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Showing results for tags 'intraepithelial'.
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Celiac.com 10/26/2017 - Making an accurate count of intraepithelial lymphocytes (IEL) is important to making an accurate diagnosis of celiac disease, but so far, researchers have not been able to establish a definitive 'normal' IEL range. In a recent multi-center study, a team of researchers set out to do just that. The research team included Kamran Rostami, Michael N Marsh, Matt W Johnson, Hamid Mohaghegh, Calvin Heal, Geoffrey Holmes, Arzu Ensari, David Aldulaimi, Brigitte Bancel, Gabrio Bassotti, Adrian Bateman, Gabriel Becheanu, Anna Bozzola, Antonio Carroccio, Carlo Catassi, Carolina Ciacci, Alexandra Ciobanu, Mihai Danciu, Mohammad H Derakhshan, Luca Elli, Stefano Ferrero, Michelangelo Fiorentino, Marilena Fiorino, Azita Ganji, Kamran Ghaffarzadehgan, James J Going, Sauid Ishaq, Alessandra Mandolesi, Sherly Mathews, Roxana Maxim, Chris J Mulde, Andra Neefjes-Borst, Marie Robert, Ilaria Russo, Mohammad Rostami-Nejad, Angelo Sidoni, Masoud Sotoudeh, Vincenzo Villanacci, Umberto Volta, Mohammad R Zali, Amitabh Srivastava. They are variously affiliated with the twenty-eight institutions listed below. The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centers in eight countries on three continents, recruited 198 patients with Marsh III histology, and another 203 control subjects. They used a single agreed upon protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. They also collected demographic and serological data. The research team used receiver operating characteristic (ROC) curve analysis to determine the optimal cut-off between normal and celiac disease (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens. The average ages of celiac and control groups were 45.5 and 38.3 years, respectively. They found that mean IEL count was 54±18/100 enterocytes in celiac disease and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the sub-classification of the Marsh III lesion. Their ROC curve analyses show that a cut-off of 25 IEL/100 enterocytes for Marsh III lesions provides the best way to distinguish between normal control and celiac disease biopsies. They saw no differences in IEL counts between Marsh III a, b and c lesions. There was an indication of a continuously graded dose–response by IEL to environmental gluten antigenic influence. Source: GUT Affiliations: The team members for this study are affiliated with the Department of Gastroenterology and Pathology, Milton Keynes University Hospital, Milton Keynes, UK; the Department of Gastroenterology, Luton and Dunstable University Hospital, Luton, UK; the Wolfson College, University of Oxford, Oxford, UK; the Gastroenterology and Liver Diseases Research Centre, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, The Islamic Republic of Iran; the Centre for Biostatistics, Faculty of Biology, Academic Health Science Centre, University of Manchester, Manchester, UK; the Department of Gastroenterology, Royal Derby Hospital, Derby, UK; the Department of Pathology, Ankara University Medical School, Ankara, Turkey; the Department of Gastroenterology, Warwick Hospital, Warwick, UK; the Service de Pathologie, Centre de Biologie et Pathologie Groupe Hospitalier du Nord, Hospices Civils de Lyon, Lyon, France; University of Perugia Medical School, Perugia, Italy; the Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Department of Pathology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Institute of Pathology Spedali Civili, Brescia, Italy; Internal Medicine and Pathology Unit, University of Palermo, Giovanni Paolo II Hospital, Sciacca, Italy; Department of Pediatrics and Surgical Pathology, Università Politecnica delle Marche, Ancona, Italy; Department of Medicine and Surgery, Scuola Medica Salernitana, University of Salerno, Salerno, Italy; Departments of Gastroenterology and Pathology, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania; College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; Digestive Disease Research Center, Tehran University Medical Science, Tehran, Iran; Center for Prevention and Diagnosis of Coeliac Disease and Pathology Unit, Fondazione IRCCS Ca' granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Medical and Surgical Sciences, University of Bologna and Diagnostic and Experimental, University of Bologna, Bologna, Italy; Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University 0f Medical Sciences, Mashhad, Iran; Pathology department, Razavi hospital, Mashhad, Iran; Department of Pathology, Southern General Hospital, Lanarkshire, UK; Department of Hepatogastroenterology and Pathology, Free University Medical Centre, Amsterdam, The Netherlands; Department of Pathology and Medicine, Yale University School of Medicine, New Haven, USA; Digestive Disease Research Center, Tehran University Medical Science, Tehran, Iran; Department of Pathology, Brigham & Women's Hospital, Boston, USA.
