Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes
(2018) In JCI Insight 3(18).- 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... (More)
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.
(Less)
- author
- author collaboration
- organization
- publishing date
- 2018-09-20
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Autoantibodies, Autoimmune Diseases, Diabetes Mellitus, Type 1/immunology, Extracellular Traps/immunology, Gene Expression, Gene Expression Profiling, Humans, Immunity, Innate, Insulin-Secreting Cells, Interferons/genetics, Neutrophils/immunology, Pancreas/immunology, Transcriptome
- in
- JCI Insight
- volume
- 3
- issue
- 18
- article number
- e122146
- publisher
- The American Society for Clinical Investigation
- external identifiers
-
- scopus:85056037710
- pmid:30232284
- ISSN
- 2379-3708
- DOI
- 10.1172/jci.insight.122146
- language
- English
- LU publication?
- yes
- id
- f6a89aed-70dd-40dd-968d-6acaa45b676b
- date added to LUP
- 2024-03-26 15:56:22
- date last changed
- 2024-04-24 07:52:31
@article{f6a89aed-70dd-40dd-968d-6acaa45b676b,
abstract = {{<p>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.</p><p>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.</p><p>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.</p><p>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.</p><p>FUNDING: Juvenile Diabetes Research Foundation (JDRF), NIH, Diabetes UK.</p>}},
author = {{Vecchio, Federica and Lo Buono, Nicola and Stabilini, Angela and Nigi, Laura and Dufort, Matthew J and Geyer, Susan and Rancoita, Paola Maria and Cugnata, Federica and Mandelli, Alessandra and Valle, Andrea and Leete, Pia and Mancarella, Francesca and Linsley, Peter S and Krogvold, Lars and Herold, Kevan C and Elding Larsson, Helena and Richardson, Sarah J and Morgan, Noel G and Dahl-Jørgensen, Knut and Sebastiani, Guido and Dotta, Francesco and Bosi, Emanuele and Battaglia, Manuela}},
issn = {{2379-3708}},
keywords = {{Autoantibodies; Autoimmune Diseases; Diabetes Mellitus, Type 1/immunology; Extracellular Traps/immunology; Gene Expression; Gene Expression Profiling; Humans; Immunity, Innate; Insulin-Secreting Cells; Interferons/genetics; Neutrophils/immunology; Pancreas/immunology; Transcriptome}},
language = {{eng}},
month = {{09}},
number = {{18}},
publisher = {{The American Society for Clinical Investigation}},
series = {{JCI Insight}},
title = {{Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes}},
url = {{http://dx.doi.org/10.1172/jci.insight.122146}},
doi = {{10.1172/jci.insight.122146}},
volume = {{3}},
year = {{2018}},
}