{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T02:52:33Z","timestamp":1777949553781,"version":"3.51.4"},"reference-count":117,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T00:00:00Z","timestamp":1777766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Celiac disease (CD) is an immune-mediated enteropathy triggered by dietary gluten in genetically predisposed individuals. Although HLA-DQ2 and HLA-DQ8 are the primary genetic determinants of susceptibility, they are not sufficient to explain disease onset and progression. A key molecular event in CD pathogenesis is the post-translational modification of gluten peptides by transglutaminase 2 (TG2), which enhances their binding to HLA-DQ molecules and promotes CD4+ T cell activation. TG2 also acts as the principal autoantigen, driving the production of anti-TG2 autoantibodies through linked recognition mechanisms. Beyond its enzymatic activity, TG2 is tightly regulated by gene regulatory mechanisms, including cytokine-driven transcription, epigenetic modulation, and stress-responsive signaling pathways. These processes determine TG2 expression and activity in the intestinal mucosa, thereby influencing the efficiency of gluten peptide modification and antigen presentation. Here, we propose that TG2 operates at the interface between gene regulation and antigen processing, linking transcriptional control of TGM2 to HLA-restricted immune activation. In this framework, disease susceptibility arises from the coordinated interaction between HLA-dependent peptide presentation, TG2-mediated modification of gluten epitopes, and regulation of TG2 expression within the intestinal mucosa. This integrated model provides a mechanistic basis for disease heterogeneity and identifies TG2 as a central regulatory node and potential therapeutic target in CD.<\/jats:p>","DOI":"10.3390\/genes17050548","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:06:21Z","timestamp":1777860381000},"page":"548","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transglutaminase 2 at the Interface of Gene Regulation and Antigen Processing in HLA-Restricted Immunity of Celiac Disease"],"prefix":"10.3390","volume":"17","author":[{"given":"Faustina Barbara","family":"Cannea","sequence":"first","affiliation":[{"name":"Department of Life and Environmental Sciences (DiSVA), Biomedical Section, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, 09042 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0540-3082","authenticated-orcid":false,"given":"Alessandra","family":"Padiglia","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences (DiSVA), Biomedical Section, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, 09042 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1053\/j.gastro.2024.03.042","article-title":"New Insights on Genes, Gluten, and Immunopathogenesis of Celiac Disease","volume":"167","author":"Abadie","year":"2024","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Aboulaghras, S., Piancatelli, D., Taghzouti, K., Balahbib, A., Alshahrani, M.M., Al Awadh, A.A., Goh, K.W., Ming, L.C., Bouyahya, A., and Oumhani, K. (2023). Meta-Analysis and Systematic Review of HLA DQ2\/DQ8 in Adults with Celiac Disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021188"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/nri3407","article-title":"Triggers and drivers of autoimmunity: Lessons from celiac disease","volume":"13","author":"Sollid","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/nm0698-713","article-title":"Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease","volume":"4","author":"Molberg","year":"1998","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"254","DOI":"10.4049\/jimmunol.175.1.254","article-title":"Refining the rules of gliadin T cell epitope binding to the disease-associated DQ2 molecule in celiac disease: Importance of proline spacing and glutamine deamidation","volume":"175","author":"Qiao","year":"2005","journal-title":"J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4175","DOI":"10.1073\/pnas.0306885101","article-title":"Structural Basis for HLA-DQ2-Mediated Presentation of Gluten Epitopes in Celiac Disease","volume":"101","author":"Kim","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Paolella, G., Sposito, S., Romanelli, A.M., and Caputo, I. (2022). Type 2 Transglutaminase in Coeliac Disease: A Key Player in Pathogenesis, Diagnosis and Therapy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147513"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e20190860","DOI":"10.1084\/jem.20190860","article-title":"B Cell Tolerance and Antibody Production to the Celiac Disease Autoantigen Transglutaminase 2","volume":"217","author":"Blazevski","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lindstad, C.B., Dewan, A.E., Stamnaes, J., Sollid, L.M., and du Pr\u00e9, M.F. (2021). TG2\u2013Gluten Complexes as Antigens for Gluten-Specific and Transglutaminase-2 Specific B Cells in Celiac Disease. