title: Non-celiac wheat sensitivity: differential diagnosis, triggers and implications.
abstract: Non allergy-non-celiac wheat sensitivity (NCWS) has become a common and often overrated diagnosis. Skepticism mainly relates to patients with prominent intestinal symptoms in the absence of general or intestinal signs of inflammation. There is consensus that the major wheat sensitivities, celiac disease and wheat allergy, have to be ruled out which may be difficult for wheat allergy. The non-inflammatory intolerances to carbohydrates, mainly lactose and FODMAPs (fermentable oligi-, di-, monosaccharides and polyols), which cause bloating or diarrhoea, can usually be excluded clinically or by simple tests. Recent studies and experimental data strongly indicate that NCWS exists in a substantial proportion of the population, that it is an innate immune reaction to wheat and that patients often present with extraintestinal symptoms, such as worsening of an underlying inflammatory disease in clear association with wheat consumption. Wheat amylase-trypsin inhibitors (ATIs) have been identified as the most likely triggers of NCWS. They are highly protease resistant and activate the toll-like receptor 4 (TLR4) complex in monocytes, macrophages and dendritic cells of the intestinal mucosa. Non-gluten containing cereals or staples display no or little TLR4 stimulating activity. Wheat ATIs are a family of up to 17 similar proteins of molecular weights around 15 kD and represent 2-4% of the wheat protein. With oral ingestion they costimulate antigen presenting cells and promote T cell activation in celiac disease, but also in other immune-mediated diseases within and outside the GI tract.
authors.affiliation: Institute for Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany; Celiac Center, Beth Israel Deaconess Medical Center, and Harvard Celiac Center, Harvard Medical School, Boston, MA, USA. Electronic address: detlef.schuppan@unimedizin-mainz.de.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.affiliation: Institute for Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Geethanjali
authors.initials: G
authors.lastname: Pickert
authors.affiliation: Institute for Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashfaq-Khan
authors.affiliation: Institute for Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Victor
authors.initials: V
authors.lastname: Zevallos
mesh_terms: D002446:Celiac Disease / Q000175:diagnosis; D003937:Diagnosis, Differential; D006801:Humans; D021182:Wheat Hypersensitivity / Q000175:diagnosis*
keywords: ATI; Adaptive; Allergy; Barley; CNS; Dendritic cell; Extraintestinal; Gliadin; Intestine; Macrophage; Monocyte; Rye