{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T20:01:27Z","timestamp":1785528087824,"version":"3.56.0"},"reference-count":50,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"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":["Clin &amp; Trans Imm"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Refractory celiac disease type II (RCDII) is an intestinal tumor of aberrant intra\u2010epithelial T\u2010lymphocytes (IEL). The severe enteropathy found in RCDII is caused by aberrant IEL that exert cytotoxicity against enterocytes. In this study, we investigated the cell death mechanism responsible for villous atrophy in RCDII.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Aberrant IEL were isolated from duodenal biopsies of RCDII patients. Enterocyte and RCDII patient\u2010derived cell lines and human small intestinal organoids were used. mRNA expression was determined with reverse transcriptase\u2010multiplex ligation\u2010dependent probe amplification. Protein expression, degranulation and enterocyte killing were measured using flow cytometry, immunofluorescence or bright field microscopy. Secretion of granzyme\u2010B was detected by enzyme immunoassay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Levels of granzyme\u2010B expression were significantly upregulated in aberrant IEL of RCDII patients compared to patients with celiac disease (CD) on gluten\u2010free diet (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0001) and correlated with severity of villous atrophy and clinical response to therapy. Killing of intestinal epithelial cells was caused by granzyme\u2010B. For granzyme\u2010B degranulation and subsequent cytotoxicity, cell\u2013cell binding via the CD103\u2010receptor, which was upregulated on aberrant IEL, was essential. In a preclinical model, aberrant IEL migrated to the intestinal organoids and induced organoid disintegration and CD103\u2010dependent cell death. Targeting CD103\u2010heterodimeric partner \u03b27 with therapeutic monoclonal antibody etrolizumab prevented enterocyte cell killing and resulted in survival of organoids.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Killing of enterocytes in RCDII patients depends on degranulation of granzyme\u2010B by aberrant IEL through CD103\u2010\u03b27 binding. By blocking this interaction, etrolizumab restores the intestinal epithelium and therefore should be considered as potential therapy for RCDII patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cti2.70099","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T02:52:06Z","timestamp":1778813526000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aberrant intra\u2010epithelial lymphocytes cause enterocyte cell\u00a0death in refractory celiac disease by\n                    <scp>CD103<\/scp>\n                    \u2010\u03b27\u2010receptor\u2010mediated granzyme\u2010B degranulation which can be restored by etrolizumab"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7422-3387","authenticated-orcid":false,"given":"Daan A R","family":"Castelijn","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"},{"name":"Department of Pathology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"},{"name":"Department of Internal Medicine St. Antonius Hospital  Nieuwegein The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanda M W","family":"van de Water","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura R","family":"de Baaij","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridget S","family":"McGlinchy","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"van Leeuwen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander P J","family":"Joosten","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Alberts","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine","family":"Reijm","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Amsterdam Institute for Infection and Immunity Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien C","family":"Hollander","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Amsterdam Institute for Infection and Immunity Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Bonnet","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Amsterdam Institute for Infection and Immunity Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne M C","family":"Kooy\u2010Winkelaar","sequence":"additional","affiliation":[{"name":"Department of Immunohematology and Blood Transfusion Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frits","family":"Koning","sequence":"additional","affiliation":[{"name":"Department of Immunohematology and Blood Transfusion Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven T","family":"Pals","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd","family":"Bouma","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris J L M","family":"Meijer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hetty J","family":"Bontkes","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Amsterdam Institute for Infection and Immunity Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris J J","family":"Mulder","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia A G M","family":"Cillessen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Gastroenterology Endocrinology and Metabolism Research Institute Amsterdam University Medical Centers  Amsterdam The 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