{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T09:00:12Z","timestamp":1785488412889,"version":"3.56.0"},"reference-count":107,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Refractory celiac disease (RCeD) is a rare but severe complication of celiac disease characterized by persistent or recurrent malabsorptive symptoms and villous atrophy despite a strict gluten-free diet, after exclusion of ongoing gluten exposure, alternative enteropathies, and overt lymphoma. RCeD comprises two biologically distinct entities. RCeD-I is associated with phenotypically normal, polyclonal intraepithelial lymphocytes and generally reflects persistent gluten-independent mucosal inflammation with a relatively favorable prognosis. RCeD-II is defined by expansion of aberrant clonal intraepithelial lymphocytes lacking normal surface T-cell markers and is increasingly regarded as a low-grade intraepithelial lymphoma or in situ lymphomatous disorder, with substantial risk of progression to enteropathy-associated T-cell lymphoma (EATL). Mechanistic studies identify epithelial stress, IL-15-driven IEL survival, stromal and innate immune amplification, and cytotoxic epithelial injury as central drivers of refractory mucosal damage. In RCeD-II, aberrant IELs acquire a hybrid T\/NK-like phenotype, persist through anti-apoptotic IL-15\/JAK\u2013STAT signaling, and induce enterocyte killing, while molecular alterations involving JAK1, STAT3, JAK\/STAT regulators, NF-\u03baB signaling, epigenetic regulators, and chromosomal abnormalities support stepwise lymphomagenesis. Recent single-cell multiomic studies further reveal genetically altered intestinal lymphocyte clones and intratumoral heterogeneity across the RCeD-II\u2013EATL continuum. From a nutritional immunology perspective, RCeD illustrates a setting in which removal of the initiating dietary antigen is insufficient to restore mucosal immune homeostasis. This review summarizes the pathogenic processes that distinguish RCeD-I from RCeD-II and link failed mucosal recovery after gluten withdrawal to persistent immune-mediated epithelial injury, aberrant IEL expansion, clonal evolution, and lymphoma progression.<\/jats:p>","DOI":"10.3390\/nu18152479","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:20:18Z","timestamp":1785486018000},"page":"2479","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Refractory Celiac Disease: Nutritional Failure, Immune Dysregulation, and Lymphomagenesis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4489-1485","authenticated-orcid":false,"given":"Ioanna","family":"Aggeletopoulou","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7790-7845","authenticated-orcid":false,"given":"Ploutarchos","family":"Pastras","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0419-0078","authenticated-orcid":false,"given":"Maria","family":"Kalafateli","sequence":"additional","affiliation":[{"name":"4th Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokratio Hospital, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3094-8209","authenticated-orcid":false,"given":"Christos","family":"Triantos","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Amakye, D., and Clarke, K. (Dig. Dis. Sci., 2026). Celiac Disease: A Comprehensive Review of Epidemiology, Pathogenesis, and Therapeutic Strategies, Dig. Dis. Sci., Online ahead of print.","DOI":"10.1007\/s10620-026-09860-3"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1002\/ueg2.70119","article-title":"European Society for the Study of Coeliac Disease 2025 Updated Guidelines on the Diagnosis and Management of Coeliac Disease in Adults. Part 1: Diagnostic Approach","volume":"13","author":"Zingone","year":"2025","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e70195","DOI":"10.1002\/ueg2.70195","article-title":"European Society for the Study of Coeliac Disease (ESsCD) 2025 Updated Guidelines on the Diagnosis and Management of Coeliac Disease in Adults. Part 2: Management, Follow-Up, and Complex Disease Courses","volume":"14","author":"Branchi","year":"2026","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1038\/ajg.2012.219","article-title":"The prevalence of celiac disease in the United States","volume":"107","author":"Ludvigsson","year":"2012","journal-title":"Am. J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/07853890.2019.1569254","article-title":"Coeliac disease: Beyond genetic susceptibility and gluten. A narrative review","volume":"51","author":"Pes","year":"2019","journal-title":"Ann. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"507","DOI":"10.14309\/ajg.0000000000000523","article-title":"Incidence of Celiac Disease Is Increasing Over Time: A Systematic Review and Meta-analysis","volume":"115","author":"King","year":"2020","journal-title":"Am. J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1097\/MPG.0000000000002497","article-title":"European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020","volume":"70","author":"Husby","year":"2020","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_8","first-page":"17","article-title":"Genetic susceptibilty and celiac disease: What role do HLA haplotypes play?","volume":"89","author":"Sciurti","year":"2018","journal-title":"Acta Biomed."