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Showing results for tags 'activation'.
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Celiac.com 09/06/2021 - Antibodies specific for peptides bound to human leukocyte antigen (HLA) molecules are valuable tools for studies of antigen presentation, and may have therapeutic potential. Human T cell receptor (TCR)–like antibodies that block immunodominant epitope recognition have potential as personalized medicine treatments for blunting gluten-activated T cell responses without compromising effector functions provided by other T cells. A team of researchers recently set out to generate human T cell receptor (TCR)–like antibodies toward the immunodominant signature gluten epitope DQ2.5-glia-α2 in celiac disease (CeD). Consuming gluten in food triggers the gastrointestinal symptoms of celiac disease in patients with CD4+ T cells specific for deamidated gluten peptides presented by disease-associated HLA-DQ class II MHC molecules. Frick and colleagues used phage display technology to look for TCR-like antibodies specific for an immunodominant gluten peptide bound by HLA-DQ2.5. By using phage display selection combined with secondary targeted engineering, the team was able to obtain highly specific antibodies with picomolar affinity. The team's antibody engineering improved affinity and binding stability, producing a superior TCR-like antibody that structurally mimicked the TCR interface with gluten peptide–MHC complexes. These TCR-like antibodies prevented triggering and expansion of gluten-responsive human CD4+ T cells both in vitro and in DQ2.5 transgenic mice. The binding geometry and interaction mode of the crystal structure of a Fab fragment of the lead antibody 3.C11 in complex with HLA-DQ2.5:DQ2.5-glia-α2 were very similar to prototypic TCRs specific for the same complex. Evaluation of celiac biopsy material confirmed celiac specificity and supports the idea that plentiful plasma cells present antigen in the inflamed gut of a celiac patient. Moreover, 3.C11 specifically blocked activation and proliferation of gluten-specific CD4+ T cells in vitro and in HLA-DQ2.5 humanized mice, suggesting that celiac disease mechanisms can potentially be blocked without weakening patient immunity. Read more in Science Immunology The research team included Rahel Frick, Lene S. Høydahl, Jan Petersen, M. Fleur du Pré, Shraddha Kumari, Grete Berntsen, Alisa E. Dewan, Jeliazko R. Jeliazkov, Kristin S. Gunnarsen, Terje Frigstad, Erik S. Vik, Carmen Llerena, Knut E.A. Lundin, Sheraz Yaqub, Jørgen Jahnsen, Jeffrey J. Gray, Jamie Rossjohn, Ludvig M. Sollid, Inger Sandlie and Geir Åge Løset. They are variously affiliated with the Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway; the Centre for Immune Regulation and Department of Biosciences, University of Oslo, Oslo, Norway; the KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway; the Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia; the Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia; Nextera AS, Oslo, Norway; the Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD, USA; the Department of Gastroenterology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; the Department of Gastrointestinal Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway; the Institute of Clinical Medicine, University of Oslo, Oslo, Norway; the Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway; the Department of Chemical and Biomolecular Engineering and Institute of NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; and the Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
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Celiac.com 10/18/2017 - Celiac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten. A team of researchers recently set out to clarify the role of small intestinal epithelial cells in the immunopathology of celiac disease, especially the influence of celiac disease-associated bacteria. The research team included G Pietz, R De, M Hedberg, V Sjöberg, O Sandström, O Hernell, S Hammarström, and ML Hammarström. They are variously affiliated with the Department of Clinical Microbiology, Immunology, and the Department of Clinical Sciences and Pediatrics at Umeå University, in Umeå, Sweden. The team collected duodenal biopsies from children with active celiac disease, treated celiac disease, and a group of clinical control subjects. They then purified intestinal epithelial cells, and analyzed them for gene expression changes at the mRNA and protein levels. To assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells, they used two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers. In patients with active celiac disease, intestinal epithelial cells significantly upregulated more than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1. Of these genes, 70 percent were upregulated by interferon-γ via the IRF1 pathway. Notably, IRF1 was also upregulated by bacteria associated with celiac disease. Intestinal epithelial cells also expressed the NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes. Over-expression of IRF1 appears to be a key factor in the epithelial reaction in celiac disease. This may be inherent, but may also be due to presence of undesirable microbes that trigger or influence IRF1. From this study, the researchers conclude that activation of IRF1 and IRF1-regulated genes together, both directly and via the interleukin-18 dependent inflammasome, would greatly increase the severity of the inflammatory response, and trigger the pathological gut response that is common in active celiac disease. Could this provide a key to unlocking the mysteries of celiac disease and its associated symptoms? Source: PLoS One. 2017 Sep 21;12(9):e0185025. doi: 10.1371/journal.pone.0185025.
