title: Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4.
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.
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Junker
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zeissig
authors.forename: Seong-Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Donatella
authors.initials: D
authors.lastname: Barisani
authors.forename: Herbert
authors.initials: H
authors.lastname: Wieser
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Leffler
authors.forename: Victor
authors.initials: V
authors.lastname: Zevallos
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
authors.forename: Simon
authors.initials: S
authors.lastname: Dillon
authors.forename: Tobias L
authors.initials: TL
authors.lastname: Freitag
authors.forename: Ciaran P
authors.initials: CP
authors.lastname: Kelly
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002446:Celiac Disease / Q000209:etiology* / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D005903:Gliadin / Q000009:adverse effects / Q000276:immunology; D057809:HEK293 Cells; D001467:Hordeum / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010940:Plant Proteins / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014908:Triticum / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology; D014361:Trypsin Inhibitors / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D020298:U937 Cells
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010940:Plant Proteins; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014361:Trypsin Inhibitors; C060586:WDAI-3 protein, Triticum aestivum; D005903:Gliadin