{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T13:57:51Z","timestamp":1761659871769,"version":"build-2065373602"},"reference-count":28,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004462","name":"Consiglio Nazionale delle Ricerche","doi-asserted-by":"publisher","award":["FOE 2021 DBA.AD005.225","FOE 2022 DSB.AD006.371"],"award-info":[{"award-number":["FOE 2021 DBA.AD005.225","FOE 2022 DSB.AD006.371"]}],"id":[{"id":"10.13039\/501100004462","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The diagnosis of celiac disease (CD) relies on the presence of serum antibodies against type 2\u2010tissue transglutaminase (tTG2) and endomysium, which in adult patients must be confirmed by assessing small intestinal mucosa damage through esophagogastroduodenoscopy. We aim to establish a non\u2010invasive method focused on detecting activated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells that are reactive to gliadin in the peripheral blood of patients with untreated CD. Peripheral blood mononuclear cells from 20 patients with untreated CD, 17 patients on a gluten\u2010free diet and 10 healthy donors were stimulated in\u00a0vitro with whole gliadin or immunodominant peptides. After 48\u2009h, cells were stained with fluorochrome\u2010conjugated monoclonal antibodies against OX40 and 4\u20101BB surface activation markers. Gliadin\u2010specific, activated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells were detected through multiparametric flow cytometry. OX40 and 4\u20101BB activation markers are upregulated on CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells following the engagement of the HLA\u2010DQ2.5\u2010gliadin complex with the T\u2010cell receptor (TCR). The frequency of gliadin\u2010specific, CD3\n                    <jats:sup>+<\/jats:sup>\n                    \/CD4\n                    <jats:sup>+<\/jats:sup>\n                    \/OX40\n                    <jats:sup>+<\/jats:sup>\n                    \/4\u20101BB\n                    <jats:sup>+<\/jats:sup>\n                    cells is significantly higher in untreated than in treated patients and healthy controls and shows a positive correlation with the anti\u2010tTG2 antibody titers. This assay, defined as the\n                    <jats:italic>G.A.T.CD4<\/jats:italic>\n                    (\n                    <jats:italic>Gliadin activated CD4<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>T cells<\/jats:italic>\n                    ) method, might support CD diagnosis, particularly in doubtful cases having low autoantibody serum titers.\n                    <jats:italic>G.A.T.CD4<\/jats:italic>\n                    can be of help in monitoring disease progression, as the pathogenic T cells expressing OX40 and 4\u20101BB activation markers are undetectable in the blood of treated patients. In the future, we aim to propose the\n                    <jats:italic>G.A.T.CD4<\/jats:italic>\n                    instead of esophagogastroduodenoscopy to perform accurate and less invasive diagnosis.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.70898","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T07:20:03Z","timestamp":1761117603000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Detection of Gliadin\u2010Activated\n                    <scp>CD4<\/scp>\n                    <sup>+<\/sup>\n                    T Cells Is a New Assay to Reveal Pathogenic Lymphocytes in Celiac Disease"],"prefix":"10.1111","volume":"29","author":[{"given":"Laura","family":"Pisapia","sequence":"first","affiliation":[{"name":"Institute of Genetics and Biophysics CNR  Naples Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcella","family":"D'Ambrosio","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics CNR  Naples Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilaria","family":"Mottola","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology CNR  Naples Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Picascia","sequence":"additional","affiliation":[{"name":"Institute of Endotypes in Oncology, Metabolism and Immunology \u201cG. Salvatore\u201d CNR  Naples Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Domenico","family":"De Girolamo","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology CEINGE Advanced Biotechnologies \u201cFranco Salvatore\u201d  Naples Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabiana","family":"Castiglione","sequence":"additional","affiliation":[{"name":"Gastroenterology, Department of Clinical Medicine and Surgery University Federico II  Naples Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia","family":"Tinto","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology CEINGE Advanced Biotechnologies \u201cFranco Salvatore\u201d  Naples Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Rispo","sequence":"additional","affiliation":[{"name":"Gastroenterology, Department of Clinical Medicine and Surgery University Federico II  Naples Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Gianfrani","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology CNR  Naples Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8937-9018","authenticated-orcid":false,"given":"Giovanna","family":"Del Pozzo","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics CNR  Naples Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/2050640619844125"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000002497"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575\u2010023\u201000872\u20102"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2024.02.050"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2017.12.016"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365\u20103083.1996.d01\u201017.x"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010019\u20100403\u20109"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202104766"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/2050640619874183"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.11.006"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803181"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102249.2012.04597.x"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2025.05.022"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PONE.0186998"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.BBRC.2021.07.037"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.IMLET.2019.12.006"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001471\u2010y"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.JIM.2023.113443"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.015"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/v15051132"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2008.04.003"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00251\u2010019\u201001141\u2010w"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0001\u20102815.2004.00237.x"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12636"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.03.002"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201073907\u20102"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2016.03.016"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI98819"}],"container-title":["Journal 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