Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease

Background and 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.