{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:15:30Z","timestamp":1793146530453,"version":"4.5.0"},"reference-count":76,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T00:00:00Z","timestamp":1719187200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T00:00:00Z","timestamp":1719187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Immunol"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100\u2009mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-\u03b3 response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an <jats:italic>HLA-DQ2<\/jats:italic>\/<jats:italic>HLA-DQ8<\/jats:italic> stratification based on gene doses to maximally eliminate the interferon-\u03b3-induced mucosal damage triggered by gluten.<\/jats:p>","DOI":"10.1038\/s41590-024-01867-0","type":"journal-article","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T10:02:51Z","timestamp":1719223371000},"page":"1218-1230","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease"],"prefix":"10.1038","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0336-0533","authenticated-orcid":false,"given":"Valeriia","family":"Dotsenko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Tewes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5400-3600","authenticated-orcid":false,"given":"Martin","family":"Hils","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Pasternack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0849-5939","authenticated-orcid":false,"given":"Jorma","family":"Isola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3948-9555","authenticated-orcid":false,"given":"Juha","family":"Taavela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Popp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jani","family":"Sarin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heini","family":"Huhtala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauliina","family":"Hiltunen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Zimmermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4976-3629","authenticated-orcid":false,"given":"Ralf","family":"Mohrbacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Greinwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1713-5545","authenticated-orcid":false,"given":"Knut E. A.","family":"Lundin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4972-1293","authenticated-orcid":false,"given":"Detlef","family":"Schuppan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5053-3794","authenticated-orcid":false,"given":"Markku","family":"M\u00e4ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7167-5094","authenticated-orcid":false,"given":"Keijo","family":"Viiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"CEC-3 Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Kull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jari","family":"Koskenpato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Scheinin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marja-Leena","family":"L\u00e4hdeaho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurdag\u00fcl","family":"Zopf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Stallmach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ansgar W.","family":"Lohse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Fusco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jost","family":"Langhorst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helga Paula","family":"T\u00f6r\u00f6k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Byrnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juozas","family":"Kupcinskas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d8istein","family":"Hovde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f8rgen","family":"Jahnsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Biedermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Zeitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,24]]},"reference":[{"key":"1867_CR1","doi-asserted-by":"crossref","first-page":"507","DOI":"10.14309\/ajg.0000000000000523","volume":"115","author":"JA King","year":"2020","unstructured":"King, J. A. et al. Incidence of celiac disease is increasing over time: a systematic review and meta-analysis. Am. J. Gastroenterol. 