{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T01:05:17Z","timestamp":1771549517867,"version":"3.50.1"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2000,5,1]],"date-time":"2000-05-01T00:00:00Z","timestamp":957139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2001,12,24]]},"abstract":"<jats:title>SUMMARY<\/jats:title><jats:p>The effector arm of the mucosal immune system comprises lymphocytes scattered at intraepithelial and lamina propria levels. Intraepithelial lymphocytes (IEL) are a large population of oligoclonal resting cells which exhibit phenotypic and functional characteristics of cytolytic T cells when activated. Several mechanisms have been demonstrated to account for their cytotoxicity. Among them, one is mediated by perforin and granzyme molecules, another is mediated by Fas ligand (FasL) which delivers apoptotic signals through Fas receptor on target cells. There is good evidence that a flat intestinal mucosa may be produced by activated T cells. The aim of our study was to evaluate FasL and perforin expression by IEL, and its possible correlation with the increased enterocyte apoptosis in coeliac mucosa. Endoscopic duodenal biopsy specimens from 10 untreated coeliac patients, 10 treated coeliac patients, and 10 biopsied controls were evaluated for enterocyte apoptosis by terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine triphosphate nick end label method, for perforin expression by immunohistochemistry, and for FasL expression by immunocytochemistry. In untreated CoD there was a significant increase of percentage of both FasL+ and perforin+ IEL which positively correlated with enterocyte apoptosis in comparison with controls. All these parameters were significantly lower in treated CoD, even though they did not normalize. Our study demonstrates that in untreated CoD FasL and perforin expression by IEL is increased, and significantly correlates with the level of enterocyte apoptosis.<\/jats:p>","DOI":"10.1046\/j.1365-2249.2000.01200.x","type":"journal-article","created":{"date-parts":[[2003,3,11]],"date-time":"2003-03-11T10:21:27Z","timestamp":1047378087000},"page":"235-240","source":"Crossref","is-referenced-by-count":42,"title":["Cytolytic mechanisms of intraepithelial lymphocytes in coeliac disease (CoD)"],"prefix":"10.1093","volume":"120","author":[{"given":"R","family":"Ciccocioppo","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Di Sabatino","sequence":"additional","affiliation":[{"name":"Gastroenterology Unit, IRCCS Policlinico S. Matteo, University of Pavia, Pavia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Parroni","sequence":"additional","affiliation":[{"name":"Experimental Medicine and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"D\u2019Al\u00f2","sequence":"additional","affiliation":[{"name":"Experimental Medicine and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M A","family":"Pistoia","sequence":"additional","affiliation":[{"name":"Surgery, University of L\u2019Aquila, L\u2019Aquila"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Doglioni","sequence":"additional","affiliation":[{"name":"Pathology Unit, Hospital of Belluno, Belluno, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M G","family":"Cifone","sequence":"additional","affiliation":[{"name":"Experimental Medicine and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G R","family":"Corazza","sequence":"additional","affiliation":[{"name":"Gastroenterology Unit, IRCCS Policlinico S. Matteo, University of Pavia, Pavia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2001,12,24]]},"reference":[{"key":"2022011221074687600_b1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0092-8674(00)80309-8","article-title":"Molecular mechanisms in cell-mediated cytotoxicity","volume":"90","author":"Moretta","year":"1997","journal-title":"Cell"},{"key":"2022011221074687600_b2","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0092-8674(00)81874-7","article-title":"Apoptosis by death factor","volume":"88","author":"Nagata","year":"1997","journal-title":"Cell"},{"key":"2022011221074687600_b3","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/369031a0","article-title":"Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice","volume":"369","author":"K\u00e4gi","year":"1994","journal-title":"Nature"},{"key":"2022011221074687600_b4","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/0016-5085(92)91819-P","article-title":"Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (\u2018celiac sprue\u2019)","volume":"102","author":"Marsh","year":"1992","journal-title":"Gastroenterology"},{"key":"2022011221074687600_b5","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":"Nature Med"},{"key":"2022011221074687600_b6","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/nm0797-797","article-title":"Identification of tissue transglutaminase as the autoantigen of celiac disease","volume":"3","author":"Dieterich","year":"1997","journal-title":"Nature Med"},{"key":"2022011221074687600_b7","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/0950-3528(95)90032-2","article-title":"Morphology of the mucosal lesion in gluten sensitivity","volume":"9","author":"Marsh","year":"1995","journal-title":"Bailli\u00e8re\u2019s Clin Gastroenterol"},{"key":"2022011221074687600_b8","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1136\/gut.39.6.811","article-title":"Increased small intestinal apoptosis in coeliac disease","volume":"39","author":"Moss","year":"1996","journal-title":"Gut"},{"key":"2022011221074687600_b9","first-page":"667","article-title":"Time\/dose response of coeliac mucosa to graded oral challenges with Frazer\u2019s fraction III of gliadin","volume":"4","author":"Marsh","year":"1992","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"2022011221074687600_b10","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1016\/0140-6736(92)91262-7","article-title":"Dose effect of DQA and DQB genes on the density of intraepithelial \u03b3\/\u03b4 T cell receptor bearing lymphocytes in healthy first-degree relatives of coeliac disease patients","volume":"339","author":"Holm","year":"1992","journal-title":"Lancet"},{"key":"2022011221074687600_b11","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1615\/CritRevImmunol.v18.i3.40","article-title":"Intraepithelial lymphocytes: origins, distribution, and function","volume":"18","author":"Beagley","year":"1998","journal-title":"Crit Rev Immunol"},{"key":"2022011221074687600_b12","first-page":"435","article-title":"Intraepithelial lymphocytes in normal human intestine do not express proteins associated with cytolytic function","volume":"151","author":"Chott","year":"1997","journal-title":"Am J Pathol"},{"key":"2022011221074687600_b13","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1136\/gut.34.2.208","article-title":"Numbers of T cell receptor (TCR) \u03b1\/\u03b2+ but not of TCR \u03b3\/\u03b4+ 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":"2022011221074687600_b14","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1083\/jcb.119.3.493","article-title":"Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation","volume":"119","author":"Gavrieli","year":"1992","journal-title":"J Cell Biol"},{"key":"2022011221074687600_b15","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1097\/00001574-199309060-00011","article-title":"Gut intraepithelial lymphocytes and gastrointestinal diseases","volume":"9","author":"Cerf-Bensussan","year":"1993","journal-title":"Curr Opin Gastroenterol"},{"key":"2022011221074687600_b16","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/0167-5699(88)91267-4","article-title":"Specificity and function of T cells bearing \u03b3\u03b4 receptor","volume":"9","author":"Janeway","year":"1988","journal-title":"Immunol Today"},{"key":"2022011221074687600_b17","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1126\/science.7973709","article-title":"Modulation of epithelial cell growth by intraepithelial \u03b3\u03b4 T cells","volume":"266","author":"Boismenu","year":"1994","journal-title":"Science"},{"key":"2022011221074687600_b18","doi-asserted-by":"crossref","first-page":"3736","DOI":"10.4049\/jimmunol.147.11.3736","article-title":"Novel function for intraepithelial lymphocytes: murine CD3+, \u03b3\u03b4 TCR T cells produce IFN-\u03b3 and IL-5","volume":"147","author":"Taguchi","year":"1991","journal-title":"J Immunol"},{"key":"2022011221074687600_b19","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1136\/gut.44.1.137","article-title":"Oral tolerance in disease","volume":"44","author":"Garside","year":"1999","journal-title":"Gut"},{"key":"2022011221074687600_b20","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/0016-5085(92)91785-3","article-title":"Spontaneous cytotoxicity of human intraepithelial lymphocytes against epithelial cell tumors","volume":"102","author":"Taunk","year":"1992","journal-title":"Gastroenterology"},{"key":"2022011221074687600_b21","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.4049\/jimmunol.157.5.1926","article-title":"Intraepithelial lymphocytes in human gut have lytic potential and a cytokine profile that suggest T helper 1 and cytotoxic functions","volume":"157","author":"Lundqvist","year":"1996","journal-title":"J Immunol"},{"key":"2022011221074687600_b22","doi-asserted-by":"crossref","first-page":"35","DOI":"10.4049\/jimmunol.156.1.35","article-title":"Activated \u03b1\u03b2-CD8+, but not \u03b1\u03b1-CD8+, TCR\u03b1\u03b2+ murine intestinal intraepithelial lymphocytes can mediate perforin-based cytotoxicity, whereas both subsets are active in Fas-based cytotoxicity","volume":"156","author":"Gelfanov","year":"1996","journal-title":"J Immunol"},{"key":"2022011221074687600_b23","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1002\/(SICI)1521-4141(199802)28:02<730::AID-IMMU730>3.0.CO;2-U","article-title":"Small bowel enteropathy: role of intraepithelial