title: Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice.
abstract: Celiac disease is a gluten intolerance caused by a T-cell response against human leukocyte antigen (HLA)-DQ2 and DQ8-bound gluten peptides. Some subjects experience gastrointestinal symptoms in the absence of villous atrophy. Here we investigate the potential mechanisms of gut dysfunction in gluten-sensitive HLA-DQ8 transgenic mice. HLA-DQ8 mice were sensitized and gavaged with gliadin 3x/wk for 3 wk (G/G). Controls included 1) nonsensitized mice gavaged with rice (C); 2) gliadin-sensitized mice gavaged with rice (G/R); and 3) BSA-sensitized mice gavaged with BSA (BSA/BSA). CD3(+) intraepithelial lymphocyte, macrophage, and FOX-P3-positive cell counts were determined. Acetylcholine release, small intestinal contractility, and epithelial ion transport were measured. Gut function was investigated after gluten withdrawal and in HLA-DQ6 mice. Intestinal atrophy was not observed in G/G mice. Recruitment of intraepithelial lymphocyte, macrophages, and FOX-P3+ cells were observed in G/G, but not in C, G/R, or BSA/BSA mice. This was paralleled by increased acetylcholine release from the myenteric plexus, muscle hypercontractility, and increased active ion transport in G/G mice. Changes in muscle contractility normalized in DQ8 mice after a gluten withdrawal. HLA-DQ6 controls did not exhibit the abnormalities in gut function observed in DQ8 mice. Gluten sensitivity in HLA-DQ8 mice induces immune activation in the absence of intestinal atrophy. This is associated with cholinergic dysfunction and a prosecretory state that may lead to altered water movements and dysmotility. The results provide a mechanism by which gluten could induce gut dysfunction in patients with a genetic predisposition but without fully evolved celiac disease.
authors.affiliation: Intestinal Disease Research Program, McMaster University, HSC 3N5C, Hamilton, Ontario, Canada. verdue@mcmaster.ca
authors.forename: E F
authors.initials: EF
authors.lastname: Verdu
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Natividad
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.forename: P A
authors.initials: PA
authors.lastname: Blennerhassett
authors.forename: C S
authors.initials: CS
authors.lastname: David
authors.forename: D M
authors.initials: DM
authors.lastname: McKay
authors.forename: J A
authors.initials: JA
authors.lastname: Murray
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000097:blood; D002217:Carbachol / Q000494:pharmacology; D002446:Celiac Disease / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005903:Gliadin / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D007419:Intestinal Secretions / Q000378:metabolism*; D007583:Jejunum / Q000187:drug effects / Q000276:immunology* / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction; D009469:Neuromuscular Junction / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000906:Antibodies; D018679:Cholinergic Agonists; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D002217:Carbachol; D005903:Gliadin; D000109:Acetylcholine