115, 507\u2013525 (2020).","journal-title":"Am. J. Gastroenterol."},{"key":"1867_CR2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0140-6736(17)31796-8","volume":"391","author":"B Lebwohl","year":"2018","unstructured":"Lebwohl, B., Sanders, D. S. & Green, P. H. R. Coeliac disease. Lancet 391, 70\u201381 (2018).","journal-title":"Lancet"},{"key":"1867_CR3","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/nrgastro.2015.131","volume":"12","author":"DA Leffler","year":"2015","unstructured":"Leffler, D. A., Green, P. H. R. & Fasano, A. Extraintestinal manifestations of coeliac disease. Nat. Rev. Gastroenterol. Hepatol. 12, 561\u2013571 (2015).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"1867_CR4","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1016\/j.autrev.2018.05.013","volume":"17","author":"GJ Kahaly","year":"2018","unstructured":"Kahaly, G. J., Frommer, L. & Schuppan, D. Celiac disease and endocrine autoimmunity\u2014the genetic link. Autoimmun. Rev. 17, 1169\u20131175 (2018).","journal-title":"Autoimmun. Rev."},{"key":"1867_CR5","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1093\/ajcn\/nqx049","volume":"107","author":"JA Syage","year":"2018","unstructured":"Syage, J. A. et al. Determination of gluten consumption in celiac disease patients on a gluten-free diet. Am. J. Clin. Nutr. 107, 201\u2013207 (2018).","journal-title":"Am. J. Clin. Nutr."},{"key":"1867_CR6","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1053\/j.gastro.2019.12.016","volume":"158","author":"JA Silvester","year":"2020","unstructured":"Silvester, J. A. et al. Most patients with celiac disease on gluten-free diets consume measurable amounts of gluten. Gastroenterology 158, 1497\u20131499 (2020).","journal-title":"Gastroenterology"},{"key":"1867_CR7","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1097\/SGA.0000000000000377","volume":"42","author":"S Roos","year":"2019","unstructured":"Roos, S., Liedberg, G. M., Hellstr\u00f6m, I. & Wilhelmsson, S. Persistent symptoms in people with celiac disease despite gluten-free diet: a concern? Gastroenterol. Nurs. 42, 496\u2013503 (2019).","journal-title":"Gastroenterol. Nurs."},{"key":"1867_CR8","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1080\/00365521.2021.1930146","volume":"56","author":"F van Megen","year":"2021","unstructured":"van Megen, F. et al. High disease burden in treated celiac patients\u2014a web-based survey. Scand. J. Gastroenterol. 56, 882\u2013888 (2021).","journal-title":"Scand. J. Gastroenterol."},{"key":"1867_CR9","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.3390\/nu10111796","volume":"10","author":"A Itzlinger","year":"2018","unstructured":"Itzlinger, A., Branchi, F., Elli, L. & Schumann, M. Gluten-free diet in celiac disease\u2014forever and for all? Nutrients 10, 1796 (2018).","journal-title":"Nutrients"},{"key":"1867_CR10","doi-asserted-by":"crossref","unstructured":"Daveson, A. J. M. et al. Baseline quantitative histology in therapeutics trials reveals villus atrophy in most patients with coeliac disease who appear well controlled on gluten\u2010free diet. GastroHep 2, 22\u201330 (2020).","DOI":"10.1002\/ygh2.380"},{"key":"1867_CR11","doi-asserted-by":"crossref","first-page":"500","DOI":"10.3390\/nu12020500","volume":"12","author":"JM Kreutz","year":"2020","unstructured":"Kreutz, J. M., Adriaanse, M. P. M., van der Ploeg, E. M. C. & Vreugdenhil, A. C. E. Nutrient deficiencies in adults and children with treated and untreated celiac disease. Nutrients 12, 500 (2020).","journal-title":"Nutrients"},{"key":"1867_CR12","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1016\/j.clnu.2016.05.002","volume":"35","author":"G Vici","year":"2016","unstructured":"Vici, G., Belli, L., Biondi, M. & Polzonetti, V. Gluten free diet and nutrient deficiencies: a review. Clin. Nutr. 35, 1236\u20131241 (2016).","journal-title":"Clin. Nutr."