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dargenio, V.N., Sgarro, N., La Grasta, G., Begucci, M., Castellaneta, S.P., Dargenio, C., Paulucci, L., Francavilla, R., and Cristofori, F. (2025). Celiac Disease as a Model of Intestinal Malnutrition: Mechanisms and Nutritional Management. Nutrients, 17.","DOI":"10.20944\/preprints202510.1964.v1"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/MCG.0000000000001267","article-title":"Celiac Disease: Extraintestinal Manifestations and Associated Conditions","volume":"54","author":"Therrien","year":"2020","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kubas, A., and Ma\u0142ecka-Wojciesko, E. (2025). Malignancies in Celiac Disease\u2014A Hidden Threat with Diagnostic Pitfalls. Biomedicines, 13.","DOI":"10.3390\/biomedicines13061507"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1097\/00042737-199910000-00019","article-title":"The histopathology of coeliac disease: Time for a standardized report scheme for pathologists","volume":"11","author":"Oberhuber","year":"1999","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1038\/ajg.2010.10","article-title":"Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet","volume":"105","author":"Rahim","year":"2010","journal-title":"Am. J. Gastroenterol."},{"key":"ref_14","first-page":"132","article-title":"Advances in nonresponsive and refractory celiac disease","volume":"167","author":"Malamut","year":"2024","journal-title":"Gastroenterology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1146\/annurev-pathmechdis-031521-032634","article-title":"The Immunobiology and Pathogenesis of Celiac Disease","volume":"18","author":"Iversen","year":"2023","journal-title":"Annu. Rev. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.4049\/jimmunol.1601693","article-title":"T Cells in Celiac Disease","volume":"198","author":"Jabri","year":"2017","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Al-Toma, A. (2025). Management Strategy for Non-Responsive and Refractory Celiac Disease in Adults: A Review Article. J. Clin. Med., 14.","DOI":"10.20944\/preprints202509.0919.v1"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1177\/2050640619844125","article-title":"European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders","volume":"7","author":"Volta","year":"2019","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Aljada, B., Zohni, A., and El-Matary, W. (2021). The Gluten-Free Diet for Celiac Disease and Beyond. Nutrients, 13.","DOI":"10.3390\/nu13113993"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sim\u00f3n, E., Molero-Luis, M., Fueyo-D\u00edaz, R., Costas-Batlle, C., Crespo-Escobar, P., and Montoro-Huguet, M.A. (2023). The Gluten-Free Diet for Celiac Disease: Critical Insights to Better Understand Clinical Outcomes. Nutrients, 15.","DOI":"10.3390\/nu15184013"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Hollon, J.R., Cureton, P.A., Martin, M.L., Puppa, E.L., and Fasano, A. (2013). Trace gluten contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-responsive celiac disease patients. BMC Gastroenterol., 13.","DOI":"10.1186\/1471-230X-13-40"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1038\/s41390-025-04266-9","article-title":"Comparing urine and stool gluten immunogenic peptides for detecting compliance to gluten-free diets","volume":"99","author":"Gkikas","year":"2026","journal-title":"Pediatr. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"201","DOI":"10.23736\/S1121-421X.20.02662-8","article-title":"Fecal gluten immunogenic peptides as indicators of dietary compliance in celiac patients","volume":"66","author":"Porcelli","year":"2020","journal-title":"Minerva Gastroenterol. Dietol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.clnu.2015.04.014","article-title":"Refractory celiac disease and EATL patients show severe malnutrition and malabsorption at diagnosis","volume":"35","author":"Wierdsma","year":"2016","journal-title":"Clin. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1159\/000506305","article-title":"The Intracellular Intensity of CD3 on Aberrant Intraepithelial Lymphocytes Is a Prognostic Factor of the Progression to Overt Lymphoma in Refractory Celiac Disease Type II (Pre-Enteropathy-Associated T Cell Lymphoma)","volume":"38","author":"Crespo","year":"2020","journal-title":"Dig. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.immuni.2016.07.018","article-title":"Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease","volume":"45","author":"Ettersperger","year":"2016","journal-title":"Immunity"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1172\/JCI41344","article-title":"IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis","volume":"120","author":"Malamut","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s00281-012-0322-z","article-title":"Refractory celiac disease: From bench to bedside","volume":"34","author":"Malamut","year":"2012","journal-title":"Semin. Immunopathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/S0016-5085(03)01047-3","article-title":"Interleukin 15: A key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease","volume":"125","author":"Mention","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Verdelho Machado, M. (2024). Refractory Celiac Disease: What the Gastroenterologist Should Know. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910383"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/S1542-3565(05)00295-8","article-title":"Effect of elemental diet on mucosal immunopathology and clinical symptoms in type 1 refractory celiac disease","volume":"3","author":"Olaussen","year":"2005","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Marasco, G., Cirota, G.G., Rossini, B., Lungaro, L., Di Biase, A.R., Colecchia, A., Volta, U., De Giorgio, R., Festi, D., and Caio, G. (2020). Probiotics, Prebiotics and Other Dietary Supplements for Gut Microbiota Modulation in Celiac Disease Patients. Nutrients, 12.","DOI":"10.3390\/nu12092674"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Penny, H.A., Rej, A., Baggus, E.M.R., Coleman, S.H., Ward, R., Wild, G., Bouma, G., Trott, N., Snowden, J.A., and Wright, J. (2022). Non-Responsive and Refractory Coeliac Disease: Experience from the NHS England National Centre. Nutrients, 14.","DOI":"10.3390\/nu14132776"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.3748\/wjg.v18.i12.1348","article-title":"Celiac disease: Management of persistent symptoms in patients on a gluten-free diet","volume":"18","author":"Dewar","year":"2012","journal-title":"World J. Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1136\/gut.2009.195131","article-title":"Classification and management of refractory coeliac disease","volume":"59","author":"Murray","year":"2010","journal-title":"Gut"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/s41575-023-00872-2","article-title":"Guidelines for best practices in monitoring established coeliac disease in adult patients","volume":"21","author":"Elli","year":"2024","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1053\/j.gastro.2008.09.069","article-title":"Presentation and long-term follow-up of refractory celiac disease: Comparison of type I with type II","volume":"136","author":"Malamut","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1053\/j.gastro.2008.10.013","article-title":"Clinical staging and survival in refractory celiac disease: A single center experience","volume":"136","author":"Kelly","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1038\/ajg.2011.104","article-title":"The incidence and clinical spectrum of refractory celiac disease in a north american referral center","volume":"106","author":"Roshan","year":"2011","journal-title":"Am. J. Gastroenterol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.dld.2022.08.022","article-title":"Clinical features of type 1 and 2 refractory celiac disease: Results from a large cohort over a decade","volume":"55","author":"Elli","year":"2023","journal-title":"Dig. Liver Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1136\/gut.2006.114512","article-title":"Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: Retrospective evaluation of single-centre experience","volume":"56","author":"Verbeek","year":"2007","journal-title":"Gut"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1002\/cyto.b.20481","article-title":"Aberrant T-lymphocytes in refractory coeliac disease are not strictly confined to a small intestinal intraepithelial localization","volume":"76","author":"Verbeek","year":"2009","journal-title":"Cytom. B Clin. Cytom."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Chibbar, R., Nostedt, J., Mihalicz, D., Deschenes, J., McLean, R., and Dieleman, L.A. (2020). Refractory Celiac Disease Type II: A Case Report and Literature Review. Front. Med., 7.","DOI":"10.3389\/fmed.2020.564875"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"12403","DOI":"10.3748\/wjg.v21.i43.12403","article-title":"Surgery in (pre)malignant celiac disease","volume":"21","author":"Nijeboer","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Scarmozzino, F., Pizzi, M., Pelizzaro, F., Angerilli, V., Dei Tos, A.P., Piazza, F., Savarino, E.V., Zingone, F., and Fassan, M. (2023). Refractory celiac disease and its mimickers: A review on pathogenesis, clinical-pathological features and therapeutic challenges. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1273305"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1136\/gutjnl-2020-322935","article-title":"Oncogenetic landscape of lymphomagenesis in coeliac disease","volume":"71","author":"Cording","year":"2022","journal-title":"Gut"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Pelizzaro, F., Marsilio, I., Fassan, M., Piazza, F., Barberio, B., D\u2019Odorico, A., Savarino, E.V., Farinati, F., and Zingone, F. (2021). The Risk of Malignancies in Celiac Disease-A Literature Review. Cancers, 13.","DOI":"10.3390\/cancers13215288"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1097\/PAS.0000000000001658","article-title":"Immunophenotypic Spectrum and Genomic Landscape of Refractory Celiac Disease Type II","volume":"45","author":"Soderquist","year":"2021","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1053\/j.gastro.2015.05.013","article-title":"Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease","volume":"149","author":"Setty","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1053\/j.gastro.2022.07.086","article-title":"AGA Clinical Practice Update on Management of Refractory Celiac Disease: Expert Review","volume":"163","author":"Green","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.dld.2017.12.001","article-title":"Risk of complications in coeliac patients depends on age at diagnosis and type of clinical presentation","volume":"50","author":"Biagi","year":"2018","journal-title":"Dig. Liver Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/apt.12606","article-title":"Refractory coeliac disease in a country with a high prevalence of clinically-diagnosed coeliac disease","volume":"39","author":"Ilus","year":"2014","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.bpg.2005.02.001","article-title":"Refractory coeliac disease","volume":"19","author":"Daum","year":"2005","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1080\/17474124.2017.1274231","article-title":"Small bowel villous atrophy: Celiac disease and beyond","volume":"11","author":"Elli","year":"2017","journal-title":"Expert. Rev. Gastroenterol. Hepatol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/apt.13867","article-title":"Dynamics of occurrence of refractory coeliac disease and associated complications over 25 years","volume":"45","author":"Eigner","year":"2017","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.cgh.2005.12.011","article-title":"Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma","volume":"4","author":"Goerres","year":"2006","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1097\/MEG.0000000000001168","article-title":"A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease","volume":"30","author":"Hrdlickova","year":"2018","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"12390","DOI":"10.1073\/pnas.2135229100","article-title":"The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses","volume":"100","author":"Vader","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s10238-024-01542-6","article-title":"Viral infections in celiac disease: What should be considered for better management","volume":"25","author":"Asri","year":"2024","journal-title":"Clin. Exp. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.4049\/jimmunol.1103609","article-title":"Cutting edge: The role of IFN-\u03b1 receptor and MyD88 signaling in induction of IL-15 expression in vivo","volume":"188","author":"Colpitts","year":"2012","journal-title":"J. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Dafik, L., Albertelli, M., Stamnaes, J., Sollid, L.M., and Khosla, C. (2012). Activation and inhibition of transglutaminase 2 in mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030642"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"G40","DOI":"10.1152\/ajpgi.00435.2015","article-title":"Mechanisms of innate immune activation by gluten peptide p31-43 in mice","volume":"311","author":"Araya","year":"2016","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1084\/jem.20102660","article-title":"Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4","volume":"209","author":"Junker","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2500063","DOI":"10.1080\/19490976.2025.2500063","article-title":"Microbial-derived peptidases are altered in celiac disease, non-celiac gluten sensitivity, and functional dyspepsia: A systematic review and re-analysis of the duodenal microbiome","volume":"17","author":"Pryor","year":"2025","journal-title":"Gut Microbes"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1042\/CS20130478","article-title":"Analysis of the cytokine profile in the duodenal mucosa of refractory coeliac disease patients","volume":"126","author":"Caruso","year":"2013","journal-title":"Clin. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1111\/imm.12690","article-title":"High Smad7 sustains inflammatory cytokine response in refractory coeliac disease","volume":"150","author":"Sedda","year":"2017","journal-title":"Immunology"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Marafini, I., Salvatori, S., Troncone, E., De Vico, P., De Cristofaro, E., and Monteleone, G. (2026). Immune cell dynamics and mechanisms of epithelial injury in celiac disease. