{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:20:21Z","timestamp":1791296421065,"version":"4.1.0"},"reference-count":44,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5590","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2002,9,27]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1126\/science.1074129","type":"journal-article","created":{"date-parts":[[2002,9,27]],"date-time":"2002-09-27T12:24:54Z","timestamp":1033129494000},"page":"2275-2279","source":"Crossref","is-referenced-by-count":1327,"title":["Structural Basis for Gluten Intolerance in Celiac Sprue"],"prefix":"10.1126","volume":"297","author":[{"given":"Lu","family":"Shan","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d8yvind","family":"Molberg","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Parrot","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Hausch","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferda","family":"Filiz","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary M.","family":"Gray","sequence":"additional","affiliation":[{"name":"Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludvig M.","family":"Sollid","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaitan","family":"Khosla","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering,"},{"name":"Department of Chemistry, and"},{"name":"Department of Biochemistry, Stanford University, Stanford, CA 94305\u20135025, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2000.8521"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.47.6.743"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.18.1.53"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(96)70237-4"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(01)05554-4"},{"key":"e_1_3_1_7_2","unstructured":"The family of storage proteins in cereals also includes secalins from rye and hordeins from barley. For review see ["},{"key":"e_1_3_1_7_3","doi-asserted-by":"publisher","DOI":"10.1016\/0950-3528(95)90027-6"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.1953.tb05563.x"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.4.603"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/73200"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0797-797"},{"key":"e_1_3_1_12_2","unstructured":"The extracellular tissue transglutaminase is the primary autoantigen in Celiac Sprue ( 10 )."},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.169.1.345"},{"key":"e_1_3_1_14_2","unstructured":"The class II HLA DQ2 molecule is expressed in >90% of Celiac Sprue patients (12)."},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.46.1.46"},{"key":"e_1_3_1_16_2","unstructured":"Materials and methods are available as supporting online material on Science Online."},{"key":"e_1_3_1_17_2","unstructured":"Single-letter abbreviations for the amino acid residues are as follows: A Ala; C Cys; D Asp; E Glu; F Phe; G Gly; H His; I Ile; K Lys; L Leu; M Met; N Asn; P Pro; Q Gln; R Arg; S Ser; T Thr; V Val; W Trp; and Y Tyr."},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.35381"},{"key":"e_1_3_1_19_2","unstructured":"L. Shan et al. unpublished data."},{"key":"e_1_3_1_20_2","unstructured":"G. M. Gray. Handbook of Physiology R.A. Frizzell M. Field Eds. (Oxford Univ. Press New York 1991) pp. 411\u2013420."},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(20)81990-5"},{"key":"e_1_3_1_22_2","unstructured":"F. Hausch L. Shan N. A. Santiago G. M. Gray C. Khosla Am. J. Physiol. in press."},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI108818"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200105)31:5<1317::AID-IMMU1317>3.0.CO;2-I"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi011715x"},{"key":"e_1_3_1_26_2","unstructured":"For example the specificity of tTGase for the \u03b1-gliadin\u2013derived peptide PQPQLPYPQPQLPY is fivefold higher than that for its target peptide sequence in fibrinogen its natural substrate ( 24 )."},{"key":"e_1_3_1_27_2","unstructured":"k cat \/K M = 440 min \u22121 mM \u22121 for LQLQPFPQPQLPYPQPQLPYPQPQLPYPQPQPF compared with k cat \/K M = 82 min \u22121 mM \u22121 for PQPQLPY ( 24 ) and k cat \/K M = 350 min \u22121 mM \u22121 for PQPQLPYPQPQLPY."},{"key":"e_1_3_1_28_2","unstructured":"G. D'Argenio"},{"key":"e_1_3_1_28_3","doi-asserted-by":"publisher","DOI":"10.1159\/000469123"},{"key":"e_1_3_1_29_2","unstructured":"T cell clones and T cell lines were established from small intestinal biopsies of adult HLA DQ2\u2013positive Celiac Sprue patients as described (8). Stimulation of T cells by peptides was measured by a [ 3 H]-thymidine incorporation assay. HLA DQ2 homozygous Epstein Barr virus\u2013transformed B cell lines were used as antigen presenting cells."},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80629-9"},{"key":"e_1_3_1_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80177-6"},{"key":"e_1_3_1_32_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.4.717"},{"key":"e_1_3_1_33_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.241504598"},{"key":"e_1_3_1_34_2","unstructured":"The stable peptide homologs to the 33-mer \u03b12-gliadin peptide are QPQPFPPQLPYPQTQPFPPQQPYPQPQPQYPQPQ (from \u03b11- and \u03b16-gliadins); QQQPFPQQPIPQQPQPYPQQPQPYPQQPFPPQQPF (from B1 hordein); QPFPQPQQTFPQQPQLPFPQQPQQPFPQPQ (from \u03b3-gliadin); QPFPQPQQPTPIQPQQPFPQRPQQPFPQPQ (from \u03c9-secalin)."},{"key":"e_1_3_1_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830210509"},{"key":"e_1_3_1_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004390100607"},{"key":"e_1_3_1_37_2","unstructured":"k cat \/K M = 121 min \u22121 mM \u22121 for APQPGPQPGPQPPQPPQPPQPPQRQPEAPAPQPPAGRELS from pertactin. k cat \/K M = 37 min \u22121 mM \u22121 for PQPPPQLQPQPQPQPQPQPPPQPQPQPQPQPQPQPQPQPQ from the human protein-tyrosine phosphatase."},{"key":"e_1_3_1_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/283162a0"},{"key":"e_1_3_1_39_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi9921337"},{"key":"e_1_3_1_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(01)00298-9"},{"key":"e_1_3_1_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0896(98)00145-X"},{"key":"e_1_3_1_42_2","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.33606"},{"key":"e_1_3_1_43_2","unstructured":"We thank H. Arentz-Hansen for providing the \u03b1-2 gliadin gene and R. Castillo for use of his laboratory for animal procedures performed in this study. We also thank M. Davis (Stanford Univ.) and C. T. Walsh (Harvard Univ.) for their critical reading of the manuscript and for their helpful suggestions. Supported by the Alan T. Waterman Award from the National Science Foundation (to C.K.) and by grants from the Research Council of Norway and the European Commission (to L.M.S.). L.S. is a recipient of the Stanford Graduate Fellowship and I.P. is a recipient of a postdoctoral fellowship from Fondation pour la Recherche Medicale."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.1074129","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T21:19:34Z","timestamp":1704835174000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.1074129"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,9,27]]},"references-count":44,"journal-issue":{"issue":"5590","published-print":{"date-parts":[[2002,9,27]]}},"alternative-id":["10.1126\/science.1074129"],"URL":"https:\/\/doi.org\/10.1126\/science.1074129","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1004210.150007","asserted-by":"object"}]},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,9,27]]}}}