},{"key":"1867_CR13","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.jcmgh.2020.07.010","volume":"11","author":"V Dotsenko","year":"2021","unstructured":"Dotsenko, V. et al. Genome-wide transcriptomic analysis of intestinal mucosa in celiac disease patients on a gluten-free diet and postgluten challenge. Cell. Mol. Gastroenterol. Hepatol. 11, 13\u201332 (2021).","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"1867_CR14","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/nm0797-797","volume":"3","author":"W Dieterich","year":"1997","unstructured":"Dieterich, W. et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat. Med. 3, 797\u2013801 (1997).","journal-title":"Nat. Med."},{"key":"1867_CR15","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/nm0698-713","volume":"4","author":"\u00d8 Molberg","year":"1998","unstructured":"Molberg, \u00d8. et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat. Med. 4, 713\u2013717 (1998).","journal-title":"Nat. Med."},{"key":"1867_CR16","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.4049\/jimmunol.161.4.1585","volume":"161","author":"Y van de Wal","year":"1998","unstructured":"van de Wal, Y. et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J. Immunol. 161, 1585\u20131588 (1998).","journal-title":"J. Immunol."},{"key":"1867_CR17","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1097\/MOG.0000000000000041","volume":"30","author":"KEA Lundin","year":"2014","unstructured":"Lundin, K. E. A. & Sollid, L. M. Advances in coeliac disease. Curr. Opin. Gastroenterol. 30, 154\u2013162 (2014).","journal-title":"Curr. Opin. Gastroenterol."},{"key":"1867_CR18","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1053\/j.gastro.2009.09.008","volume":"137","author":"D Schuppan","year":"2009","unstructured":"Schuppan, D., Junker, Y. & Barisani, D. Celiac disease: from pathogenesis to novel therapies. Gastroenterology 137, 1912\u20131933 (2009).","journal-title":"Gastroenterology"},{"key":"1867_CR19","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1056\/NEJMoa2032441","volume":"385","author":"D Schuppan","year":"2021","unstructured":"Schuppan, D. et al. A randomized trial of a transglutaminase 2 inhibitor for celiac disease. N. Engl. J. Med. 385, 35\u201345 (2021).","journal-title":"N. Engl. J. Med."},{"key":"1867_CR20","doi-asserted-by":"crossref","first-page":"12390","DOI":"10.1073\/pnas.2135229100","volume":"100","author":"W Vader","year":"2003","unstructured":"Vader, W. et al. The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc. Natl Acad. Sci. USA 100, 12390\u201312395 (2003).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1867_CR21","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s00281-012-0321-0","volume":"34","author":"F Koning","year":"2012","unstructured":"Koning, F. Celiac disease: quantity matters. Semin. Immunopathol. 34, 541\u2013549 (2012).","journal-title":"Semin. Immunopathol."},{"key":"1867_CR22","doi-asserted-by":"crossref","first-page":"108819","DOI":"10.1016\/j.celrep.2021.108819","volume":"34","author":"GA Busslinger","year":"2021","unstructured":"Busslinger, G. A. et al. Human gastrointestinal epithelia of the esophagus, stomach, and duodenum resolved at single-cell resolution. Cell Rep. 34, 108819 (2021).","journal-title":"Cell Rep."},{"key":"1867_CR23","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1186\/1471-2105-10-307","volume":"10","author":"P T\u00f6r\u00f6nen","year":"2009","unstructured":"T\u00f6r\u00f6nen, P., Ojala, P. J., Marttinen, P. & Holm, L. Robust extraction of functional signals from gene set analysis using a generalized threshold free scoring function. BMC Bioinformatics 10, 307 (2009).","journal-title":"BMC Bioinformatics"},{"key":"1867_CR24","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1124\/jpet.111.187385","volume":"341","author":"TR DiRaimondo","year":"2012","unstructured":"DiRaimondo, T. R., Kl\u00f6ck, C. & Khosla, C. Interferon-\u03b3 activates transglutaminase 2 via a phosphatidylinositol-3-kinase-dependent pathway: implications for celiac sprue therapy. J. Pharmacol. Exp. Ther. 341, 104\u2013114 (2012).