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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.
Jefferson Adams posted an article in Cancer, Lymphoma and Celiac DiseaseCeliac.com 11/08/2012 - T-cell lymphoma is a deadly type of cancer that is more common in people with celiac disease than in the general population. Currently, there is no cure for T-cell lymphoma, and no promising treatment exists for people who suffer from this condition. However, that may be set to change, as the results of a new study suggest that new treatments for T-cell lymphoma my be on the horizon. The study appears in the journal Clinical Lymphoma Myeloma and Leukemia. The study team included J.R. Bertino, M. Lubin, N. Johnson-Farley, W.C. Chan, L. Goodell, and S. Bhagavathi. They are affiliated with the Departments of Medicine, Pharmacology, and Pathology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ. The team was attempting to address the fact that doctors treating T-cell lymphomas, especially types of T-cell lymphoma known as peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL) have limited treatment options and cannot cure the condition. Their study noted that a high percentage of PTCL, AITL, and ALCL, along with T-cell leukemia and T-cell lymphoblastic leukemia lack the enzyme methylthioadenosine phosphorylase (MTAP). Their published results also note that MTAP-deficient cells cannot cleave endogenous methylthioadenosine to adenine and 5-methylthioribose-1-phosphate, a precursor of methionine, and as a result have enhanced sensitivity to inhibitors of de novo purine biosynthesis. A recently introduced antifolate, pralatrexate, which has been shown to inhibit de novo purine biosynthesis, has been approved for treatment of PTCL and may have an increasing role in therapy. An alternative strategy involving coadministration of methylthioadenosine and high-dose 6-thioguanine has been proposed and may prove to be selectively toxic to MTAP-deficient uncommon lymphomas. As a result of these MTAP results, the team suggests that new therapies and treatments for T-cell lymphoma may be possible going forward. Source: Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):306-9. doi: 10.1016/j.clml.2012.07.001.
Celiac.com 04/13/2010 - A team of clinicians recently described a case of immune modulation by non-Hodgkin lymphoma in a patient with two primary intestinal T-Cell lymphomas and long-standing celiac disease. F. MuÌˆhr-Wilkenshoff, M. Friedrich, H. D. Foss, M. Hummel, M. Zeitz, and S. Daum made up the research team. They are variously affiliated with the Medical Clinic I, Gastroenterology, Rheumatology and Infectious Diseases, and with the Department of Pathology, Charité of the Campus Benjamin Franklin of University Medicine Berlin, Germany. About 20–30% of all non-Hodgkin lymphomas (NHLs) are gastrointestinal in nature. Of these gastrointestinal lymphomas, about 20–30% occur in small intestine The clinical team recently reported the case of a 72-year-old patient who had been diagnosed with celiac disease when he was 52-years old. The man had not followed a gluten-free diet, yet showed no evidence of enteropathy or celiac-associated antibodies, but still developed a jejunal T-cell lymphoma. Doctors resected the lymphoma due to perforation and treated the patient with four courses of IMVP-16. The patient began and maintained a strict gluten-free diet. Two years later, the patient appeared with weight loss and a clonally divergent refractory sprue type II with loss of antigen (CD8; T-cell receptor-) expression in intraepithelial lymphocytes. At this time, he showed high titers of celiac-associated antibodies, although he was on a strict GFD. The research team notes that the missing enteropathy under a gluten-containing diet supports the idea of immune suppression in malignant diseases, especially non-Hodgkin lymphoma. They also note that the fact that, even while maintaining a strict gluten-free diet, the patient developed refractory sprue type II, an early form of another independent T-cell lymphoma, along with celiac-associated antibodies, suggests that clonal intraepithelial lymphocytes might be stimulating antibody production. Thus, they conclude that isolated detection of celiac-associated antibodies in patients with celiac disease does not prove that patients have deviated from their gluten-free diets. Source: Digestion 2010;81:231–234 DOI: 10.1159/000269810
Small Intestinal Intraepithelial Gamma/Delta T-Lymphocytes Occur Inversely to Lymphomas in Refractory Celiac Disease
Jefferson Adams posted an article in Cancer, Lymphoma and Celiac DiseaseCeliac.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+ CD3âˆ’ 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 TCRÎ³/Î´+ IELs may play an important role in repairing mucosa, maintaining homeostasis, and guarding against tumor development. TCRÎ³/Î´+ 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 TCRÎ³/Î´+ 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 TCRÎ³ Î´+ IELs compared to either RCD I or celiac disease patients. Whereas, patients with uncomplicated celiac disease showed significantly higher numbers of TCRÎ³ Î´+ IELs than were found in the control group. The results showed the relationship between TCRÎ³ Î´+ IELs and aberrant IELs to be negative. It is interesting to note that TCRÎ³ Î´+ IELs numbers do rise in RCD II patients after effective treatment. The negative relationship between TCRÎ³ Î´+ and abnormal IELs, together with their known role in regulating uncomplicated celiac disease, suggests that TCRÎ³ Î´+ 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