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Celiac.com 10/07/2013 - People with non-celiac gluten-sensitivity often report gut and non-gut symptoms shortly after eating gluten; symptoms disappear on gluten-free diets, although these patients have no serologic markers of celiac disease, and no intestinal damage. However, there is no evidence to suggest any changes to blood or mucosa in those individuals. To better understand non-celiac gluten sensitivity, a research team recently assessed immunologic responses of duodenal mucosa samples and peripheral blood basophils, isolated from NCGS patients, after exposure to gliadin. The research team included Cristina Bucci, Fabiana Zingone, Ilaria Russo, Ivonne Morra, Raffaella Tortora, Norberto Pogna, Giulia Scalia, Paola Iovino, and Carolina Ciacci. They are affiliated with CEINGE in Naples, Italy; the Consiglio per la Ricerca e la Sperimentazione in Agricoltura in Rome, Italy; the Gastrointestinal Unit of the Department of Medicine and Surgery at the University of Salerno in Salerno, Italy; and with the Gastrointestinal Unit at the Department of Clinical and Experimental Medicine of Federico II University of Naples. Between January 2010 and July 2011, the research team gathered mucosa samples from 34 celiac disease patients who followed gluten-free diets for at least 6 months, 35 patients with untreated celiac disease, 16 patients with non-celiac gluten sensitivity (NCGS) and 34 healthy control subjects. The team diagnosed non-celiac gluten sensitivity based on patient symptoms and current diagnositic guidelines. For each of the 119 patients, the team conducted a complete clinical evaluation to exclude celiac disease while on a gluten-containing diet, a skin prick test to exclude wheat allergy, and upper endoscopy at 2 tertiary medical centers in Italy. After incubating each biopsy sample with gliadin, the team measured inflammatory markers, including anti-phosphotyrosine-monoclonal antibody (PY99), HLA-DR, intercellular cell adhesion molecule-1 (ICAM-1), CD3, CD25 and CD69. After incubation with gliadin, mucosa samples from the 69 patients with celiac disease showed increased immunofluorescence intensity for early and delayed markers of inflammation. They also found low levels of some of these markers in three patients with non-celiac gluten sensitivity and three controls. The team found normal mucosal architecture in 56.3% of patients with non-celiac gluten sensitivity. The remaining seven patients showed increased intraepithelial infiltration, but without eosinophils. They found no villous atrophy in patients with non-celiac gluten sensitivity, and no significant increases in the levels of CD63 and CD203c. The team did find that one patient each in the NCGS and control groups, whose results indicated only weak PY99 and ICAM-1 positivity, also had Helicobacter pylori infection. Unlike mucosa from patients with celiac disease, once incubated with gliadin, mucosa from patients with NCGS does not express markers of inflammation, nor does the gliadin activate their basophils. The in vitro gliadin challenge therefore should not be used to diagnose NCGS. This study does suggest that wheat components, other than proteins, might be associated with GI symptoms in patients with IBS, and should be assessed for a possible role in the pathogenesis of NCGS. Source: Clinical Gastroenterology and Hepatology. Volume 11, Issue 10 , Pages 1294-1299.e1, October 2013
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