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"1867_CR25","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1136\/gut.2007.129882","volume":"57","author":"D Fina","year":"2008","unstructured":"Fina, D. et al. Interleukin 21 contributes to the mucosal T helper cell type 1 response in coeliac disease. Gut 57, 887\u2013892 (2008).","journal-title":"Gut"},{"key":"1867_CR26","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.3390\/cells11101667","volume":"11","author":"C B\u00fcchold","year":"2022","unstructured":"B\u00fcchold, C. et al. Features of ZED1227: the first-in-class tissue transglutaminase inhibitor undergoing clinical evaluation for the treatment of celiac disease. Cells 11, 1667 (2022).","journal-title":"Cells"},{"key":"1867_CR27","doi-asserted-by":"crossref","first-page":"10815","DOI":"10.3390\/ijms241310815","volume":"24","author":"J Isola","year":"2023","unstructured":"Isola, J. et al. The oral transglutaminase 2 inhibitor ZED1227 accumulates in the villous enterocytes in celiac disease patients during gluten challenge and drug treatment. Int. J. Mol. Sci. 24, 10815 (2023).","journal-title":"Int. J. Mol. Sci."},{"key":"1867_CR28","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/nature03988","volume":"437","author":"G Pascual","year":"2005","unstructured":"Pascual, G. et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-\u03b3. Nature 437, 759\u2013763 (2005).","journal-title":"Nature"},{"key":"1867_CR29","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/ni1005-966","volume":"6","author":"ST Bailey","year":"2005","unstructured":"Bailey, S. T. & Ghosh, S. \u2018PPAR\u2019ting ways with inflammation. Nat. Immunol. 6, 966\u2013967 (2005).","journal-title":"Nat. Immunol."},{"key":"1867_CR30","doi-asserted-by":"crossref","first-page":"199","DOI":"10.2119\/molmed.2009.00173","volume":"16","author":"MP Simula","year":"2010","unstructured":"Simula, M. P. et al. PPAR signaling pathway and cancer-related proteins are involved in celiac disease-associated tissue damage. Mol. Med. 16, 199\u2013209 (2010).","journal-title":"Mol. Med."},{"key":"1867_CR31","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1136\/gut.2009.183608","volume":"59","author":"A Luciani","year":"2010","unstructured":"Luciani, A. et al. Lysosomal accumulation of gliadin p31-43 peptide induces oxidative stress and tissue transglutaminase-mediated PPARgamma downregulation in intestinal epithelial cells and coeliac mucosa. Gut 59, 311\u2013319 (2010).","journal-title":"Gut"},{"key":"1867_CR32","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1038\/nri912","volume":"2","author":"RA Daynes","year":"2002","unstructured":"Daynes, R. A. & Jones, D. C. Emerging roles of PPARS in inflammation and immunity. Nat. Rev. Immunol. 2, 748\u2013759 (2002).","journal-title":"Nat. Rev. Immunol."},{"key":"1867_CR33","first-page":"29","volume":"77","author":"J ter Steege","year":"1997","unstructured":"ter Steege, J., Buurman, W., Arends, J. W. & Forget, P. Presence of inducible nitric oxide synthase, nitrotyrosine, CD68, and CD14 in the small intestine in celiac disease. Lab. Investig. J. Tech. Methods Pathol. 77, 29\u201336 (1997).","journal-title":"Lab. Investig. J. Tech. Methods Pathol."},{"key":"1867_CR34","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s00210-003-0771-y","volume":"368","author":"MC Maiuri","year":"2003","unstructured":"Maiuri, M. C. et al. Gliadin increases iNOS gene expression in interferon-\u03b3-stimulated RAW 264.7 cells through a mechanism involving NF-\u03baB. Naunyn. Schmiedebergs Arch. Pharmacol. 368, 63\u201371 (2003).","journal-title":"Naunyn. Schmiedebergs Arch. Pharmacol."},{"key":"1867_CR35","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.cccn.2005.01.029","volume":"356","author":"I Daniels","year":"2005","unstructured":"Daniels, I., Cavill, D., Murray, I. A. & Long, R. G. Elevated expression of iNOS mRNA and protein in coeliac disease. Clin. Chim. Acta 356, 134\u2013142 (2005).","journal-title":"Clin. Chim. Acta"},{"key":"1867_CR36","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1097\/00042737-200310000-00005","volume":"15","author":"IA Murray","year":"2003","unstructured":"Murray, I. A., Bullimore, D. W. & Long, R. G. Fasting plasma nitric oxide products in coeliac disease. Eur. J. Gastroenterol. Hepatol. 