Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice.
Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice.
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麸质敏感 HLA-DQ8 转基因小鼠中麦醇溶蛋白依赖性神经肌肉和上皮分泌反应。
DOI：
10.1152/ajpgi.00225.2007
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Murray,JA
中科院分区：
文献类型：
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作者：
Verdu,EF;Huang,X;Natividad,J;Lu,J;Blennerhassett,PA;David,CS;McKay,DM;Murray,JA
乳糜泻是由针对人类白细胞抗原（HLA）-DQ 2和DQ 8结合的谷蛋白肽的T细胞应答引起的谷蛋白不耐受。一些受试者在没有绒毛萎缩的情况下出现胃肠道症状。在这里，我们研究了谷蛋白敏感的HLA-DQ 8转基因小鼠肠道功能障碍的潜在机制。将HLA-DQ 8小鼠致敏并用麦胶蛋白3×/wk灌胃3 wk（G/G）。对照组包括：1）非致敏小鼠灌胃大米（C）;2）麦醇溶蛋白致敏小鼠灌胃大米（G/R）; 3）BSA致敏小鼠灌胃BSA（BSA/BSA）。测定CD 3+上皮内淋巴细胞、巨噬细胞和FOX-P3阳性细胞计数。测定乙酰胆碱释放、小肠收缩力和上皮离子转运。在面筋撤除后和在HLA-DQ 6小鼠中研究肠道功能。在G/G小鼠中未观察到肠萎缩。在G/G中观察到上皮内淋巴细胞、巨噬细胞和FOX-P3+细胞的募集，但在C、G/R或BSA/BSA小鼠中未观察到。这是由肌间神经丛的乙酰胆碱释放增加，肌肉过度收缩，并增加G/G小鼠的主动离子转运。在麸质戒断后，DQ 8小鼠中肌肉收缩性的变化正常化。HLA-DQ 6对照没有表现出在DQ 8小鼠中观察到的肠功能异常。HLA-DQ 8小鼠中的谷蛋白敏感性在不存在肠萎缩的情况下诱导免疫活化。这与胆碱能功能障碍和分泌前状态有关，可能导致水运动改变和运动障碍。这些结果提供了一种机制，通过这种机制，麸质可以诱导具有遗传易感性但没有完全演变为乳糜泻的患者的肠道功能障碍。
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 3×/wk for 3 wk (G/G). Controls included1) nonsensitized mice gavaged with rice (C);2) gliadin-sensitized mice gavaged with rice (G/R); and3) 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.