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Celiac.com 12/22/2016 - The nature of gut intraepithelial lymphocytes (IELs) lacking antigen receptors remains controversial. A team of researchers recently set out to better understand the mechanisms by which innate intraepithelial lymphocytes develop in the intestine and become cancerous in celiac disease patients. The research team included J Ettersperger, N Montcuquet, G Malamut, N Guegan, S Lopez-Lastra, S Gayraud, C Reimann, E Vidal, N Cagnard, P Villarese, I Andre-Schmutz, R Gomes Domingues, C Godinho-Silva, H Veiga-Fernandes, L Lhermitte, V Asnafi, E Macintyre, C Cellier, K Beldjord, JP Di Santo, N Cerf-Bensussan, and B Meresse. They are variously affiliated with the INSERM UMR1163, Laboratory of Intestinal Immunity, Institut Imagine; Laboratory of Human Lymphohematopoiesis; Institut Necker-Enfants-Malades, INSERM UMR1151 and, Biological Hematology, AP-HP Necker-Enfants-Malades; the Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine in Paris, France; AP-HP, Department of Gastroenterology, Hôpital Européen Georges Pompidou, 75015 Paris, France; Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France; Innate Immunity Unit, Institut Pasteur, 75015 Paris, France; INSERM U 668, Paris, France; Paris-Descartes Bioinformatic Platform, 75015 Paris, France; and with the Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa in Lisbon, Portugal. The team was able to show, in humans and in mice, innate intestinal IELs expressing intracellular CD3 (iCD3(+)) differentiate along an Id2 transcription factor (TF)-independent pathway in response to TF NOTCH1, interleukin-15 (IL-15), and Granzyme B signals. In NOTCH1-activated human hematopoietic precursors, IL-15 induced Granzyme B, which cleaved NOTCH1 into a peptide lacking transcriptional activity. As a result, NOTCH1 target genes necessary for T cell differentiation were silenced, and precursors were reprogrammed into innate cells with T cell marks, including intracellular CD3 and T cell rearrangements. In the intraepithelial lymphoma complicating celiac disease, iCD3(+) innate IELs acquired gain-of-function mutations in Janus kinase 1 or Signal transducer and activator of transcription 3, which enhanced their response to IL-15. The research team observed and described gut T cell-like innate IELs, decoded their pathway of change, and showed their malignant transformation in celiac disease. This study offers an exciting glimpse into the hard work being done in the far corners of celiac disease and cancer research. Source: Immunity. 2016 Sep 20;45(3):610-25. doi: 10.1016/j.immuni.2016.07.018. Epub 2016 Sep 6.
