Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4
Open Access
- 3 December 2012
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 209 (13), 2395-2408
- https://doi.org/10.1084/jem.20102660
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.This publication has 53 references indexed in Scilit:
- Human T cell microparticles circulate in blood of hepatitis patients and induce fibrolytic activation of hepatic stellate cellsHepatology, 2010
- Elevating optimal human nutrition to a central goal of plant breeding and production of plant-based foodsPlant Science, 2009
- Between Celiac Disease and Irritable Bowel Syndrome: The “No Man's Land” of Gluten SensitivityThe American Journal of Gastroenterology, 2009
- Coeliac diseaseThe Lancet, 2009
- Allergenicity resulting from functional mimicry of a Toll-like receptor complex proteinNature, 2008
- Gliadin Induces an Increase in Intestinal Permeability and Zonulin Release by Binding to the Chemokine Receptor CXCR3Gastroenterology, 2008
- Recognition of microorganisms and activation of the immune responseNature, 2007
- Adaptive immune cells temper initial innate responsesNature Medicine, 2007
- Negative regulation of Toll-like receptor-mediated immune responsesNature Reviews Immunology, 2005
- Toll-like receptor control of the adaptive immune responsesNature Immunology, 2004