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Showing results for tags 't cell'.
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Celiac.com 11/22/2021 - B cells have important antibody-independent functions and are now recognized as key players in autoimmune diseases traditionally thought to be T cell-mediated. However, researchers still don't have a good understanding of the role of B cells as antigen-presenting cells. By studying the autoantibody response against the enzyme transglutaminase 2 in celiac disease, a research team set out to gain insight into the mechanisms controlling initiation of a T cell-mediated autoimmune condition. The research team included Rasmus Iversen, Bishnudeo Roy, Jorunn Stamnaes, Lene S. Høydahl, Kathrin Hnida, Ralf S. Neumann, Ilma R. Korponay-Szabó, Knut E. A. Lundin, and Ludvig M. Sollid. They are variously affiliated with the KG Jebsen Coeliac Disease Research Centre, University of Oslo, NO-0372 Oslo, Norway; the Department of Immunology, Oslo University Hospital, NO-0372 Oslo, Norway; the Celiac Disease Center, Heim Pál National Pediatric Institute, HU-1089 Budapest, Hungary; and the Department of Gastroenterology, Oslo University Hospital, NO-0372 Oslo, Norway. Their team found that production of antibodies against the preferred epitope matched the clinical onset of disease, indicating that B cells of this type can be main antigen-presenting cells for pathogenic gluten-specific T cells. Specifically, TG2-specific plasma cells in celiac disease mainly target epitopes in the N-terminal region of the antigen. This epitope preference mirrors presentation of deamidated gluten peptides to T cells by B cells binding enzymatically active TG2. Specific targeting of N-terminal TG2 epitopes was associated with clinical onset of celiac disease, suggesting that efficient collaboration between TG2-specific B cells and gluten-specific T cells is a prerequisite for disease development. By elucidating the autoantibody response against the enzyme transglutaminase 2 in celiac disease, the team has shown that B cells targeting particular epitopes are triggered deliberately, and that this epitope bias reflects efficient presentation of gluten antigen to T cells. The study offers a glimpse into the mechanisms driving the onset of T cell-mediated autoimmune conditions, and the findings of this study may lead to future targets for celiac disease treatments. Read more in PNAS July 23, 2019 116 (30) 15134-15139; first published July 8, 2019.
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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 08/23/2019 - A team of researchers recently set out to use experimental autoimmune encephalomyelitis as a model for better understanding multiple sclerosis. The research team included Naresha Saligrama, Fan Zhao, Michael J. Sikora, William S. Serratelli, Ricardo A. Fernandes, David M. Louis, Winnie Yao, Xuhuai Ji, Juliana Idoyaga, Vinit B. Mahajan, Lars M. Steinmetz, Yueh-Hsiu Chien, Stephen L. Hauser, Jorge R. Oksenberg, K. Christopher Garcia & Mark M. Davis. The team showed that induction triggers successive waves of clonally expanded CD4+, CD8+ and γδ+ T cells in the blood and central nervous system, similar to gluten-challenges in patients with celiac disease. The team also found major expansions of CD8+ T cells in patients with multiple sclerosis. In patients with autoimmune encephalomyelitis, they discovered that most expanded CD4+ T cells are specific for the inducing myelin peptide MOG35–55. By contrast, surrogate peptides derived from a yeast peptide major histocompatibility complex library of some of the clonally expanded CD8+ T cells inhibit disease by suppressing the proliferation of MOG-specific CD4+ T cells. These results suggest that the induction of auto-reactive CD4+ T cells triggers an opposing mobilization of regulatory CD8+ T cells, and according to the researchers: "These results suggest that the induction of autoreactive CD4+ T cells triggers an opposing mobilization of regulatory CD8+ T cells...(W)e show here that the simultaneous mobilization of oligoclonal T cells, seen previously in patients with celiac disease, has a parallel not only in EAE, but also to some extent in newly diagnosed patients with MS." Read more in Nature.com The researchers are variously affiliated with the Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; the Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA; the Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA; the Department of Neurology and UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA; the Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA; and the Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
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