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Celiac.com 10/11/2016 - Celiac disease is an autoimmune disease in genetically susceptible individuals and is triggered by adverse immune reactions to gluten, a protein found in wheat and other grains. Researchers led by a research group at Finland's University of Tampere, led by Keijo Viiri, PhD, recently discovered a mechanism that triggers aberrant features in celiac disease and colorectal cancer. Disturbances in this mechanism seem to trigger certain symptoms celiac disease, and possibly in colorectal cancer. The research team's recent study offers new details on the pathogenesis of the differentiation defect of the epithelium in the small intestine in celiac disease. When people with celiac disease eat gluten, they suffer intestinal mucosal damage with villus atrophy and crypt hyperplasia. At the cellular level, epithelial cells are less differentiated and hyper-proliferative leading to the malabsorption of nutrients. Researchers discovered that a certain epigenetic mechanism, called Polycomb, governs the homeostasis between the intestinal stem cells in the crypt and the differentiated epithelium in the villi. Polycomb acts by silencing genes epigenetically by methylating histone proteins that are packing the DNA. "Polycomb is well-known for its function to regulate embryonal development. We discovered that Polycomb is also able to regulate the homeostasis of the small intestine in adults. The regulation of intestinal homeostasis is a tremendous task as the epithelium of the intestine needs to be replenished completely every 4-5 days," says Academy of Finland Postdoctoral Researcher and Principal Investigator Keijo Viiri. This study demonstrates that in people with celiac disease, dietary gluten triggers excessive activity of Polycomb leading to the aberrant silencing of genes necessary for the differentiation of villus epithelium and to the concomitant differentiation defect in celiac disease. Moreover, the study demonstrates that Polycomb target genes are also dysregulated in colorectal cancer, which suggests that aberrant Polycomb activity is common in intestinal diseases entailing a differentiation defect on the intestinal epithelium. From a clinical point of view, this work provides new insight into the pathogenesis of the intestinal damage in celiac disease and provides diagnostic markers for the disease. Since Polycomb regulates only genes imperative for development, this work is also instrumental to further understand the biology of the intestinal homeostasis. Source: ScienceDaily via Suomen Akatemia (Academy of Finland)
Celiac.com 10/25/2012 - Abnormal intraepithelial lymphocytes (IELs) are the main feature of refractory celiac disease type II (RCDII). However, researchers still don't know exactly how these abnormal IELs originate. A pair of researchers recently commented on efforts to learn how these abnormal IELs might come about. The pair were Victor F. Zevallos, and Detlef Schuppan, of the center for Molecular and Translational Medicine, Department of Medicine I at the University Medical Center of Johannes Gutenberg University Mainz, in Mainz, Germany. Their commentary focuses on efforts by a separate research team, Schmitz, et al., which had already used a broad spectrum of cell specific markers, RNA array and immunological techniques, to explore abnormal IEL cell lines from four RCDII patients, and compare them with IELs from the fetal intestine, the intestine of children and adults and the thymus. IELs are highly varied lymphocytes cells with innate and adaptive features that live in the small and large intestine. IELs play an important role in maintaining gut tolerance to common food antigens versus defense against pathogens. A number of nutritional factors influence the development and spread of IELs, especially vitamins and their active metabolites, such as retinoic acid, and phytochemicals such as ligands of the aryl hydrocarbon receptor from cruciferous vegetables. However, when IELs activate and expand uncontrollably in response to chronic inflammatory conditions in the gut, they trigger mucosal damage, which can lead to celiac disease, and in some cases, to malignant cancers. Up to 5% of people with celiac disease, especially those who are over fifty years old when diagnosed, continue to suffer from clinical symptoms and villous atrophy even when following a gluten-free diet. After excluding ongoing gluten consumption and other potential underlying diseases, all four patients studied by Schmitz could be diagnosed with RCD, which is classically classified as type I or type II, based on the histological co-expression of CD3 and CD8 in RCDI, or absence of such co-expression in RCDII. Read the entire report in Gut. Source: Gut doi:10.1136/gutjnl-2012-303030
Celiac.com 04/23/2012 - Aberrant intra-epithelial lymphocytes (IELs) are one of the major features of refractory celiac disease type II RCDII. They are categorized as pre-malignant cells, which can give rise to aggressive enteropathy-associated T cell lymphoma (EATL). A medical research team recently studied the origin and immuno-phenotype of aberrant IEL in RCDII patients. The research team included G.J. Tack, R.L. van Wanrooij, A.W. Langerak, J.M. Tjon, B.M. von Blomberg, D.A. Heideman, J. van Bergen, F. Koning, G. Bouma, C.J. Mulder, and M.W Schreurs. They are affiliated with the Gastroenterology and Hepatology, VU University Medical Center, The Netherlands. The team set out to better understand the origin and characteristics of aberrant IELs by scrutinizing T-cell receptor (TCR) rearrangements, and through immunophenotypic analysis of aberrant IELs. For their study, the team looked for TCR delta, gamma, and beta rearrangements in duodenal biopsies from 18 RCDII patients. they also analyzed three RCDII cell lines. They also conducted phenotypical analysis on IELs isolated from biopsies taken from RCDII patients. They found that aberrant IELs showed an increased expression of granzyme B, along with a reduced expression of PCNA. Biopsies of RCDII patients showed heterogenic TCR rearrangements in the aberrant IEL cells. The researchers suggest that this is likely due to a variation in maturity. Similarly, RCDII cell lines showed a heterogenic TCR rearrangement pattern. From their data, the team concludes that aberrant IELs originate from deranged immature T lymphocytes and show clear differentiation to a cytotoxic phenotype. Among RCDII patients, aberrant IELs showed different stages of maturity, and only the patients who had the most mature aberrant IEL cells developed an EATL. Source: Molecular Immunology. 2012 Feb 22.