Paradoxical coexpression of proinflammatory and down-regulatory cytokines in intestinal T cells in childhood celiac disease.
OBJECTIVE
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)-gamma 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-gamma and IL-10 but no concomitant increases in tumor necrosis factor alpha, transforming growth factor beta1, or IL-2 and no induction of IL-4. A marked shift of IFN-gamma 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-gamma. Intraepithelial T lymphocytes in treated, symptom-free celiac patients still had increased IFN-gamma levels compared with controls.


CONCLUSIONS
In celiac patients, gluten intake seems to cause an overreaction in intraepithelial T lymphocytes, with uncontrolled production of IFN-gamma 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.
Departments of Clinical Microbiology, Immunology, and Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden.
Göte
G
Forsberg
Olle
O
Hernell
Silvia
S
Melgar
Anne
A
Israelsson
Sten
S
Hammarström
Marie-Louise
ML
Hammarström
D000293:Adolescent; D002446:Celiac Disease / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007223:Infant; D018836:Inflammation Mediators / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D013601:T-Lymphocytes / Q000378:metabolism*
D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger