Association Between Innate Response to Gliadin and Activation of Pathogenic T Cells in Coeliac Disease

Lancet. 2003 Jul 5;362(9377):30-7. 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(alpha)-2 and p(alpha)-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=0.005 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Celiac Disease / immunology*
  • Cells, Cultured
  • Disease Progression
  • Duodenum / immunology
  • Duodenum / pathology
  • Gliadin / immunology*
  • Humans
  • Immunity, Innate*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / pathology
  • Lymphocyte Activation*
  • Middle Aged
  • Peptide Fragments / immunology
  • T-Lymphocytes / immunology*

Substances

  • Peptide Fragments
  • Gliadin