{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T07:44:34Z","timestamp":1792395874305,"version":"4.4.0"},"reference-count":25,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["HLA"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Celiac disease (CD) is classically associated with the HLA\u2010DQ2.5 and HLA\u2010DQ8 heterodimers; however, a clinically relevant subset of patients fulfilling diagnostic criteria lacks these canonical risk HLA\u2010DQ molecules, indicating the presence of alternative antigen\u2010presentation pathways. Among potential contributors, HLA\u2010DQ5 and HLA\u2010DQ9 remain poorly characterised at the immunopeptidomic level. In this study, we applied an integrated in silico framework to systematically investigate the gliadin\u2010derived peptide repertoire presented by canonical and non\u2010canonical HLA\u2010DQ molecules. Peptides derived from \u03b1\u2010, \u03b3\u2010 and \u03c9\u2010gliadin families were generated following simulated tissue transglutaminase\u2013mediated deamidation and multi\u2010enzyme gastrointestinal digestion. Binding affinities to HLA\u2010DQ2.5, DQ8, DQ5 and DQ9 were predicted using NetMHCIIpan 4.3 and integrated with peptide stability and sequence abundance into a composite Biological Plausibility score. The analysis identified \u03b3\u2010gliadin\u2013derived peptides as the dominant immunogenic drivers across all investigated HLA\u2010DQ molecules, owing to their enhanced digestive stability and high allelic promiscuity. Hierarchical clustering of binding profiles revealed a repertoire\u2010dependent functional overlap between HLA\u2010DQ9 and the canonical DQ8 molecule, particularly for \u03b3\u2010gliadin motifs. In contrast, HLA\u2010DQ5 displayed functional complementarity, selectively presenting a distinct subset of gliadin peptides that were poorly recognised by classical risk HLA\u2010DQ molecules. Collectively, these findings provide a mechanistic framework for CD pathogenesis in individuals lacking HLA\u2010DQ2.5 and HLA\u2010DQ8, demonstrating that non\u2010canonical HLA\u2010DQ molecules can sustain pathogenic CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell responses through convergent and complementary antigen\u2010presentation pathways. As a predictive in silico framework, this work refines the genetic paradigm of CD by emphasising functional organisation of the gluten immunopeptidome over simple allele presence and provides a mechanistic rationale for future experimental validation of non\u2010canonical HLA\u2010DQ\u2013restricted gliadin presentation.\n                  <\/jats:p>","DOI":"10.1111\/tan.70820","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T23:29:05Z","timestamp":1782516545000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Silico Analysis of Functional Overlap and Complementarity of\n                    <scp>HLA<\/scp>\n                    \u2010\n                    <scp>DQ5<\/scp>\n                    and\n                    <scp>DQ9<\/scp>\n                    in Gliadin Presentation: Expanding the Immunopeptidomic Landscape of Celiac Disease"],"prefix":"10.1111","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1844-0421","authenticated-orcid":false,"given":"Antonio","family":"Milano","sequence":"first","affiliation":[{"name":"Laboratorio di Immunogenetica \u2010 Servizio di Immunoematologia e Medicina Trasfusionale \u2010 Fondazione IRCCS San Gerardo Dei Tintori  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8473-202X","authenticated-orcid":false,"given":"Roberto","family":"Crocchiolo","sequence":"additional","affiliation":[{"name":"Servizio di Immunoematologia e Medicina Trasfusionale \u2010 ASST Grande Ospedale Metropolitano Niguarda  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noemi","family":"Anzaldi","sequence":"additional","affiliation":[{"name":"Laboratorio di Immunogenetica \u2010 Servizio di Immunoematologia e Medicina Trasfusionale \u2010 Fondazione IRCCS San Gerardo Dei Tintori  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Calligaro","sequence":"additional","affiliation":[{"name":"Laboratorio di Immunogenetica \u2010 Servizio di Immunoematologia e Medicina Trasfusionale \u2010 Fondazione IRCCS San Gerardo Dei Tintori  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Gangi","sequence":"additional","affiliation":[{"name":"Laboratorio di Immunogenetica \u2010 Servizio di Immunoematologia e Medicina Trasfusionale \u2010 Fondazione IRCCS San Gerardo Dei Tintori  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariarosa","family":"Riva","sequence":"additional","affiliation":[{"name":"Laboratorio di Immunogenetica \u2010 Servizio di Immunoematologia e Medicina Trasfusionale \u2010 Fondazione IRCCS San Gerardo Dei Tintori  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara Mariadele","family":"Scollo","sequence":"additional","affiliation":[{"name":"Laboratorio di Immunogenetica \u2010 Servizio di Immunoematologia e Medicina Trasfusionale \u2010 Fondazione IRCCS San Gerardo Dei Tintori  Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri885"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0b013e31821a23d0"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0797-797"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0698-713"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.4.603"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0306885101"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.07.013"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.05.015"},{"key":"e_1_2_9_10_1","first-page":"60","article-title":"Celiac Disease and Type 1 Diabetes: Genetics, Pathogenesis and Immunotherapeutics","volume":"494","author":"Sollid L. 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Y.","year":"2015","journal-title":"Journal of Immunology"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2135229100"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0198-8859(03)00027-2"},{"key":"e_1_2_9_16_1","first-page":"142","article-title":"HLA DQ and DP Genes in Celiac Disease: DQ Beta 1*0201 Is Not the Only Genetic Risk Factor","volume":"47","author":"Polvi A.","year":"1996","journal-title":"Human Immunology"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00251-012-0599-z"},{"key":"e_1_2_9_18_1","article-title":"Association of HLA\u2010DQ Alleles With Celiac Disease in Children From Southwest of Iran","volume":"2023","author":"Keshtkari A.","year":"2023","journal-title":"International Journal of Peptides"},{"key":"e_1_2_9_19_1","first-page":"1531","article-title":"Intestinal T Cell Responses to Gluten Peptides Are Largely Confined to HLA\u2010DQ2.5 and HLA\u2010DQ8","volume":"188","author":"Camarca A.","year":"2012","journal-title":"Journal of Immunology"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31796-8"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1100"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1189"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M204521200"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa379"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27620"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1385\/1-59259-890-0:571"}],"container-title":["HLA"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/tan.70820","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/tan.70820","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/tan.70820","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T07:21:57Z","timestamp":1792394517000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/tan.70820"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":25,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1111\/tan.70820"],"URL":"https:\/\/doi.org\/10.1111\/tan.70820","archive":["Portico"],"relation":{},"ISSN":["2059-2302","2059-2310"],"issn-type":[{"value":"2059-2302","type":"print"},{"value":"2059-2310","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]},"assertion":[{"value":"2026-01-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70820"}}