15, 1091\u20131095 (2003).","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"1867_CR37","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1126\/science.284.5416.951","volume":"284","author":"A Diefenbach","year":"1999","unstructured":"Diefenbach, A., Schindler, H., R\u00f6llinghoff, M., Yokoyama, W. M. & Bogdan, C. Requirement for type 2 NO synthase for IL-12 signaling in innate immunity. Science 284, 951\u2013955 (1999).","journal-title":"Science"},{"key":"1867_CR38","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1093\/bioinformatics\/btz474","volume":"36","author":"R Orenbuch","year":"2020","unstructured":"Orenbuch, R. et al. arcasHLA: high-resolution HLA typing from RNAseq. Bioinformatics 36, 33\u201340 (2020).","journal-title":"Bioinformatics"},{"key":"1867_CR39","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1172\/JCI27620","volume":"116","author":"S Tollefsen","year":"2006","unstructured":"Tollefsen, S. et al. HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. J. Clin. Invest. 116, 2226\u20132236 (2006).","journal-title":"J. Clin. Invest."},{"key":"1867_CR40","doi-asserted-by":"crossref","first-page":"13611","DOI":"10.1074\/jbc.M111.320374","volume":"287","author":"S Tollefsen","year":"2012","unstructured":"Tollefsen, S. et al. Structural and functional studies of trans-encoded HLA-DQ2.3 (DQA1*03:01\/DQB1*02:01) protein molecule. J. Biol. Chem. 287, 13611\u201313619 (2012).","journal-title":"J. Biol. Chem."},{"key":"1867_CR41","doi-asserted-by":"crossref","first-page":"e0144634","DOI":"10.1371\/journal.pone.0144634","volume":"10","author":"S Senger","year":"2015","unstructured":"Senger, S. et al. Celiac disease histopathology recapitulates Hedgehog downregulation, consistent with wound healing processes activation. PLoS ONE 10, e0144634 (2015).","journal-title":"PLoS ONE"},{"key":"1867_CR42","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/j.1365-2249.2007.03500.x","volume":"150","author":"K Juuti-Uusitalo","year":"2007","unstructured":"Juuti-Uusitalo, K., M\u00e4ki, M., Kainulainen, H., Isola, J. & Kaukinen, K. Gluten affects epithelial differentiation-associated genes in small intestinal mucosa of coeliac patients. Clin. Exp. Immunol. 150, 294\u2013305 (2007).","journal-title":"Clin. Exp. Immunol."},{"key":"1867_CR43","doi-asserted-by":"crossref","first-page":"76006","DOI":"10.1371\/journal.pone.0076006","volume":"8","author":"M Nanayakkara","year":"2013","unstructured":"Nanayakkara, M., Lania, G., Maglio, M., Kosova, R. & Sarno, M. Enterocyte proliferation and signaling are constitutively altered in celiac disease. PLoS ONE 8, 76006 (2013).","journal-title":"PLoS ONE"},{"key":"1867_CR44","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/eji.1830230231","volume":"23","author":"TS Halstensen","year":"1993","unstructured":"Halstensen, T. S. & Brandtzaeg, P. Activated T lymphocytes in the celiac lesion: non-proliferative activation (CD25) of CD4+ \u03b1\/\u03b2 cells in the lamina propria but proliferation (Ki-67) of \u03b1\/\u03b2 and \u03b3\/\u03b4 cells in the epithelium. Eur. J. Immunol. 23, 505\u2013510 (1993).","journal-title":"Eur. J. Immunol."},{"key":"1867_CR45","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1136\/gut.34.2.208","volume":"34","author":"T Kutlu","year":"1993","unstructured":"Kutlu, T. et al. Numbers of T cell receptor (TCR) \u03b1\u03b2+ but not of TCR \u03b3\u03b4+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet. Gut 34, 208\u2013214 (1993).","journal-title":"Gut"},{"key":"1867_CR46","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1042\/BC20100023","volume":"102","author":"U Laforenza","year":"2010","unstructured":"Laforenza, U. et al. Solute transporters and aquaporins are impaired in celiac disease. Biol. Cell 102, 457\u2013467 (2010).","journal-title":"Biol. Cell"},{"key":"1867_CR47","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-73288-6","volume":"10","author":"B Banaganapalli","year":"2020","unstructured":"Banaganapalli, B. et al. Exploring celiac disease candidate pathways by global gene expression profiling and gene network cluster analysis. Sci. Rep. 10, 16290 (2020).","journal-title":"Sci. Rep."