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Science 27 September 2002:
Vol. 297. no. 5590, pp. 2275 - 2279
DOI: 10.1126/science.1074129
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Reports

Structural Basis for Gluten Intolerance in Celiac Sprue

Lu Shan,1 Øyvind Molberg,5 Isabelle Parrot,1 Felix Hausch,1 Ferda Filiz,1 Gary M. Gray,2 Ludvig M. Sollid,5 Chaitan Khosla134*

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.

1 Department of Chemical Engineering,
2 Department of Medicine,
3 Department of Chemistry, and
4 Department of Biochemistry, Stanford University, Stanford, CA 94305-5025, USA.
5 Institute of Immunology, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway.
*   To whom correspondence should be addressed. E-mail: ck{at}chemeng.stanford.edu

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