Wheat Amylase Trypsin Inhibitors Drive Intestinal Inflammation via Activation of Toll-Like Receptor 4

J Exp Med. 2012 Dec 17;209(13):2395-408. doi: 10.1084/jem.20102660. Epub 2012 Dec 3.

Abstract

Ingestion of wheat, barley, or rye triggers small intestinal inflammation in patients with celiac disease. Specifically, the storage proteins of these cereals (gluten) elicit an adaptive Th1-mediated immune response in individuals carrying HLA-DQ2 or HLA-DQ8 as major genetic predisposition. This well-defined role of adaptive immunity contrasts with an ill-defined component of innate immunity in celiac disease. We identify the α-amylase/trypsin inhibitors (ATIs) CM3 and 0.19, pest resistance molecules in wheat, as strong activators of innate immune responses in monocytes, macrophages, and dendritic cells. ATIs engage the TLR4-MD2-CD14 complex and lead to up-regulation of maturation markers and elicit release of proinflammatory cytokines in cells from celiac and nonceliac patients and in celiac patients' biopsies. Mice deficient in TLR4 or TLR4 signaling are protected from intestinal and systemic immune responses upon oral challenge with ATIs. These findings define cereal ATIs as novel contributors to celiac disease. Moreover, ATIs may fuel inflammation and immune reactions in other intestinal and nonintestinal immune disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Celiac Disease / etiology*
  • Celiac Disease / immunology*
  • Celiac Disease / metabolism
  • Cell Line
  • Gliadin / adverse effects
  • Gliadin / immunology
  • HEK293 Cells
  • Hordeum / adverse effects
  • Hordeum / genetics
  • Hordeum / immunology
  • Humans
  • Immunity, Innate
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Myeloid Differentiation Factor 88 / deficiency
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • Plant Proteins / adverse effects*
  • Plant Proteins / genetics
  • Plant Proteins / immunology*
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Toll-Like Receptor 4 / deficiency
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*
  • Triticum / adverse effects*
  • Triticum / genetics
  • Triticum / immunology
  • Trypsin Inhibitors / adverse effects*
  • Trypsin Inhibitors / genetics
  • Trypsin Inhibitors / immunology*
  • U937 Cells

Substances

  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Plant Proteins
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Trypsin Inhibitors
  • WDAI-3 protein, Triticum aestivum
  • Gliadin