},{"key":"1867_CR48","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1136\/gut.2005.086637","volume":"56","author":"MV Barone","year":"2007","unstructured":"Barone, M. V. et al. Growth factor-like activity of gliadin, an alimentary protein: implications for coeliac disease. Gut 56, 480\u2013488 (2007).","journal-title":"Gut"},{"key":"1867_CR49","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/S0140-6736(03)13803-2","volume":"362","author":"L Maiuri","year":"2003","unstructured":"Maiuri, L. et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 362, 30\u201337 (2003).","journal-title":"Lancet"},{"key":"1867_CR50","doi-asserted-by":"crossref","first-page":"4385","DOI":"10.1007\/s00018-018-2898-5","volume":"75","author":"H Bragde","year":"2018","unstructured":"Bragde, H., Jansson, U., Fredrikson, M., Grodzinsky, E. & S\u00f6derman, J. Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies. Cell. Mol. Life Sci. 75, 4385\u20134401 (2018).","journal-title":"Cell. Mol. Life Sci."},{"key":"1867_CR51","doi-asserted-by":"crossref","first-page":"562434","DOI":"10.3389\/fgene.2020.562434","volume":"11","author":"A van der Graaf","year":"2020","unstructured":"van der Graaf, A. et al. Systematic prioritization of candidate genes in disease loci identifies TRAFD1 as a master regulator of IFN\u03b3 signaling in celiac disease. Front. Genet. 11, 562434 (2020).","journal-title":"Front. Genet."},{"key":"1867_CR52","doi-asserted-by":"crossref","first-page":"e0212329","DOI":"10.1371\/journal.pone.0212329","volume":"14","author":"J Bajor","year":"2019","unstructured":"Bajor, J. et al. Classical celiac disease is more frequent with a double dose of HLA-DQB1*02: a systematic review with meta-analysis. PLoS ONE 14, e0212329 (2019).","journal-title":"PLoS ONE"},{"key":"1867_CR53","first-page":"315","volume":"4","author":"A Al-Toma","year":"2006","unstructured":"Al-Toma, A. et al. Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma. Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc. 4, 315\u2013319 (2006).","journal-title":"Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc."},{"key":"1867_CR54","doi-asserted-by":"crossref","first-page":"518483","DOI":"10.1155\/2013\/518483","volume":"2013","author":"P Nijeboer","year":"2013","unstructured":"Nijeboer, P., van Wanrooij, R. L. J., Tack, G. J., Mulder, C. J. J. & Bouma, G. Update on the diagnosis and management of refractory coeliac disease. Gastroenterol. Res. Pract. 2013, 518483 (2013).","journal-title":"Gastroenterol. Res. Pract."},{"key":"1867_CR55","doi-asserted-by":"crossref","first-page":"7062","DOI":"10.1074\/jbc.M007894200","volume":"276","author":"KJ Waite","year":"2001","unstructured":"Waite, K. J., Floyd, Z. E., Arbour-Reily, P. & Stephens, J. M. Interferon-gamma-induced regulation of peroxisome proliferator-activated receptor gamma and STATs in adipocytes. J. Biol. Chem. 276, 7062\u20137068 (2001).","journal-title":"J. Biol. Chem."},{"key":"1867_CR56","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jaut.2004.05.004","volume":"23","author":"MC Wapenaar","year":"2004","unstructured":"Wapenaar, M. C. et al. The interferon gamma gene in celiac disease: augmented expression correlates with tissue damage but no evidence for genetic susceptibility. J. Autoimmun. 23, 183\u2013190 (2004).","journal-title":"J. Autoimmun."},{"key":"1867_CR57","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1017\/S0007114521002488","volume":"127","author":"M Guennouni","year":"2022","unstructured":"Guennouni, M. et al. Gluten contamination in labelled gluten-free, naturally gluten-free and meals in food services in low-, middle- and high-income countries: a systematic review and meta-analysis. Br. J. Nutr. 127, 1528\u20131542 (2022).","journal-title":"Br. J. Nutr."