Gastroenterology

Gastroenterology

Volume 123, Issue 3, September 2002, Pages 667-678
Gastroenterology

Clinical–Alimentary Tract
Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease,☆☆

https://doi.org/10.1053/gast.2002.35355Get rights and content

Abstract

Background & Aims: Specific T-lymphocyte reactions are central in the pathogenesis of celiac disease, an inflammatory small-bowel enteropathy caused by a permanent intolerance to gluten. To delineate local T-lymphocyte responses to gluten, the cytokine expression in jejunal T lymphocytes of pediatric celiac patients with active disease, i.e., untreated and gluten-challenged celiac patients, was determined and compared with that of treated, symptom-free celiac patients and controls. Methods: Biopsy samples were collected from celiac patients and controls. Intraepithelial and lamina propria T lymphocytes were isolated separately, and the cytokine messenger RNA levels were determined by using quantitative real-time reverse-transcription polymerase chain reaction. Interferon (IFN)-γ and interleukin (IL)-10 were determined at the protein level by immunohistochemistry. Results: Active celiac disease was characterized by distortions in cytokine expression by T lymphocytes, with highly significant increases of IFN-γ and IL-10 but no concomitant increases in tumor necrosis factor α, transforming growth factor β1, or IL-2 and no induction of IL-4. A marked shift of IFN-γ and IL-10 production from the lamina propria to the epithelium was characteristic of active celiac disease, and as many as one fourth of the intraepithelial lymphocytes expressed IFN-γ. Intraepithelial T lymphocytes in treated, symptom-free celiac patients still had increased IFN-γ levels compared with controls. Conclusions: In celiac patients, gluten intake seems to cause an overreaction in intraepithelial T lymphocytes, with uncontrolled production of IFN-γ and IL-10. This may cause both recruitment of intraepithelial lymphocytes and a leaky epithelium, leading to a vicious circle with amplified immune activity and establishment of intestinal lesions.

GASTROENTEROLOGY 2002;123:667-678

Section snippets

Patients and biopsy sampling

Intestinal biopsy specimens were collected from children admitted to the Department of Pediatrics at the University Hospital of Northern Sweden, Umeå, on suspicion of CD. One or two adjacent biopsy specimens were collected from distal duodenum/proximal jejunum at the region of the ligament of Treitz by using a Watson pediatric capsule; part of 1 biopsy sample was used for routine pathology examination and grading by the Alexander score14 and the rest for cytokine analyses. On the same day, a

Study design, T-cell isolation, and preliminary cytokine mRNA screening

T cells were isolated from the epithelial (CD3+ IEL) and lamina propria (CD3+ LPL) compartments of jejunum biopsy samples from children with CD and control patients with no known food intolerance and proven normal intestinal histology (Figure 1A and B). Biopsy specimens from CD patients were from patients presenting with active disease (untreated CD), from patients treated with a glutenfree diet for more than 7 months with normalized histology (treated CD), and from patients challenged with a

Discussion

To the best of our knowledge this is the first study in which the cytokine mRNA expression in isolated intestinal T cells of children has been determined in the absence of in vitro stimulation. The experimental approach using real-time quantitative RT-PCR in combination with the unique clinical material from children belonging to CD patients with active and inactive disease or patients with no known food intolerance has generated several novel insights. First, T cells in the normal small

Acknowledgements

The skillful technical assistance of Marianne Sjöstedt, Elisabeth Granström, and Yvonne Andersson is gratefully acknowledged.

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    Address requests for reprints to: Prof. Marie-Louise Hammarström, Immunology, Umeå University, SE-90185 Umeå, Sweden. e-mail: [email protected]; fax: (46) 90-7852250.

    ☆☆

    Supported by grants from the Swedish Natural Science Research Council (to M.-L.H), the Swedish Foundation for Health Care Sciences and Allergy Research (to M.-L.H and O.H.), the Swedish Medical Research Council (to O.H.), the Medical Faculty of Umeå University (to M.-L.H.), and the County of Västerbotten (to O.H. and M.-L. H.).

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