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0259082"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.coi.2011.08.006","article-title":"Celiac Disease and Transglutaminase 2: A Model for Posttranslational Modification of Antigens and HLA Association in the Pathogenesis of Autoimmune Disorders","volume":"23","author":"Sollid","year":"2011","journal-title":"Curr. Opin. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1152\/physrev.00003.2023","article-title":"Tissue Transglutaminase: A Multifunctional and Multisite Regulator in Health and Disease","volume":"104","author":"Yao","year":"2024","journal-title":"Physiol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1038\/s42003-024-06672-x","article-title":"Distinct Conformational States Enable Transglutaminase 2 to Promote Cancer Cell Survival versus Cell Death","volume":"7","author":"Aplin","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_13","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (2025). Celiac disease. GeneReviews, University of Washington. Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1116\/."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"449","DOI":"10.3748\/wjg.v28.i4.449","article-title":"Celiac Disease: From Genetics to Epigenetics","volume":"28","author":"Gnodi","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1042\/bj20021234","article-title":"Transglutaminases: Nature\u2019s Biological Glues","volume":"368","author":"Griffin","year":"2002","journal-title":"Biochem. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1152\/physrev.00019.2013","article-title":"Transglutaminase Regulation of Cell Function","volume":"94","author":"Eckert","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Pinkas, D.M., Strop, P., Brunger, A.T., and Khosla, C. (2007). Transglutaminase 2 undergoes a large conformational change upon activation. PLoS Biol., 5.","DOI":"10.1371\/journal.pbio.0050327"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12603","DOI":"10.1074\/jbc.M600146200","article-title":"Mutation of a Critical Arginine in the GTP-Binding Site of Transglutaminase 2 Disinhibits Intracellular Cross-Linking Activity","volume":"281","author":"Begg","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1073\/pnas.042454899","article-title":"Structural Basis for the Guanine Nucleotide-Binding Activity of Tissue Transglutaminase and Its Regulation of Transamidation Activity","volume":"99","author":"Liu","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1146\/annurev.immunol.18.1.53","article-title":"Molecular basis of celiac disease","volume":"18","author":"Sollid","year":"2000","journal-title":"Annu. Rev. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.immuni.2012.06.006","article-title":"Celiac disease: An immunological jigsaw","volume":"36","author":"Meresse","year":"2012","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"25402","DOI":"10.1074\/jbc.M109.097162","article-title":"Redox regulation of transglutaminase 2 activity","volume":"285","author":"Stamnaes","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1007\/s00726-011-1018-8","article-title":"Monitoring of Transglutaminase 2 under Different Oxidative Stress Conditions","volume":"42","author":"Caccamo","year":"2012","journal-title":"Amino Acids"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1016\/j.bcp.2010.06.029","article-title":"Transglutaminase 2: A Multi-Tasking Protein in the Complex Circuitry of Inflammation and Cancer","volume":"80","author":"Mehta","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104894","DOI":"10.1016\/j.critrevonc.2025.104894","article-title":"Current Insights on Transglutaminase 2: Exploring Its Functions, Mechanisms, and Therapeutic Potential in Glioblastoma","volume":"214","author":"Lan","year":"2025","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zaltron, E., Vianello, F., Ruzza, A., Palazzo, A., Brillo, V., Celotti, I., Scavezzon, M., Rossin, F., Leanza, L., and Severin, F. (2024). The Role of Transglutaminase 2 in Cancer: An Update. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25052797"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Liu, B., Cai, Z., Wang, Y., Liu, X., Zhang, B., Zheng, Q., Li, J., Li, C., Cui, Y., and Lv, P. (2024). Transglutaminase 2 Regulates Endothelial Cell Calcification via IL-6-Mediated Autophagy. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1393534"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"168569","DOI":"10.1016\/j.jmb.2024.168569","article-title":"Transcriptomics Studies Reveal Functions of Transglutaminase 2 in Breast Cancer Cells Using Membrane Permeable and Impermeable Inhibitors","volume":"436","author":"Ancona","year":"2024","journal-title":"J. Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/ajg.2013.79","article-title":"ACG clinical guidelines: Diagnosis and management of celiac disease","volume":"108","author":"Hill","year":"2013","journal-title":"Am. J. Gastroenterol."},{"key":"ref_30","first-page":"e196102","article-title":"A Dendritic Cell Population Responsible for Transglutaminase 2\u2013Mediated Gluten Antigen Presentation in Celiac Disease","volume":"9","author":"Yang","year":"2024","journal-title":"JCI Insight"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wolf, J., Willscher, E., Loeffler-Wirth, H., Schmidt, M., Flemming, G., Zurek, M., Uhlig, H.H., H\u00e4ndel, N., and Binder, H. (2021). Deciphering the Transcriptomic Heterogeneity of Duodenal Coeliac Disease Biopsies. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052551"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1126\/science.1074129","article-title":"Structural basis for gluten intolerance in celiac sprue","volume":"297","author":"Shan","year":"2002","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/nri885","article-title":"Coeliac Disease: Dissecting a Complex Inflammatory Disorder","volume":"2","author":"Sollid","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_34","first-page":"41ra51","article-title":"Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease","volume":"2","author":"Stewart","year":"2010","journal-title":"Sci. Transl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"G571","DOI":"10.1152\/ajpgi.00185.2016","article-title":"Identification of food-grade subtilisins as gluten-degrading enzymes to treat celiac disease","volume":"311","author":"Wei","year":"2016","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1053\/gast.2002.33606","article-title":"The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides","volume":"122","author":"Vader","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"34109","DOI":"10.1074\/jbc.M204521200","article-title":"Gliadin T cell epitope selection by tissue transglutaminase in celiac disease: Role of enzyme specificity and pH influence on the transamidation versus deamidation process","volume":"277","author":"Fleckenstein","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Martucciello, S., Sposito, S., Esposito, C., Paolella, G., and Caputo, I. (2020). Interplay between Type 2 Transglutaminase (TG2), Gliadin Peptide 31\u201343 and Anti-TG2 Antibodies in Celiac Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103673"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1007\/s12551-021-00856-z","article-title":"Gliadin Proteolytically Resistant Peptides: The Interplay between Structure and Self-Assembly in Gluten-Related Disorders","volume":"13","author":"Herrera","year":"2021","journal-title":"Biophys. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Balakireva, A.V., and Zamyatnin, A.A. (2016). Properties of Gluten Intolerance: Gluten Structure, Evolution, Pathogenicity and Detoxification Capabilities. Nutrients, 8.","DOI":"10.3390\/nu8100644"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1038\/s41590-024-01867-0","article-title":"Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease","volume":"25","author":"Dotsenko","year":"2024","journal-title":"Nat. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Maglio, M., and Troncone, R. (2020). Intestinal Anti-Tissue Transglutaminase 2 Autoantibodies: Pathogenic and Clinical Implications for Celiac Disease. Front. Nutr., 7.","DOI":"10.3389\/fnut.2020.00073"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1084\/jem.191.4.603","article-title":"The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase","volume":"191","author":"Molberg","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s00281-012-0305-0","article-title":"Role of Transglutaminase 2 in Celiac Disease Pathogenesis","volume":"34","author":"Diraimondo","year":"2012","journal-title":"Semin. Immunopathol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Siegel, M., Strnad, P., Watts, R.E., Choi, K., Jabri, B., Omary, M.B., and Khosla, C. (2008). Extracellular Transglutaminase 2 Is Catalytically Inactive, but Is Transiently Activated upon Tissue Injury. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001861"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Amundsen, S.F., Stamnaes, J., Lundin, K.E.A., and Sollid, L.M. (2023). Expression of Transglutaminase 2 in Human Gut Epithelial Cells: Implications for Coeliac Disease. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0287662"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/j.1365-2249.2010.04317.x","article-title":"Epithelial Transport and Deamidation of Gliadin Peptides: A Role for Coeliac Disease Patient Immunoglobulin A","volume":"164","author":"Rauhavirta","year":"2011","journal-title":"Clin. Exp. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Caccamo, D., Ferlazzo, N., Curr\u00f2, M., Ricca, S., and Ientile, R. (2018). Transglutaminase 2 Up-Regulation Is Associated with Inflammatory Response in PBMC from Healthy Subjects with Hypovitaminosis D. Med. Sci., 6.","DOI":"10.3390\/medsci6040103"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1016\/j.bbapap.2008.08.011","article-title":"The Propensity for Deamidation and Transamidation of Peptides by Transglutaminase 2 Is Dependent on Substrate Affinity and Reaction Conditions","volume":"1784","author":"Stamnaes","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_50","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_51","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1002\/eji.202249862","article-title":"Transglutaminase 2 Affinity and Enzyme\u2013Substrate Intermediate Stability as Determining Factors for T-Cell Responses to Gluten Peptides in Celiac Disease","volume":"52","author":"Amundsen","year":"2022","journal-title":"Eur. J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Voisine, J., and Abadie, V. (2021). Interplay between Gluten, HLA, Innate and Adaptive Immunity Orchestrates the Development of Coeliac Disease. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.674313"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1172\/JCI27620","article-title":"HLA-DQ2 and -DQ8 Signatures of Gluten T Cell Epitopes in Celiac Disease","volume":"116","author":"Tollefsen","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Cannea, F.B., Diana, D., Rossino, R., and Padiglia, A. (2026). Structural insights into HLA-DQ\u2013associated susceptibility to celiac disease through an integrated genetic and in silico approach in a Sardinian population. Genes, 17.","DOI":"10.3390\/genes17020145"},{"key":"ref_55","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_56","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/s41385-020-0294-6","article-title":"Mechanisms of activation of innate-like intraepithelial T lymphocytes","volume":"13","author":"Vandereyken","year":"2020","journal-title":"Mucosal Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.cell.2017.08.046","article-title":"Intestinal epithelial and intraepithelial T cell crosstalk mediates a dynamic response to infection","volume":"171","author":"Reis","year":"2017","journal-title":"Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1136\/gut.2005.075119","article-title":"Recent advances in coeliac disease","volume":"55","author":"West","year":"2006","journal-title":"Gut"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.humimm.2008.10.018","article-title":"HLA-DQ and Risk Gradient for Celiac Disease","volume":"70","author":"Megiorni","year":"2009","journal-title":"Hum. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/ng.543","article-title":"Multiple common variants for celiac disease influencing immune gene expression","volume":"42","author":"Dubois","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.molmed.2010.09.003","article-title":"A genetic perspective on coeliac disease","volume":"16","author":"Trynka","year":"2010","journal-title":"Trends Mol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0140-6736(17)31796-8","article-title":"Coeliac disease","volume":"391","author":"Lebwohl","year":"2018","journal-title":"Lancet"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Caio, G., Volta, U., Sapone, A., Leffler, D.A., De Giorgio, R., Catassi, C., and Fasano, A. (2019). Celiac disease: A comprehensive current review. BMC Med., 17.","DOI":"10.1186\/s12916-019-1380-z"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"goaf086","DOI":"10.1093\/gastro\/goaf086","article-title":"Targeting Transglutaminase 2: Pathways to Celiac Disease Therapies","volume":"13","author":"Endrizzi","year":"2025","journal-title":"Gastroenterol. Rep."