},{"key":"1867_CR58","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-022-32691-5","volume":"13","author":"N Atlasy","year":"2022","unstructured":"Atlasy, N. et al. Single cell transcriptomic analysis of the immune cell compartment in the human small intestine and in celiac disease. Nat. Commun. 13, 4920 (2022).","journal-title":"Nat. Commun."},{"key":"1867_CR59","unstructured":"Clinical Trials Register. https:\/\/www.clinicaltrialsregister.eu\/ctr-search\/trial\/2017-002241-30\/LT"},{"key":"1867_CR60","doi-asserted-by":"crossref","first-page":"e76163","DOI":"10.1371\/journal.pone.0076163","volume":"8","author":"J Taavela","year":"2013","unstructured":"Taavela, J. et al. Validation of morphometric analyses of small-intestinal biopsy readouts in celiac disease. PLoS ONE 8, e76163 (2013).","journal-title":"PLoS ONE"},{"key":"1867_CR61","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1053\/j.gastro.2011.07.050","volume":"141","author":"T Sato","year":"2011","unstructured":"Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett\u2019s epithelium. Gastroenterology 141, 1762\u20131772 (2011).","journal-title":"Gastroenterology"},{"key":"1867_CR62","doi-asserted-by":"publisher","unstructured":"Dotsenko, V., Sioofy-Khojine, A.-B., Hy\u00f6ty, H. & Viiri, K. Human intestinal organoid models for celiac disease research. in Methods in Cell Biology (Academic Press, 2023). https:\/\/doi.org\/10.1016\/bs.mcb.2023.01.008","DOI":"10.1016\/bs.mcb.2023.01.008"},{"key":"1867_CR63","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1186\/s12876-019-1089-7","volume":"19","author":"J Taavela","year":"2019","unstructured":"Taavela, J. et al. Histological, immunohistochemical and mRNA gene expression responses in coeliac disease patients challenged with gluten using PAXgene fixed paraffin-embedded duodenal biopsies. BMC Gastroenterol. 19, 189 (2019).","journal-title":"BMC Gastroenterol."},{"key":"1867_CR64","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).","journal-title":"Genome Biol."},{"key":"1867_CR65","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","volume":"57","author":"Y Benjamini","year":"1995","unstructured":"Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B Methodol. 57, 289\u2013300 (1995).","journal-title":"J. R. Stat. Soc. Ser. B Methodol."},{"key":"1867_CR66","unstructured":"Alexa, A. & Rahnenfuhrer, J. topGO: enrichment analysis for Gene Ontology. (2022)."},{"key":"1867_CR67","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1039\/C5MB00663E","volume":"12","author":"G Yu","year":"2016","unstructured":"Yu, G. & He, Q.-Y. ReactomePA: an R\/Bioconductor package for Reactome pathway analysis and visualization. Mol. Biosyst. 12, 477\u2013479 (2016).","journal-title":"Mol. Biosyst."},{"key":"1867_CR68","doi-asserted-by":"publisher","unstructured":"T\u00f6r\u00f6nen, P., Ojala, P. J., Marttinen, P. & Holm, L. BMC Bioinformatics Robust extraction of functional signals from gene set analysis using a generalized threshold free scoring function. (2009) https:\/\/doi.org\/10.1186\/1471-2105-10-307","DOI":"10.1186\/1471-2105-10-307"},{"key":"1867_CR69","doi-asserted-by":"crossref","unstructured":"Mishra, P. & Holm, L. Gene expression Gene set analysis: limitations in popular existing methods and proposed improvements. 30, 2747\u20132756 (2014).","DOI":"10.1093\/bioinformatics\/btu374"},{"key":"1867_CR70","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-07882-8","volume":"10","author":"X Wang","year":"2019","unstructured":"Wang, X., Park, J., Susztak, K., Zhang, N. R. & Li, M. Bulk tissue cell type deconvolution with multi-subject single-cell expression reference. Nat. Commun. 10, 1\u20139 (2019).","journal-title":"Nat. Commun."},{"key":"1867_CR71","unstructured":"Elmentaite, R. et al. Cells of the human intestinal tract mapped across space and time. Nat. 2021 5977875 597, 250\u2013255 (2021)."},{"key":"1867_CR72","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s00281-021-00901-9","volume":"44","author":"T Naito","year":"2022","unstructured":"Naito, T. & Okada, Y. HLA imputation and its application to genetic and molecular fine-mapping of the MHC region in autoimmune diseases. Semin. Immunopathol. 