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Celiac.com 02/17/2020 - Celiac disease is a common inflammatory autoimmune disorder triggered when dietary gluten causes intestinal damage in genetically susceptible people who have either of two genes, the HLA-DQ8 or HLA-DQ2 haplotypes. More and more, doctors see a need to come up with non-dietary treatments, but there is currently no good gluten- and HLA-dependent model. Human data has led to a great deal of information about the origins of celiac disease, but no one has yet revealed the roles of disease-predisposing HLA molecules, and of adaptive and innate immunity in celiac-related tissue damage. A large team of top researchers recently set out to determine if interleukin-15 gluten and HLA-DQ8 drive tissue destruction in celiac disease. The research team included Valérie Abadie, Sangman M. Kim, Thomas Lejeune, Brad A. Palanski, Jordan D. Ernest, Olivier Tastet, Jordan Voisine, Valentina Discepolo, Eric V. Marietta, Mohamed B. F. Hawash, Cezary Ciszewski, Romain Bouziat, Kaushik Panigrahi, Irina Horwath, Matthew A. Zurenski, Ian Lawrence, Anne Dumaine, Vania Yotova, Jean-Christophe Grenier, Joseph A. Murray, Chaitan Khosla, Luis B. Barreiro and Bana Jabri. The team used a mouse model to mimic the over-expression of interleukin-15 (IL-15) in the gut epithelium and lamina propria that marks active celiac disease, carries HLA-DQ8, and shows villous atrophy after gluten exposure. For villous atrophy to occur, IL-15 must be over-expressed in both the epithelium and the lamina propria, which shows the crucial role of IL-15 in the development of celiac disease. Moreover, CD4+ T cells and HLA-DQ8 play a central part in permitting cytotoxic T cells to mediate intestinal epithelial cell lysis. The team's results also demonstrate a role for the cytokine interferon-γ (IFNγ) and the enzyme transglutaminase 2 (TG2) in tissue destruction. By revealing the intricate interplay between gluten, genetics and IL-15-driven tissue inflammation, this mouse model casts light on the mechanisms behind celiac disease, and may help to drive the development of new treatments. Read more at Nature.com The researchers are variously affiliated with the Department of Medicine, University of Chicago, Chicago, IL, USA, Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA; the Department of Biology, University of San Francisco, San Francisco, CA, USA; the Department of Chemistry, Stanford University, Stanford, CA, USA; the Department of Chemical Engineering, Stanford University, Stanford, CA, USA; the Stanford ChEM-H, Stanford University, Stanford, CA, USA; the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; the Department of Immunology, Mayo Clinic, Rochester, MN, USA; the Department of Dermatology, Mayo Clinic, Rochester, MN, USA; the Department of Microbiology, Infectiology, and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; the Department of Genetics, Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada; Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; the Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, Quebec, Canada.

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.

Celiac.com 03/18/2011 - By blocking an inflammatory protein called interleukin-15 (IL-15), doctors may be able to treat and prevent symptoms of celiac disease in some people, according to a new study in the journal Nature. The data suggest that the inflammatory response to gluten in people with celiac disease may be triggered by interleukin-15 and retinoic acid, which is a derivative of vitamin A. The team notes that researchers previously thought that retinoic acid would lessen the inflammation in the intestine. Instead their study showed that it might actually worsen inflammation. According to Bana Jabri, MD, PhD, a member of the Celiac Disease Center and Comprehensive cancer Center at the University of Chicago, the team results showed that "elevated levels of IL-15 in the gut could initiate all the early stages of celiac disease in those who were genetically susceptible, and that blocking IL-15 could prevent the disease in our mouse model. It also demonstrated that in the treatment of inflammatory intestinal diseases, vitamin A and its retinoic acid metabolites are likely to do more harm than good.” The researchers found that by blocking IL-15 in mice that were genetically engineered to have celiac disease, they were able to reverse the symptoms, and the mice were able to eat gluten without suffering the symptoms of celiac disease. One reason this is good news, is that a number of medicines designed to block IL-15 are already being developed for other inflammation related diseases, such as rheumatoid arthritis. Source: Nature. 2011 Mar 10;471(7337):220-4.