},{"key":"ref_65","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_66","doi-asserted-by":"crossref","first-page":"504","DOI":"10.2741\/4117","article-title":"TGM2 and Implications for Human Disease: Role of Alternative Splicing","volume":"18","author":"Lai","year":"2013","journal-title":"Front. Biosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.bbamcr.2011.09.012","article-title":"Transglutaminase 2: A molecular Swiss army knife","volume":"1823","author":"Gundemir","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e194858","DOI":"10.1172\/JCI194858","article-title":"IFN-\u03b3 Is a Direct Driver of Crypt Hyperplasia in Celiac Disease","volume":"135","author":"Stamnaes","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"76","DOI":"10.3892\/mmr.2022.12592","article-title":"Role of TGM2 in T-Cell Lymphoblastic Lymphoma via Regulation of IL-6\/JAK\/STAT3 Signalling","volume":"25","author":"Wang","year":"2022","journal-title":"Mol. Med. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1186\/bcr3371","article-title":"Tissue Transglutaminase as a Central Mediator in Inflammation-Induced Progression of Breast Cancer","volume":"15","author":"Agnihotri","year":"2013","journal-title":"Breast Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/j.1365-2249.2011.04545.x","article-title":"Transglutaminase 2 Expression Is Enhanced Synergistically by Interferon-\u03b3 and Tumour Necrosis Factor-\u03b1 in Human Small Intestine","volume":"168","author":"Bayardo","year":"2012","journal-title":"Clin. Exp. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1053\/j.gastro.2020.04.018","article-title":"Evidence That Pathogenic Transglutaminase 2 in Celiac Disease Derives from Enterocytes","volume":"159","author":"Iversen","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB Signaling in Inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13062-025-00644-9","article-title":"Gliadin-Dependent UPR Induction Directly Triggers the Expression of TG2 and Pro-Inflammatory Cytokines, Dysregulates Intestinal Permeability, and Reduces CFTR Expression in Intestinal Epithelial Cells of Celiac Disease Patients","volume":"20","author":"Monzani","year":"2025","journal-title":"Biol. Direct"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1136\/gutjnl-2020-322566","article-title":"Gluten-Induced RNA Methylation Changes Regulate Intestinal Inflammation via Allele-Specific XPO1 Translation in Epithelial Cells","volume":"71","author":"Zhang","year":"2022","journal-title":"Gut"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"100176","DOI":"10.1016\/j.jtauto.2022.100176","article-title":"An Update on Epigenetic Regulation in Autoimmune Diseases","volume":"5","author":"Mei","year":"2022","journal-title":"J. Transl. Autoimmun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"25","DOI":"10.4274\/jpr.galenos.2024.08456","article-title":"Epigenetic Mechanisms of Genes Influencing Immune Response in Patients with Celiac Disease","volume":"11","author":"Baran","year":"2024","journal-title":"J. Pediatr. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"103784","DOI":"10.1016\/j.autrev.2025.103784","article-title":"Epigenetics in Autoimmune Diseases: Unraveling the Hidden Regulators of Immune Dysregulation","volume":"24","author":"Bagni","year":"2025","journal-title":"Autoimmun. Rev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e63","DOI":"10.1002\/mef2.63","article-title":"Role of Epigenetic Modifications and Aging in Inflammatory Bowel Disease","volume":"2","author":"Zhou","year":"2023","journal-title":"MedComm Future Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/jleuko\/qiae026","article-title":"Epigenetic Regulation of Innate Immune Dynamics during Inflammation","volume":"115","author":"Caldwell","year":"2024","journal-title":"J. Leukoc. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1007\/s12015-020-10055-0","article-title":"Chromatin Dynamics in Intestinal Epithelial Homeostasis: A Paradigm of Cell Fate Determination versus Cell Plasticity","volume":"16","author":"Rispal","year":"2020","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Xiao, X., Mao, X., Chen, D., Yu, B., He, J., Yan, H., and Wang, J. (2022). miRNAs Can Affect Intestinal Epithelial Barrier in Inflammatory Bowel Disease. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.868229"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Tan, S.Y.X., Zhang, J., and Tee, W.-W. (2022). Epigenetic Regulation of Inflammatory Signaling and Inflammation-Induced Cancer. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.931493"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Moro, I., Rojas-M\u00e1rquez, H., Sebastian-delaCruz, M., Mentxaka-Salgado, J., Olazagoitia-Garmendia, A., Mendoza, L.M., Lluch, A., Fantuzzi, F., Lambert, C., and Ares Blanco, J. (2023). A Long Non-Coding RNA That Harbors a SNP Associated with Type 2 Diabetes Regulates the Expression of TGM2 Gene in Pancreatic Beta Cells. