Structural basis for gluten intolerance in Celiac sprue
Structural basis for gluten intolerance in Celiac sprue
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DOI：
10.1126/science.1074129
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发表时间：
2002-09-27
期刊：
影响因子：
56.9
通讯作者：
Khosla, C
中科院分区：
文献类型：
--
作者：
Shan, L;Molberg, O;Khosla, C
乳糜泻是一种广泛流行的小肠自身免疫性疾病，在遗传易感人群中因接触膳食麸质而诱发。鉴定出的 33 聚体肽具有多种特征，表明它是口炎性腹泻患者对麸质炎症反应的主要引发剂。对大鼠和人类的体外和体内研究表明，它对于所有胃、胰腺和肠刷状缘膜蛋白酶的分解都是稳定的。该肽与组织转谷氨酰胺酶（乳糜泻中的主要自身抗原）反应，其选择性比该胞外酶的已知天然底物高得多。它是来自 14 名乳糜泻患者中的 14 名肠道来源的人类 T 细胞系的有效诱导剂。在所有对乳糜泻患者有毒的粮食中都发现了这种肽的同系物，但在所有无毒粮食中都没有这种肽的同系物。通过暴露于细菌脯氨酰内肽酶，该肽可以在体外和体内试验中解毒，这提出了一种治疗乳糜泻的口服肽酶补充疗法的策略。
Celiac Sprue, a widely prevalent autoimmune disease of the small intestine, is induced in genetically susceptible individuals by exposure to dietary gluten. A 33-mer peptide was identified that has several characteristics suggesting it is the primary initiator of the inflammatory response to gluten in Celiac Sprue patients. In vitro and in vivo studies in rats and humans demonstrated that it is stable toward breakdown by all gastric, pancreatic, and intestinal brush-border membrane proteases. The peptide reacted with tissue transglutaminase, the major autoantigen in Celiac Sprue, with substantially greater selectivity than known natural substrates of this extracellular enzyme. It was a potent inducer of gut-derived human T cell lines from 14 of 14 Celiac Sprue patients. Homologs of this peptide were found in all food grains that are toxic to Celiac Sprue patients but are absent from all nontoxic food grains. The peptide could be detoxified in in vitro and in vivo assays by exposure to a bacterial prolyl endopeptidase, suggesting a strategy for oral peptidase supplement therapy for Celiac Sprue.