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Celiac.com 09/15/2014 - Duodenal intraepithelial lymphocytosis (D-IEL) is an early marker for celiac disease, even though a majority of cases are due to non-celiac disease conditions. Researchers I. Aziz, T. Key, J.G. Goodwin, and D.S. Sanders wanted to identify the predictors of celiac disease in patients presenting with D-IEL. For their study, they reviewed 215 adults with D-IEL who had undergone prospective and systematic evaluation for celiac disease and other recognized associations. They confirmed celiac disease based on presence of HLA-DQ2 and/or DQ8, persistence or progression of D-IEL following a gluten challenge, and an improvement in symptoms with a gluten-free diet. To compare factors in celiac and non-celiac cases, and to determine their sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), the team used binary logistic regression models, adjusted for age and sex. They diagnosed celiac disease in 48 cases (22%) and non-celiac in 167 cases (78%). They found no statistical difference between the celiac and non-celiac group in terms of baseline demographics, anemia, hematinics, or clinical symptoms, such as diarrhea, weight loss, abdominal pain. Compared with their non-celiac counterparts, celiac patients were significantly more likely to have a positive family history of celiac disease (21% vs. 3.6%, OR 6.73; PPV 62.5%, NPV 81%, specificity 96.4%), positive HLA-DQ status (100% vs. 49.1%; PPV 36.4%, NPV 100%, specificity 50.9%), and presence of endomysial antibody (EMA) (48% vs. 0%; PPV 100%, NPV 87%, specificity 100%); all P≤0.001. A total of 29.2% celiac and 83.2% non-celiac cases showed normal tissue transglutaminase antibody (TTG) levels (OR 0.084, P<0.001; PPV 9.2%). Between the groups, there was no difference in the prevalence of TTG levels 1 to 2×upper limit of normal (29.2% celiac vs. 14.4% non-celiac; PPV 33% to 38%). However, TTG levels between 3 and 20×ULN were much more common in the celiac group (33.3% vs. 2.4%, PPV 66.6% to 89%), whereas a TTG>20×ULN was exclusive to celiac disease (8.3%, P<0.001, PPV 100%). For patients with D-IEL, only a positive EMA or TTG greater than 20×ULN at the outset can yield an immediate celiac diagnosis. On their own, factors such as gastrointestinal symptoms, family history, anemia, or other celiac serology results do not reliably distinguish celiac from non-celiac patients. Source: J Clin Gastroenterol. 2014 Jul 10.
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Celiac.com 05/19/2010 - Enteropathy-associated T cell lymphoma is a serious complication of celiac disease, and a major cause of mortality in untreated celiac disease. One possible trigger for Enteropathy-associated T cell lymphoma development is chronic exposure of intraepithelial lymphocytes (IELs) to strong anti-apoptotic signals, that is, signals that interfere in the normal mortality of the IEL cells. These signals are triggered by IL-15, a cytokine that is over-expressed in the enterocytes of people with celiac disease. However, researchers have not yet fully mapped the signaling pathway by which IL-15 transmits these anti-apoptotic signals. Researchers consider type II refractory celiac disease (RCDII) to be a middle step between celiac disease and enteropathy-associated T cell lymphoma. Eliminating abnormal IELs at the RCDII stage would likely block EATL development. So far, though, scientists have not found successful immunosuppressive and/or chemotherapeutic approaches able to accomplish this, and RCDII outcomes remain very poor. A team of researchers recently set out to map the IL-15–driven survival pathway in human IELs, and to determine whether IL-15 triggered pathway in human intraepithelial lymphocytes represents a possible new target in type II refractory celiac disease and enteropathy-associated T cell lymphoma. The research team was made up of Georgia Malamut, Raja El Machhour, Nicolas Montcuquet, Séverine Martin-Lannerée, Isabelle Dusanter-Fourt, Virginie Verkarre, Jean-Jacques Mention, Gabriel Rahmi, Hiroshi Kiyono, Eric A. Butz, Nicole Brousse, Christophe Cellier, Nadine Cerf-Bensussan, and Bertrand Meresse. The are variously affiliated with INSERM U989, the Université Paris Descartes, Faculté de Médecine René Descartes, the Department of Gastroenterology, AP-HP, Hôpital Européen Georges Pompidou, the Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), INSERM U1016, the Department of