44, 15\u201328 (2022).","journal-title":"Semin. Immunopathol."},{"key":"1867_CR73","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","volume":"3","author":"TD Schmittgen","year":"2008","unstructured":"Schmittgen, T. D. & Livak, K. J. Analyzing real-time PCR data by the comparative Ct method. Nat. Protoc. 3, 1101\u20131108 (2008).","journal-title":"Nat. Protoc."},{"key":"1867_CR74","doi-asserted-by":"crossref","first-page":"5518","DOI":"10.1016\/S0021-9258(18)96373-8","volume":"241","author":"JE Folk","year":"1966","unstructured":"Folk, J. E. & Cole, P. W. Mechanism of action of guinea pig liver transglutaminase I. Purification and properties of the enzyme: identification of a functional cysteine essential for activity. J. Biol. Chem. 241, 5518\u20135525 (1966).","journal-title":"J. Biol. Chem."},{"key":"1867_CR75","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1089\/dia.2007.0229","volume":"9","author":"M Kiviniemi","year":"2007","unstructured":"Kiviniemi, M. et al. A High-Throughput Population Screening System for the Estimation of Genetic Risk for Type 1 Diabetes: An Application for the TEDDY (The Environmental Determinants of Diabetes in the Young) Study. Diabetes Technol. Ther. 9, 460\u2013472 (2007).","journal-title":"Diabetes Technol. Ther."},{"key":"1867_CR76","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ab.2014.07.029","volume":"465","author":"A Lehmusvuori","year":"2014","unstructured":"Lehmusvuori, A., Kiviniemi, M., Ilonen, J. & Soukka, T. Closed-tube human leukocyte antigen DQA1\u221705 genotyping assay based on switchable lanthanide luminescence probes. Anal. Biochem. 465, 6\u201311 (2014).","journal-title":"Anal. Biochem."}],"container-title":["Nature Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41590-024-01867-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41590-024-01867-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41590-024-01867-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T13:11:27Z","timestamp":1720098687000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41590-024-01867-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,24]]},"references-count":76,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,7]]}},"alternative-id":["1867"],"URL":"https:\/\/doi.org\/10.1038\/s41590-024-01867-0","relation":{},"ISSN":["1529-2908","1529-2916"],"issn-type":[{"value":"1529-2908","type":"print"},{"value":"1529-2916","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,24]]},"assertion":[{"value":"22 June 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 May 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"V.D. and K.V. received funding from Dr. Falk Pharma to Tampere University to conduct the study. B.T., T.Z., R.M. and R.G. are employees of Dr. Falk Pharma. The data presented here are the subject of patent applications EP24173619.8 and EP24173615.6 filed by Dr. Falk Pharma, and B.T., T.Z., R.M., R.G., V.D. and K.V. are inventors on these applications. M.H. and R.P. are employees of Zedira. A.P. is a consultant for JiLab Oy. J.T. is a consultant for Jilab Oy and Dr. Falk Pharma. K.E.A.L. is a consultant for Amyra, Bioniz Pharmaceuticals, Chugai Pharmaceutical, Dr. Falk Pharma, Itrexon Actobios, TOPAS Therapeutics and Takeda California. D.S. is the data and safety monitor for Boehringer Ingelheim (Phil.) and is a consultant for the Dr. Falk Pharma, Takeda, Immunic, Sanofi and TOPAS Therapeutics. J.I. is the owner of Jilab Oy. M.M. is the founder, owner and Chair of the Board of Maki HealthTech (MHT). MHT receives Management\/Advisory Affiliation fees from Dr. Falk Pharma and other funding not related to the research from Topas Therapeutics, Calypso Biotech, Vaccitech, ImmunogenX, Equillium and Immunic. MHT holds patents (patent number 7361480 (United States) and European Patent Office Number 1390753) licensed to Labsystems Diagnostics from where MHT receives royalties via Tampere University Hospital. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}