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1766513"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1136\/gut.34.2.208","article-title":"Numbers of T cell receptor (TCR) alpha beta+ but not of TcR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet","volume":"34","author":"Kutlu","year":"1993","journal-title":"Gut"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s00281-012-0316-x","article-title":"Intraepithelial lymphocytes in celiac disease immunopathology","volume":"34","author":"Abadie","year":"2012","journal-title":"Semin. Immunopathol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.immuni.2004.06.018","article-title":"A direct role for NKG2D\/MICA interaction in villous atrophy during celiac disease","volume":"21","author":"Mention","year":"2004","journal-title":"Immunity"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1172\/JCI30989","article-title":"Small intestinal CD8+TCRgammadelta+NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease","volume":"118","author":"Bhagat","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1053\/j.gastro.2006.12.025","article-title":"Inhibition of TGF-beta signaling by IL-15: A new role for IL-15 in the loss of immune homeostasis in celiac disease","volume":"132","author":"Benahmed","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1038\/s41586-020-2003-8","article-title":"IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease","volume":"578","author":"Abadie","year":"2020","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1053\/j.gastro.2013.12.023","article-title":"Interleukin 15 and CD4+ T cells cooperate to promote small intestinal enteropathy in response to dietary antigen","volume":"146","author":"Korneychuk","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/S0140-6736(03)13803-2","article-title":"Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease","volume":"362","author":"Maiuri","year":"2003","journal-title":"Lancet"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Barone, M.V., Zanzi, D., Maglio, M., Nanayakkara, M., Santagata, S., Lania, G., Miele, E., Ribecco, M.T., Maurano, F., and Auricchio, R. (2011). Gliadin-mediated proliferation and innate immune activation in celiac disease are due to alterations in vesicular trafficking. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017039"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"20518","DOI":"10.3390\/ijms151120518","article-title":"Gliadin peptides as triggers of the proliferative and stress\/innate immune response of the celiac small intestinal mucosa","volume":"15","author":"Barone","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1038\/nri2670","article-title":"Tissue-mediated control of immunopathology in coeliac disease","volume":"9","author":"Jabri","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/cei.13414","article-title":"Phenotypic shift of small intestinal intra-epithelial type 1 innate lymphoid cells in celiac disease is associated with enhanced cytotoxic potential","volume":"200","author":"Uhde","year":"2020","journal-title":"Clin. Exp. Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"116039","DOI":"10.1016\/j.celrep.2025.116039","article-title":"Immune signaling mediates stromal changes to support epithelial reprogramming in celiac duodenum","volume":"44","author":"Richards","year":"2025","journal-title":"Cell Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/s41586-024-07716-2","article-title":"A human autoimmune organoid model reveals IL-7 function in coeliac disease","volume":"632","author":"Santos","year":"2024","journal-title":"Nature"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Malamut, G., and Cerf-Bensussan, N. (2022). Mechanisms of Lymphomagenesis in Celiac Disease: Lessons for Therapy. Refractory Celiac Disease, Springer International Publishing.","DOI":"10.1007\/978-3-030-90142-4"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1136\/gutjnl-2012-302265","article-title":"Identification of a potential physiological precursor of aberrant cells in refractory coeliac disease type II","volume":"62","author":"Schmitz","year":"2013","journal-title":"Gut"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.molimm.2012.01.014","article-title":"Origin and immunophenotype of aberrant IEL in RCDII patients","volume":"50","author":"Tack","year":"2012","journal-title":"Mol. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.clim.2007.09.002","article-title":"Flow cytometric determination of aberrant intra-epithelial lymphocytes predicts T-cell lymphoma development more accurately than T-cell clonality analysis in Refractory Celiac Disease","volume":"126","author":"Verbeek","year":"2008","journal-title":"Clin. Immunol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1136\/gutjnl-2018-317371","article-title":"NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: A CELAC study","volume":"68","author":"Cheminant","year":"2019","journal-title":"Gut"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1136\/jclinpath-2018-205023","article-title":"Clonal T cell receptor gene rearrangements in coeliac disease: Implications for diagnosing refractory coeliac disease","volume":"71","author":"Hussein","year":"2018","journal-title":"J. Clin. Pathol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.immuni.2014.09.005","article-title":"Development, differentiation, and diversity of innate lymphoid cells","volume":"41","author":"Diefenbach","year":"2014","journal-title":"Immunity"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e70099","DOI":"10.1002\/cti2.70099","article-title":"Aberrant intra-epithelial lymphocytes cause enterocyte cell death in refractory celiac disease by CD103-\u03b27-receptor-mediated granzyme-B degranulation which can be restored by etrolizumab","volume":"15","author":"Castelijn","year":"2026","journal-title":"Clin. Transl. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1084\/jem.20061524","article-title":"Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis","volume":"204","author":"Jalil","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"4834","DOI":"10.4049\/jimmunol.176.8.4834","article-title":"STAT5-mediated signals sustain a TCR-initiated gene expression program toward differentiation of CD8 T cell effectors","volume":"176","author":"Verdeil","year":"2006","journal-title":"J. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1006\/cimm.1996.0293","article-title":"Interleukin-15 induces the expression of mRNAs of cytolytic mediators and augments cytotoxic activities in primary murine lymphocytes","volume":"174","author":"Ye","year":"1996","journal-title":"Cell Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1038\/ajg.2012.199","article-title":"Diagnostic yield of capsule endoscopy in refractory celiac disease","volume":"107","author":"Barret","year":"2012","journal-title":"Am. J. Gastroenterol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"15","DOI":"10.15403\/jgld.2014.1121.281.cel","article-title":"Capsule endoscopy in the management of refractory coeliac disease","volume":"28","author":"Zammit","year":"2019","journal-title":"J. Gastrointest. Liver Dis."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/nrgastro.2015.155","article-title":"Mechanisms and management of refractory coeliac disease","volume":"12","author":"Nijeboer","year":"2015","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3674","DOI":"10.1182\/blood-2014-04-566513","article-title":"Phenotypically aberrant clonal T cells in the lungs of patients with type II refractory celiac disease","volume":"123","author":"Juvin","year":"2014","journal-title":"Blood"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1136\/gut.52.2.205","article-title":"Refractory coeliac sprue is a diffuse gastrointestinal disease","volume":"52","author":"Verkarre","year":"2003","journal-title":"Gut"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/S0016-5085(98)70530-X","article-title":"Abnormal intestinal intraepithelial lymphocytes in refractory sprue","volume":"114","author":"Cellier","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Abdullah, S.A.A., Goa, P., Vandenberghe, E., and Flavin, R. (2023). Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma. Diagnostics, 13.","DOI":"10.3390\/diagnostics13162629"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1038\/leu.2016.178","article-title":"Mutations in the JAK\/STAT and RAS signaling pathways are common in intestinal T-cell lymphomas","volume":"30","author":"Nicolae","year":"2016","journal-title":"Leukemia"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"12602","DOI":"10.1038\/ncomms12602","article-title":"Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations","volume":"7","author":"Roberti","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3857","DOI":"10.1016\/j.cell.2022.09.023","article-title":"The JAK-STAT pathway at 30: Much learned, much more to do","volume":"185","author":"Philips","year":"2022","journal-title":"Cell"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1038\/s41467-018-04013-1","article-title":"The molecular basis of JAK\/STAT inhibition by SOCS1","volume":"9","author":"Liau","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/S0016-5085(03)00692-9","article-title":"Recurrent partial trisomy 1q22-q44 in clonal intraepithelial lymphocytes in refractory celiac sprue","volume":"125","author":"Verkarre","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"eadp6812","DOI":"10.1126\/scitranslmed.adp6812","article-title":"Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease","volume":"17","author":"Singh","year":"2025","journal-title":"Sci. Transl. Med."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Malamut, G., Gu\u00e9gan, N., Carbone, F., de Giacomoni, A., Ferment, A., Masson, C., Luka, M., Cording, S., Bole, C., and Fumery, M. (Gastroenterology, 2026). Clonal Lymphocyte Expansions and JAK-STAT Pathway Mutations Define a Pathogenic Continuum Driving Resistance to Gluten-Free Diet in Celiac Disease, Gastroenterology, Online ahead of print.","DOI":"10.1053\/j.gastro.2026.03.025"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/s41375-025-02777-2","article-title":"Divergent molecular pathways drive monomorphic epitheliotropic and enteropathy-associated intestinal T-cell lymphoma","volume":"40","author":"Vallois","year":"2026","journal-title":"Leukemia"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/15\/2479\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T08:32:11Z","timestamp":1785486731000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/15\/2479"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,31]]},"references-count":107,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["nu18152479"],"URL":"https:\/\/doi.org\/10.3390\/nu18152479","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,31]]}}}