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Abnormal neutrophil...
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Vecchio, FedericaSan Raffaele Scientific Institute
(författare)
Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes
- Artikel/kapitelEngelska2018
Förlag, utgivningsår, omfång ...
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2018-09-20
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American Society for Clinical Investigation,2018
Nummerbeteckningar
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LIBRIS-ID:oai:lup.lub.lu.se:f6a89aed-70dd-40dd-968d-6acaa45b676b
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https://lup.lub.lu.se/record/f6a89aed-70dd-40dd-968d-6acaa45b676bURI
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https://doi.org/10.1172/jci.insight.122146DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:art swepub-publicationtype
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Ämneskategori:ref swepub-contenttype
Anmärkningar
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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.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Lo Buono, NicolaSan Raffaele Scientific Institute
(författare)
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Stabilini, Angela
(författare)
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Nigi, LauraUniversity of Siena
(författare)
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Dufort, Matthew JBenaroya Research Institute
(författare)
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Geyer, SusanUniversity of South Florida
(författare)
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Rancoita, Paola MariaVita-Salute San Raffaele University
(författare)
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Cugnata, FedericaVita-Salute San Raffaele University
(författare)
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Mandelli, Alessandra
(författare)
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Valle, Andrea
(författare)
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Leete, PiaUniversity of Exeter
(författare)
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Mancarella, FrancescaUniversity of Siena
(författare)
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Linsley, Peter SBenaroya Research Institute
(författare)
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Krogvold, LarsUniversity of Oslo
(författare)
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Herold, Kevan CYale University
(författare)
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Elding Larsson, HelenaLund University,Lunds universitet,Pediatrisk endokrinologi,Forskargrupper vid Lunds universitet,Paediatric Endocrinology,Lund University Research Groups,Skåne University Hospital(Swepub:lu)pedi-hla
(författare)
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Richardson, Sarah JUniversity of Exeter
(författare)
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Morgan, Noel GUniversity of Exeter
(författare)
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Dahl-Jørgensen, KnutUniversity of Oslo
(författare)
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Sebastiani, GuidoUniversity of Siena
(författare)
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Dotta, FrancescoUniversity of Siena
(författare)
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Bosi, Emanuele
(författare)
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Battaglia, ManuelaSan Raffaele Scientific Institute
(författare)
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San Raffaele Scientific InstituteUniversity of Siena
(creator_code:org_t)
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DRI_Biorepository Group
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Type 1 Diabetes TrialNet Study Group
Sammanhörande titlar
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Ingår i:JCI Insight: American Society for Clinical Investigation3:182379-3708
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Vecchio, Federic ...
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Lo Buono, Nicola
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Stabilini, Angel ...
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Nigi, Laura
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Dufort, Matthew ...
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Geyer, Susan
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visa fler...
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Rancoita, Paola ...
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Cugnata, Federic ...
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Mandelli, Alessa ...
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Valle, Andrea
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Leete, Pia
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Mancarella, Fran ...
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Linsley, Peter S
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Krogvold, Lars
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Herold, Kevan C
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Elding Larsson, ...
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Richardson, Sara ...
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Morgan, Noel G
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Dahl-Jørgensen, ...
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Sebastiani, Guid ...
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Dotta, Francesco
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Bosi, Emanuele
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Battaglia, Manue ...
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