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1101934"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Soderquest, K., Hertweck, A., Giambartolomei, C., Henderson, S., Mohamed, R., Goldberg, R., Perucha, E., Franke, L., Herrero, J., and Plagnol, V. (2017). Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. PLoS Genet., 13.","DOI":"10.1371\/journal.pgen.1006587"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Kumar, M., Yip, L., Wang, F., Marty, S.E., and Fathman, C.G. (2025). Autoimmune disease: Genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies?. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1626082"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Garcia, E., and Ismail, S. (2020). Spatiotemporal Regulation of Signaling: Focus on T Cell Activation and the Immunological Synapse. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093283"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Su, T., Qin, X.-Y., and Furutani, Y. (2021). Transglutaminase 2 as a Marker for Inflammation and Therapeutic Target in Sepsis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041897"},{"key":"ref_89","unstructured":"Anaya, J.-M., Shoenfeld, Y., Rojas-Villarraga, A., Levy, R.A., and Cervera, R. (2013). Non-HLA genes and autoimmune diseases. Autoimmunity: From Bench to Bedside, El Rosario University Press. Chapter 18."},{"key":"ref_90","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_91","doi-asserted-by":"crossref","unstructured":"Cebolla, \u00c1., Moreno, M.L., Coto, L., and Sousa, C. (2018). Gluten immunogenic peptides as standard for the evaluation of potential harmful prolamin content in food and human specimen. Nutrients, 10.","DOI":"10.20944\/preprints201811.0165.v1"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.jcmgh.2020.07.010","article-title":"Genome-wide transcriptomic analysis of intestinal mucosa in celiac disease patients on a gluten-free diet and postgluten challenge","volume":"11","author":"Dotsenko","year":"2021","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"12385","DOI":"10.1038\/s41598-025-90300-z","article-title":"Single-cell transcriptome sequencing indicates the cellular heterogeneity of small intestine tissue in celiac disease","volume":"15","author":"Shi","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"6","DOI":"10.4062\/biomolther.2025.247","article-title":"Targeting the primordial chaperone to overcome acquired drug resistance in cancer: TG2-mediated autophagy","volume":"34","author":"Kim","year":"2026","journal-title":"Biomol. Ther."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3390\/nu4040243","article-title":"Celiac disease, inflammation and oxidative damage: A nutrigenetic approach","volume":"4","author":"Ferretti","year":"2012","journal-title":"Nutrients"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"37866","DOI":"10.1074\/jbc.M111.287490","article-title":"Activation of extracellular transglutaminase 2 by thioredoxin","volume":"286","author":"Jin","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1161\/CIRCRESAHA.109.215228","article-title":"Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness","volume":"107","author":"Santhanam","year":"2010","journal-title":"Circ. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e2407066121","DOI":"10.1073\/pnas.2407066121","article-title":"Structural and mechanistic analysis of Ca2+-dependent regulation of transglutaminase 2 activity using a Ca2+-bound intermediate state","volume":"121","author":"Sewa","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Furini, G., and Verderio, E.A.M. (2019). Spotlight on the transglutaminase 2\u2013heparan sulfate interaction. Med. Sci., 7.","DOI":"10.3390\/medsci7010005"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Engstr\u00f6m, N., B\u00f6hn, L., Josefsson, A., St\u00f6rsrud, S., and Scheers, N. (2024). Development of celiac-safe foods: Prevention of transglutaminase 2 (TG2) deamidation of gluten in healthy non-celiac volunteers. Front. Nutr., 11.","DOI":"10.3389\/fnut.2024.1308463"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Matera, M., and Guandalini, S. (2024). How the microbiota may affect celiac disease and what we can do. Nutrients, 16.","DOI":"10.3390\/nu16121882"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/S1074-5521(03)00045-0","article-title":"Design, synthesis, and evaluation of gluten peptide analogs as selective inhibitors of human tissue transglutaminase","volume":"10","author":"Hausch","year":"2003","journal-title":"Chem. Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1056\/NEJMoa2032441","article-title":"A randomized trial of a transglutaminase 2 inhibitor for celiac disease","volume":"385","author":"Schuppan","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"B\u00fcchold, C., Hils, M., Gerlach, U., Weber, J., Pelzer, C., Heil, A., Aeschlimann, D., and Pasternack, R. (2022). Features of ZED1227: The first-in-class tissue transglutaminase inhibitor undergoing clinical evaluation for the treatment of celiac disease. Cells, 11.","DOI":"10.3390\/cells11101667"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Scalvini, D., Scarcella, C., Mantica, G., Bartolotta, E., Maimaris, S., Fazzino, E., Biagi, F., and Schiepatti, A. (2025). Beyond gluten-free diet: A critical perspective on phase 2 trials on non-dietary pharmacological therapies for coeliac disease. Front. Nutr., 11.","DOI":"10.3389\/fnut.2024.1501817"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"6898","DOI":"10.1039\/D5FO01270H","article-title":"Design, synthesis and evaluation of gluten peptide analogues as inhibitors of the HLA\/DQ8-mediated celiac immune response","volume":"16","author":"Treppiccione","year":"2025","journal-title":"Food Funct."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/S2468-1253(22)00428-9","article-title":"Efficacy and safety of gluten peptide-based antigen-specific immunotherapy (Nexvax2) in adults with coeliac disease after bolus exposure to gluten (RESET CeD): An interim analysis of a terminated randomized, double-blind, placebo-controlled phase 2 study","volume":"8","author":"Daveson","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Di Sabatino, A., Lenti, M.V., Corazza, G.R., and Gianfrani, C. (2018). Vaccine immunotherapy for celiac disease. Front. Med., 5.","DOI":"10.3389\/fmed.2018.00187"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.tips.2023.09.006","article-title":"Celiac disease: Mechanisms and emerging therapeutics","volume":"44","author":"Besser","year":"2023","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1097\/MOG.0000000000001080","article-title":"New therapies in celiac disease","volume":"41","author":"Santonicola","year":"2025","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Kounatidis, D., Pavlou, A., Evangelopoulos, A., Psaroudaki, M., Kotsi, E., Petrakou, I., Paraskevopoulos, P., Stamatopoulos, V., Mylona, E., and Vallianou, N.G. (2026). Rethinking celiac disease management: Treatment approaches beyond the gluten-free diet. Biomedicines, 14.","DOI":"10.3390\/biomedicines14010029"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3359","DOI":"10.1021\/acs.biochem.8b00204","article-title":"Cystamine and disulfiram inhibit human transglutaminase 2 via an oxidative mechanism","volume":"57","author":"Palanski","year":"2018","journal-title":"Biochemistry"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/S2468-1253(17)30110-3","article-title":"Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: Two randomised, double-blind, placebo-controlled phase 1 studies","volume":"2","author":"Goel","year":"2017","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1001\/jamapediatrics.2020.2893","article-title":"Early gluten introduction and celiac disease in the EAT study: A prespecified analysis of the EAT randomized clinical trial","volume":"174","author":"Logan","year":"2020","journal-title":"JAMA Pediatr."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41572-018-0054-z","article-title":"Coeliac disease","volume":"5","author":"Lindfors","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s40168-020-00906-w","article-title":"Multi-omics analysis reveals the influence of genetic and environmental risk factors on developing gut microbiota in infants at risk of celiac disease","volume":"8","author":"Leonard","year":"2020","journal-title":"Microbiome"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1136\/gutjnl-2021-326257","article-title":"Immunopathogenesis and Environmental Triggers in Coeliac Disease","volume":"71","author":"Levescot","year":"2022","journal-title":"Gut"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/5\/548\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:14:59Z","timestamp":1777860899000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/5\/548"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,3]]},"references-count":117,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["genes17050548"],"URL":"https:\/\/doi.org\/10.3390\/genes17050548","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,3]]}}}