18006603

pubmed:Citation

1

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.

eng

IM

MEDLINE

0193-1857

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NLM

G217-25

pubmed-meshheading:18006603-Acetylcholine, pubmed-meshheading:18006603-Animals, pubmed-meshheading:18006603-Antibodies, pubmed-meshheading:18006603-Carbachol, pubmed-meshheading:18006603-Celiac Disease, pubmed-meshheading:18006603-Cholinergic Agonists, pubmed-meshheading:18006603-Disease Models, Animal, pubmed-meshheading:18006603-Forkhead Transcription Factors, pubmed-meshheading:18006603-Gliadin, pubmed-meshheading:18006603-HLA-DQ Antigens, pubmed-meshheading:18006603-Immunity, Innate, pubmed-meshheading:18006603-Intestinal Mucosa, pubmed-meshheading:18006603-Intestinal Secretions, pubmed-meshheading:18006603-Jejunum, pubmed-meshheading:18006603-Lymphocytes, pubmed-meshheading:18006603-Macrophages, pubmed-meshheading:18006603-Membrane Potentials, pubmed-meshheading:18006603-Mice, pubmed-meshheading:18006603-Mice, Transgenic, pubmed-meshheading:18006603-Muscle Contraction, pubmed-meshheading:18006603-Neuromuscular Junction

Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice.

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