Pathology, AP-HP, of the Hôpital Necker-Enfants Malades in Paris, with the Division of Mucosal Immunology, Department of Microbiology and Immunology at the Institute of Medical Science at the University of Tokyo in Japan, and the Inflammation Department of AMGEN Inc., in Seattle, Washington, USA. Their current findings reveal that the survival signals IL-15 directs to freshly isolated human IELs, and to human IEL cell lines derived from celiac disease patients with type II refractory celiac disease, depend on anti-apoptotic factors Bcl-2 and/or Bcl-xL. The signals require IL-15Rβ, Jak3, and STAT5 for proper function, but functioned independently of PI3K, ERK, and STAT3. In support of these findings, the team recorded elevated levels of Bcl-xL, phospho-Jak3, and phospho-STAT5 in IELs from patients with active celiac disease and RCDII. Moreover, by incubating patient duodenal biopsies with a fully humanized human IL-15–specific Ab, the team effectively blocked Jak3 and STAT5 phosphorylation. Also, treatment with IL-15–specific Ab caused IEL cell mortality, and wiped out the massive IEL build-up in mice over-expressing human IL-15 in their gut epithelium. The study marks the first successful mapping of the IL-15–driven survival pathway in human IELs, and demonstrates that IL-15 and its downstream effectors are meaningful therapeutic targets in RCDII. These findings will likely help to pave the way for the development of successful immunosuppressive and/or chemotherapeutic treatments that destroy abnormal IELs at the RCDII stage and help to block EATL development, improving outcomes for RCDII patients. Source: Journal of Clinical Investigation doi:10.1172/JCI41344
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Celiac.com 12/28/2009 - A team of researchers recently set out to compare continual monitoring of intraepithelial lymphocyte immunophenotype and clonality against snapshot analysis in the surveillance of refractory celiac disease. The research team was made up of H. Liu, R. Brais, A. Lavergne-Slove, Q. Jeng, K. Payne K, H. Ye, Z. Liu, J. Carreras, Y. Huang, C. M. Bacon, R. Hamoudi, V. Save, L. Venkatraman, P. G. Isaacson, J. Woodward, and M. Q. Du of Addenbrooke's Hospital, Cambridge, UK. Often, people with refractory celiac disease suffer from abnormal immunophenotype and monoclonality of intraepithelial lymphocytes (IELs). No good studies have been done to compare the utility of continual monitoring of IEL immunophenotype and clonality in monitoring refractory celiac disease (RCD). To address this deficiency, and to gather some data for comparison, the team used CD3e/CD8 double immunohistochemistry and PCR-based clonality analysis of the rearranged TCR genes to evaluate diagnostic and follow-up biopsies from 33 people with proven celiac disease, 7 with suspected refractory celiac disease, 41 with proven refractory celiac disease, and 20 with enteropathy associated T-cell lymphoma (including 11 evolved from RCD). The team found aberrant immunophenotype (CD3epsilon(+)CD8(-) IEL >/=40%) and monoclonality in occasional celiac disease biopsies, either transiently in celiac patients not following a gluten free diet, or in those who later developed refractory celiac disease, suspected RCD, or enteropathy associated T-cell lymphoma (EATL). By comparison, they found aberrant immunophenotype and monoclonality respectively in 30 of 41 (73%) and 24 of 37 (65%) biopsies at the time of diagnosis for refractory celiac disease. Among the patients with refractory celiac disease showed no such abnormalities in their diagnostic biopsies, 8 of 10 (80%) and 5 of 11 (45%) cases showed aberrant immunophenotype and monoclonality respectively upon follow-up. Whether found in initial or follow-up biopsies, the ongoing development of both aberrant immunophenotype and monoclonality is a common facet of refractory celiac disease. One key point was that the presence of both persistent monoclonality and aberrant immunophenotype, especially <>/=>80% CD3epsilon(+)CD8(-) IEL, was a strong predictor of enteropathy associated T-cell lymphoma development in patients with RCD (P=0.001). From these findings, the team found concludes that the continual monitoring of both immunophenotype and clonality of IEL is superior to snapshot analysis for diagnosis and follow-up of refractory celiac disease, and could provide a useful tool for surveillance of patients at risk of developing EATL. Source: Gut. 2009 Dec 8.
