IL-15 and coculture in the presence of epithelial cell lines expressing membrane IL-15. Results: IL-15 was massively overexpressed not only in lamina propria but also in the intestinal epithelium of patients with active celiac disease and refractory celiac sprue. IL-15 was not secreted but delivered at the surface of enterocytes. IL-15 specifically induced the expansion and survival of the clonal abnormal intraepithelial lymphocytes that characterize refractory celiac sprue and triggered their secretion of interferon gamma and their cytotoxicity against intestinal epithelial cells. Comparable activating signals could be delivered by IL-15 expressed at the membrane of the T84 enterocyte cell line. Conclusions: These data provide strong evidence that uncontrolled overexpression of IL-15 in refractory celiac sprue perpetuates epithelial damage and promotes the emergence of T-cell clonal proliferations. Blocking IL-15 might prove useful to treat this severe complication of celiac disease.

Section snippets

Patients and controls

Forty-five adult patients (age range, 19–75 years; mean age, 43 years) had uncomplicated celiac disease. Eight had been diagnosed in childhood according to European Society for Paediatric Gastroenterology and Nutrition criteria18 and 37 as adults based on detection of villous atrophy, anti-endomysium antibodies, and HLA-DQA1∗0501/DQB1∗0201 genotype. At the time of the study, 22 patients had active celiac disease with partial-to-subtotal villous atrophy and 23 had been on a strict GFD and were

IL-15 protein is up-regulated in the small intestinal epithelium of patients with active celiac disease and RCS

IL-15 is a poorly secreted cytokine hardly detectable by enzyme-linked immunosorbent assay.23, 24 In contrast, cells synthesizing IL-15 can be detected by immunohistochemistry.25 Therefore, IL-15 protein expression was first analyzed by immunohistochemistry on formol-fixed sections of small intestinal biopsy specimens from patients with celiac disease and RCS because this fixative is well suited for detection of intracellular antigens. As shown in Figure 1, in histologically normal control

Discussion

Altered homeostasis of IELs is a hallmark of celiac disease not explained by the current pathogenic scheme. A role for IL-15, a cytokine with a key role in homeostasis of murine IELs,15 was indirectly suggested by our previous work showing induction of CD94 on IELs of patients with celiac disease.4 Herein, we show for the first time that IL-15 is exposed at the surface of enterocytes in patients with active celiac disease and RCS and provide direct evidence for a role of enterocyte-derived

Acknowledgements

The authors thank the members of the French Celiac Disease Study Group, particularly Y. Bouhnik, A. Lavergne-Slove, P. Desreumaux, and J. C. Delchier, for providing information and samples from their patients as well as O. Hermine for helpful discussion.

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    ☆

    Supported by INSERM (Réseau Progrès), Assistance Publique des Hôpitaux de Paris (PHRC96096), La Fondation pour la Recherche sur le Cancer (ARC9216), and La Fondation Princesse Grace de Monaco. J.-J.M. has a fellowship from the Institut Danone, and M.B.A. has a fellowship from INSERM.

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    Copyright © 2003 American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.