lymphocytes and of cytokines (IL-12, IFN-\u03b3, TNF) in the induction of epithelial cell death and renewal","volume":"28","author":"Guy-Grand","year":"1998","journal-title":"Eur J Immunol"},{"key":"2022011221074687600_b24","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1136\/gut.12.12.988","article-title":"Quantification of intraepithelial lymphocytes in human jejunum","volume":"12","author":"Ferguson","year":"1971","journal-title":"Gut"},{"key":"2022011221074687600_b25","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1136\/gut.25.2.158","article-title":"Jejunal intraepithelial lymphocytes in coeliac disease: are they increased or decreased?","volume":"25","author":"Corazza","year":"1984","journal-title":"Gut"},{"key":"2022011221074687600_b26","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1046\/j.1365-2249.1999.00827.x","article-title":"Functional expression of Fas and Fas ligand on human intestinal intraepithelial lymphocytes","volume":"116","author":"Morimoto","year":"1999","journal-title":"Clin Exp Immunol"},{"key":"2022011221074687600_b27","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/S0016-5085(97)70092-1","article-title":"Fas-mediated cytotoxicity by intestinal intraepithelial lymphocytes during acute graft-versus-host disease in mice","volume":"113","author":"Sakai","year":"1997","journal-title":"Gastroenterology"},{"key":"2022011221074687600_b28","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1172\/JCI896","article-title":"Fas ligand-mediated killing by intestinal intraepithelial lymphocytes. Participation in intestinal graft-versus-host disease","volume":"101","author":"Lin","year":"1998","journal-title":"J Clin Invest"},{"key":"2022011221074687600_b29","first-page":"1351","article-title":"Evidence that intestinal intraepithelial lymphocytes are activated cytotoxic T cells in celiac disease but not in giardiasis","volume":"148","author":"Oberhuber","year":"1996","journal-title":"Am J Pathol"},{"key":"2022011221074687600_b30","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1097\/00005176-199810000-00004","article-title":"Are intraepithelial lymphocytes in celiac mucosa responsible for inducing programmed cell death (apoptosis) in enterocytes? Histochemical demonstration of perforins in cytoplasmic granules of intraepithelial lymphocytes","volume":"27","author":"Shiner","year":"1998","journal-title":"J Pediatric Gastroenterol Nutrition"},{"key":"2022011221074687600_b31","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1136\/gut.32.8.881","article-title":"Compliance of adolescents with coeliac disease with a gluten-free diet","volume":"32","author":"Mayer","year":"1991","journal-title":"Gut"},{"key":"2022011221074687600_b32","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1136\/gut.34.11.1515","article-title":"Dose dependent effects of protracted ingestion of small amounts of gliadin in coeliac disease children: a clinical and jejunal morphometric study","volume":"34","author":"Catassi","year":"1993","journal-title":"Gut"},{"key":"2022011221074687600_b33","first-page":"1","article-title":"Enteropathy-associated T cell lymphoma is recognized by a monoclonal antibody (HML-1) that defines a membrane molecule on human mucosal lymphocytes","volume":"132","author":"Spencer","year":"1988","journal-title":"Am J Pathol"},{"key":"2022011221074687600_b34","doi-asserted-by":"crossref","first-page":"3785","DOI":"10.1182\/blood.V84.11.3785.bloodjournal84113785","article-title":"Granzyme B-expressing peripheral T-cell lymphomas: neoplastic equivalents of activated cytotoxic T cells with preference for mucosa-associated lymphoid tissue localization","volume":"84","author":"De Bruin","year":"1994","journal-title":"Blood"},{"key":"2022011221074687600_b35","first-page":"S68","article-title":"Classification of intestinal T-cell neoplasms and their differential diagnosis","volume":"111","author":"Chott","year":"1999","journal-title":"Am J Clin Pathol"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1046%2Fj.1365-2249.2000.01200.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1046%2Fj.1365-2249.2000.01200.x","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/120\/2\/235\/42129518\/j.1365-2249.2000.01200.x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/120\/2\/235\/42129518\/j.1365-2249.2000.01200.x.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T21:13:46Z","timestamp":1682111626000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/120\/2\/235\/6461657"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,5]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2001,12,24]]},"published-print":{"date-parts":[[2001,12,24]]}},"URL":"https:\/\/doi.org\/10.1046\/j.1365-2249.2000.01200.x","relation":{},"ISSN":["1365-2249","0009-9104"],"issn-type":[{"value":"1365-2249","type":"electronic"},{"value":"0009-9104","type":"print"}],"subject":[],"published-other":{"date-parts":[[2000,5]]},"published":{"date-parts":[[2000,5]]}}}