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Celiac.com 01/20/2009 - Refractory celiac disease is a serious condition that occurs when celiac symptoms and intestinal damage continue even when the patient consumes a gluten-free diet. There are two types of refractory celiac disease (RCD). In RCD type I, immuno-phenotype of intraepithelial lymphocytes (IELs) are normal and polyclonal, while RCD) type II, is noted for the presence of an abnormal intraepithelial lymphocyte (IEL) population (CD7+ CD3− CD4/8-cytoplasmic CD3+). More than half of people with this condition develop enteropathy-associated T-cell lymphoma (EATL), a rare but virulent form of cancer with high mortality rates. A team of doctors recently set out to examine the relationship between lymphoma development and intraepithelial gamma/delta T-lymphocytes in the small intestine of patients with all types of celiac disease, as compared to the general population. The team was made up of Wieke H.M. Verbeek, M.D., B. Mary E. von Blomberg, Ph.D., Petra E.T. Scholten, B.Sc., D. Joop Kuik, M.Sc., Chris J.J. Mulder, M.D. Ph.D., and Marco W.J. Schreurs, Ph.D., all from Amsterdam’s VU University Medical Center. A certain type of IELs called TCRγ/δ+ IELs may play an important role in repairing mucosa, maintaining homeostasis, and guarding against tumor development. TCRγ/δ+ IELs in the human intestine have recently shown promise in the regulation of uncomplicated celiac disease. In the study, the research team wanted to see if patients with RCD II had fewer TCRγ/δ+ IELs than either RDC I, or celiac disease, an thus provide a possible explanation for ongoing mucosal damage and inflammation, and the development of abnormal T cells that tend to morph into EATL. The team used a method called multi-parameter flow cytometric immuno-phenotyping on IELs obtained from recent small bowel biopsy specimens from a fairly large, distinct celiac disease and control groups (N = 87). Patients with RCD II showed a much lower ratio of TCRγ δ+ IELs compared to either RCD I or celiac disease patients. Whereas, patients with uncomplicated celiac disease showed significantly higher numbers of TCRγ δ+ IELs than were found in the control group. The results showed the relationship between TCRγ δ+ IELs and aberrant IELs to be negative. It is interesting to note that TCRγ δ+ IELs numbers do rise in RCD II patients after effective treatment. The negative relationship between TCRγ δ+ and abnormal IELs, together with their known role in regulating uncomplicated celiac disease, suggests that TCRγ δ+ IELs may play a crucial role in helping the body to repair mucosa, maintain homeostasis and possibly even guard against tumor development. These cells may serve as important markers, along with the abnormal T cells, to help distinguish between types of celiac disease, and to gage the effectiveness of treatment efforts. Am J Gastroenterol 2008;103:3152–3158
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Celiac.com 08/29/2007 - A study that appeared in the August issue of Journal of Clinical Gastroenterology, found that celiac disease and small intestinal bacterial growth both show increased levels of intraepithelial lymphocytes (IELs), especially gammadelta+ IELs. A sharp increase in gammadelta+ IELs has been noted in people with celiac disease, but little is known about the role of this particular class of IELs in other intestinal pathologies. A team of researchers led by J.M. Remes-Troche set out to assess the levels of IEls, especially of gammadelta+, in the duodenal mucosa biopsies from individuals w/ celiac disease and to compare them with those of patients with small intestinal bacterial overgrowth (SIBO), and irritable bowel syndrome (IBS). The study team looked at 12 individuals with untreated celiac disease, 8 patients with SIBO, and 10 patients with diarrhea-predominant IBS. All patients were given an upper-endoscopy for mucosal biopsy and jejunal aspirate. Intraepithelial cells were isolated from 2 small bowel biopsies, and labeled with monoclonal antibodies CD103-PE (phycoerythrin), CD3-FITC (fluoresecein isothio-cynate), celiac disease-7R-PE, CD45RO-APC (allophycocyanin), and TcR gammadelta-FITC. Researchers conducted flow cytometry analysis using a standard FACScan. Total IEL levels and subsequent levels were catalogued as percentages as follows: 16.7 +/- 6% for IBS patients; 25.7 +/- 17% for SIBO patients; and 26 +/- +/- 13% in celiac patients (P=0.2). Patients with SIBO & celiac disease showed significantly higher percentages of gammadelta+ IELs (14.6 +/- 8% and 15.7 +/- 13%) compared to IBS patients (4.1 +/- 2.5%, P<0.05). The results of the study indicate that gammadelta+ IELs might play a crucial role against intestinal bacterial infections. Journal of Clinical Gastroenterology. 2007 Aug;41(7):671-676 health writer who lives in San Francisco and is a frequent author of articles for Celiac.com.
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