Interleukin 21 contributes to the mucosal T helper cell type 1 response in coeliac disease.
BACKGROUND
In coeliac disease (CD), the upper bowel lesion is associated with a marked infiltration of the mucosa with Th1 cells secreting interferon gamma (IFNgamma) and expressing the Th1-associated transcription factor, T-bet. However, the molecular mechanisms which regulate T-bet and promote the Th1 cell response are unknown.


OBJECTIVE
To examine whether interleukin 21 (IL21), a cytokine that regulates T cell activation, has a role in CD.


METHODS
Duodenal mucosal samples were taken from CD patients and normal controls. IL21 and T-bet were examined by real-time PCR and western blotting, and IFNgamma was assessed by real-time PCR and ELISA. The effect of blockade of endogenous IL21 on the expression of T-bet was examined in an ex vivo culture of biopsies taken from untreated CD patients. Finally, the role of IL21 in controlling T-bet and IFNgamma was also evaluated in cultures of biopsies taken from treated CD patients and cultured with a peptic-tryptic digest of gliadin (PT) in the presence or absence of a neutralising IL21 antibody.


RESULTS
Enhanced IL21 RNA and protein expression was seen in duodenal samples from untreated CD patients. Blockade of IL21 activity in biopsies of untreated CD patients reduced T-bet and IFNgamma secretion. Stimulation of treated CD biopsies with PT enhanced IL21 expression, and neutralisation of IL21 largely prevented PT-driven T-bet and IFNgamma induction.


CONCLUSIONS
IL21 is overproduced in the mucosa of CD patients, where it helps sustain T-bet expression and IFNgamma production.
Fina
D
D
Dipartimento di Medicina Interna e Centro di Eccellenza per lo studio delle malattie complesse e multifattoriali, Universitè Tor Vergata, Rome, Italy.
Sarra
M
M
Caruso
R
R
Del Vecchio Blanco
G
G
Pallone
F
F
MacDonald
T T
TT
Monteleone
G
G
D000328:Adult; D002446:Celiac Disease / Q000276:immunology*; D004386:Duodenum / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D005903:Gliadin / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology; D008875:Middle Aged; D009924:Organ Culture Techniques; D020825:T-Box Domain Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21
D007378:Interleukins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma; D005903:Gliadin; D000098546:Interleukin-21