Federica Vecchio1, Nicola Lo Buono1, Angela Stabilini1, Laura Nigi2, Matthew J Dufort3, Susan Geyer4, Paola Maria Rancoita5, Federica Cugnata5, Alessandra Mandelli1, Andrea Valle1, Pia Leete6, Francesca Mancarella2, Peter S Linsley3, Lars Krogvold7, Kevan C Herold8, Helena Elding Larsson9, Sarah J Richardson6, Noel G Morgan6, Knut Dahl-Jørgensen7, Guido Sebastiani2, Francesco Dotta2, Emanuele Bosi1,10,11, Manuela Battaglia1,11. 1. Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy. 2. Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, and Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy. 3. Systems Immunology Division, Benaroya Research Institute, Seattle, Washington, USA. 4. University of South Florida, TNCC, Tampa, Florida, USA. 5. Centre of Statistics for Biomedical Sciences (CUSSB), Vita-Salute San Raffaele University, Milan, Italy. 6. Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, RILD Building Barrack Road, Exeter, Devon, United Kingdom. 7. Pediatric Department, Oslo University Hospital HF, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway. 8. Departments of Immunobiology and Internal Medicine, Yale University, New Haven, Connecticut, USA. 9. Department of Clinical Sciences, Lund University/CRC, Skane University Hospital SUS, Malmo, Sweden. 10. Vita-Salute San Raffaele University, Milan, Italy, and the Department of Internal Medicine, IRCCS San Raffaele Hospital, Milan, Italy. 11. TrialNet Clinical Center, IRCCS San Raffaele Hospital, Milan, Italy.
Abstract
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.
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.
Authors: Eneida Villanueva; Srilakshmi Yalavarthi; Celine C Berthier; Jeffrey B Hodgin; Ritika Khandpur; Andrew M Lin; Cory J Rubin; Wenpu Zhao; Stephen H Olsen; Matthew Klinker; David Shealy; Michael F Denny; Joel Plumas; Laurence Chaperot; Matthias Kretzler; Allen T Bruce; Mariana J Kaplan Journal: J Immunol Date: 2011-05-25 Impact factor: 5.422
Authors: Qing Li; Baohui Xu; Sara A Michie; Kathleen H Rubins; Robert D Schreriber; Hugh O McDevitt Journal: Proc Natl Acad Sci U S A Date: 2008-08-20 Impact factor: 11.205
Authors: Yi-Guang Chen; Susanne M Cabrera; Shuang Jia; Mary L Kaldunski; Joanna Kramer; Sami Cheong; Rhonda Geoffrey; Mark F Roethle; Jeffrey E Woodliff; Carla J Greenbaum; Xujing Wang; Martin J Hessner Journal: Diabetes Date: 2014-04-23 Impact factor: 9.461
Authors: Manuela Battaglia; Simi Ahmed; Mark S Anderson; Mark A Atkinson; Dorothy Becker; Polly J Bingley; Emanuele Bosi; Todd M Brusko; Linda A DiMeglio; Carmella Evans-Molina; Stephen E Gitelman; Carla J Greenbaum; Peter A Gottlieb; Kevan C Herold; Martin J Hessner; Mikael Knip; Laura Jacobsen; Jeffrey P Krischer; S Alice Long; Markus Lundgren; Eoin F McKinney; Noel G Morgan; Richard A Oram; Tomi Pastinen; Michael C Peters; Alessandra Petrelli; Xiaoning Qian; Maria J Redondo; Bart O Roep; Desmond Schatz; David Skibinski; Mark Peakman Journal: Diabetes Care Date: 2019-11-21 Impact factor: 19.112
Authors: Juan Huang; James Alexander Pearson; F Susan Wong; Li Wen; Zhiguang Zhou Journal: Diabetes Metab Res Rev Date: 2021-06-22 Impact factor: 4.876