Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes
| Autor: | Jay M. Sosenko, D. J. Becker, Kevan C. Herold, E. Leschek, James W. Thomas, Francesco Dotta, Jeffrey L. Mahon, K. Nanto-Salonen, Diane K. Wherrett, Lisa M. Spain, Andrew Muir, Polly J. Bingley, Massimo Trucco, Jeffrey P. Krischer, S. E. Gitelman, Alessandra Mandelli, Mark S. Anderson, Sarah J. Richardson, Peter S. Linsley, Riccardo Bonfanti, Eleonora Bianconi, George S. Eisenbarth, M. Siegelman, J. Peyman, Angela Stabilini, M. Redondo, Bernhard J. Hering, Richard A. Insel, Maurizio De Pellegrin, Franco Meschi, Francesca Ragogna, Mark A. Clements, Lars Krogvold, Mark Peakman, Alberto Pugliese, J. Blum, William E. Russell, P. Chase, Pia Leete, Anette-Gabriele Ziegler, Mark A. Atkinson, Jane H. Buckner, Andrea Rigamonti, Tihamer Orban, Laura Nigi, Philip Raskin, Guido Sebastiani, Louis H. Philipson, Linda A. DiMeglio, Clara Bonura, Manuela Battaglia, Jay S. Skyler, David A. Baidal, Giulio Frontino, Emanuele Bosi, Matthew J. Dufort, Andrea Valle, William E. Winter, Peter A. Gottlieb, C. G. Fathman, Helena Elding Larsson, Robin Goland, Michael J. Clare-Salzler, M. G. Roncarolo, Raphael Clynes, Peter A. Antinozzi, Andrea K. Steck, Mikael Knip, Olli Simell, R. Parkman, Bart O. Roep, Desmond A. Schatz, Henry Rodriguez, Nicola Lo Buono, John M. Wentworth, Andrea Laurenzi, Francesca Mancarella, P. Savage, Jennifer B. Marks, G. Grave, Paola M.V. Rancoita, Federica Vecchio, Åke Lernmark, Darrell M. Wilson, Noel G. Morgan, Thomas W.H. Kay, Francine R. Kaufman, Federica Cugnata, Christophe Benoist, Susan Geyer, Peter G. Colman, Mark D. Pescovitz, Robert S. Sherwin, Gerald T. Nepom, John E. Wagner, Antoinette Moran, Knut Dahl-Jørgensen, Jerry P. Palmer, Kasia Bourcier, Wayne V. Moore, Carla J. Greenbaum, Pauline Grogan |
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| Přispěvatelé: | Vecchio, Federica, Lo Buono, Nicola, Stabilini, Angela, Nigi, Laura, Dufort, Matthew J., Geyer, Susan, Rancoita, Paola Maria, Cugnata, Federica, Mandelli, Alessandra, Valle, Andrea, Leete, Pia, Mancarella, Francesca, Linsley, Peter S., Krogvold, Lar, Herold, Kevan C., Elding Larsson, Helena, Richardson, Sarah J., Morgan, Noel G., Dahl-Jørgensen, Knut, Sebastiani, Guido, Dotta, Francesco, Bosi, Emanuele, Battaglia, Manuela |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
endocrine system diseases Neutrophils Immunology Gene Expression Autoimmunity Disease Immunofluorescence medicine.disease_cause Extracellular Traps Autoimmune Diseases 03 medical and health sciences Insulin-Secreting Cells Diabetes mellitus Autoimmune disease medicine Humans Pancreas Autoantibodies Innate immunity Type 1 diabetes Innate immune system medicine.diagnostic_test business.industry Gene Expression Profiling General Medicine Neutrophil extracellular traps medicine.disease Immunity Innate 3. Good health Diabetes Mellitus Type 1 030104 developmental biology medicine.anatomical_structure Interferons Clinical Medicine Transcriptome business |
| Popis: | BACKGROUND. Neutrophils and their inflammatory mediators are key pathogenic components in multiple autoimmune diseases, while their role in human type 1 diabetes (T1D), a disease that progresses sequentially through identifiable stages prior to the clinical onset, is not well understood. We previously reported that the number of circulating neutrophils is reduced in patients with T1D and in presymptomatic at-risk subjects. The aim of the present work was to identify possible changes in circulating and pancreas-residing neutrophils throughout the disease course to better elucidate neutrophil involvement in human T1D. METHODS. Data collected from 389 subjects at risk of developing T1D, and enrolled in 4 distinct studies performed by TrialNet, were analyzed with comprehensive statistical approaches to determine whether the number of circulating neutrophils correlates with pancreas function. To obtain a broad analysis of pancreas-infiltrating neutrophils throughout all disease stages, pancreas sections collected worldwide from 4 different cohorts (i.e., nPOD, DiViD, Siena, and Exeter) were analyzed by immunohistochemistry and immunofluorescence. Finally, circulating neutrophils were purified from unrelated nondiabetic subjects and donors at various T1D stages and their transcriptomic signature was determined by RNA sequencing. RESULTS. Here, we show that the decline in β cell function is greatest in individuals with the lowest peripheral neutrophil numbers. Neutrophils infiltrate the pancreas prior to the onset of symptoms and they continue to do so as the disease progresses. Of interest, a fraction of these pancreas-infiltrating neutrophils also extrudes neutrophil extracellular traps (NETs), suggesting a tissue-specific pathogenic role. Whole-transcriptome analysis of purified blood neutrophils revealed a unique molecular signature that is distinguished by an overabundance of IFN-associated genes; despite being healthy, said signature is already present in T1D-autoantibody-negative at-risk subjects. CONCLUSIONS. These results reveal an unexpected abnormality in neutrophil disposition both in the circulation and in the pancreas of presymptomatic and symptomatic T1D subjects, implying that targeting neutrophils might represent a previously unrecognized therapeutic modality. FUNDING. Juvenile Diabetes Research Foundation (JDRF), NIH, Diabetes UK. |
| Databáze: | OpenAIRE |
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