Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease

Maiuri, Luigi, Ciacci, Carolina, Ricciardelli, Ida, Vacca, Loredana, Raia, Valeria, Auricchio, Salvatore, Picard, Jean, Osman, Mohamed, Quaratino, Sonia and Londei, Marco (2003) Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. The Lancet, 362 (9377), 30-37. (doi:10.1016/S0140-6736(03)13803-2).

Abstract

Background: the adaptive immune system is central to the development of coeliac disease. Adaptive immune responses are, however, controlled by a preceding activation of the innate immune system. We investigated whether gliadin, a protein present in wheat flour, could activate an innate as well as an adaptive immune response in patients with coeliac disease.
Methods: duodenal biopsy samples from 42 patients with untreated coeliac disease, 37 treated patients, and 18 controls, were cultured in vitro for 3 h or 24 h, in the presence of either immunodominant gliadin epitopes (p?-2 and p?-9) or a non-immunodominant peptide (p31–43) known to induce small intestine damage in coeliac disease. We also incubated biopsy samples from nine untreated and six treated patients with a non-immunodominant peptide for 3 h, before incubation with immunodominant gliadin epitopes. Different combinations of interleukin-15 or signal transduction inhibitors were added to selected incubations.
Findings: only the non-immunodominant peptide induced rapid expression of interleukin-15, cd83, cyclo-oxygenase (COX)-2, and CD25 by CD3– cells (p=O005 vs medium alone) and enterocyte apoptosis (p<0·0001). Only the non-immunodominant peptide induced p38 MAP kinase activation in CD3– cells. Pre-incubation with the non-immunodominant peptide enabled immunodominant epitopes to induce T-cell activation (p=0·001) and enterocyte apoptosis. Inhibition of interleukin-15 or of p38 MAP kinase controlled such activity.
Interpretation: a gliadin fragment can activate the innate immune system, affecting the in situ T-cell recognition of dominant gliadin epitopes. Although our findings emphasise the key role of gliadin-specific T cells, they suggest a complex pathogenic situation, and show that inhibition of interleukin-15 or p38 MAP kinase might have the potential to control coeliac disease.

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