Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes

Federica Vecchio; Nicola Lo Buono; Angela Stabilini; Laura Nigi; Matthew J. Dufort; Susan Geyer; Paola Maria Rancoita; Federica Cugnata; Alessandra Mandelli; Andrea Valle; Pia Leete; Francesca Mancarella; Peter S. Linsley; Lars Krogvold; Kevan C. Herold; Helena Elding Larsson; Sarah J. Richardson; Noel G. Morgan; Knut Dahl-Jørgensen; Guido Sebastiani; Francesco Dotta; Emanuele Bosi; Eleonora Bianconi; Riccardo Bonfanti; Clara Bonura; Maurizio De Pellegrin; Giulio Frontino; Pauline Grogan; Andrea Laurenzi; Franco Meschi; Francesca Ragogna; Andrea Rigamonti; C. J. Greenbaum; M. Atkinson; D. Baidal; D. Becker; P. Bingley; J. Buckner; M. Clements; P. Colman; L. DiMeglio; S. Gitelman; R. Goland; P. Gottlieb; M. Knip; J. Krischer; A. Lernmark; W. Moore; A. Moran; A. Muir; J. Palmer; M. Peakman; L. Philipson; P. Raskin; M. Redondo; H. Rodriguez; W. Russell; L. Spain; D. A. Schatz; J. Sosenko; J. Wentworth; D. Wherrett; D. Wilson; W. Winter; A. Ziegler; M. Anderson; P. Antinozzi; C. Benoist; J. Blum; K. Bourcier; P. Chase; M. Clare-Salzler; R. Clynes; G. Eisenbarth; C. G. Fathman; G. Grave; B. Hering; R. Insel; F. Kaufman; T. Kay; E. Leschek; J. Mahon; J. B. Marks; K. Nanto-Salonen; G. Nepom; T. Orban; R. Parkman; M. Pescovitz; J. Peyman; A. Pugliese; B. Roep; M. Roncarolo; P. Savage; O. Simell; R. Sherwin; M. Siegelman; J. S. Skyler; A. Steck; J. Thomas; M. Trucco; J. Wagner; Manuela Battaglia

doi:10.1172/jci.insight.122146

Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes

Federica Vecchio, Nicola Lo Buono, Angela Stabilini, Laura Nigi, Matthew J. Dufort, Susan Geyer, Paola Maria Rancoita, Federica Cugnata, Alessandra Mandelli, Andrea Valle, Pia Leete, Francesca Mancarella, Peter S. Linsley, Lars Krogvold, Kevan C. Herold, Helena Elding Larsson, Sarah J. Richardson, Noel G. Morgan, Knut Dahl-Jørgensen, Guido SebastianiFrancesco Dotta, Emanuele Bosi, Eleonora Bianconi, Riccardo Bonfanti, Clara Bonura, Maurizio De Pellegrin, Giulio Frontino, Pauline Grogan, Andrea Laurenzi, Franco Meschi, Francesca Ragogna, Andrea Rigamonti, C. J. Greenbaum, M. Atkinson, D. Baidal, D. Becker, P. Bingley, J. Buckner, M. Clements, P. Colman, L. DiMeglio, S. Gitelman, R. Goland, P. Gottlieb, M. Knip, J. Krischer, A. Lernmark, W. Moore, A. Moran, A. Muir, J. Palmer, M. Peakman, L. Philipson, P. Raskin, M. Redondo, H. Rodriguez, W. Russell, L. Spain, D. A. Schatz, J. Sosenko, J. Wentworth, D. Wherrett, D. Wilson, W. Winter, A. Ziegler, M. Anderson, P. Antinozzi, C. Benoist, J. Blum, K. Bourcier, P. Chase, M. Clare-Salzler, R. Clynes, G. Eisenbarth, C. G. Fathman, G. Grave, B. Hering, R. Insel, F. Kaufman, T. Kay, E. Leschek, J. Mahon, J. B. Marks, K. Nanto-Salonen, G. Nepom, T. Orban, R. Parkman, M. Pescovitz, J. Peyman, A. Pugliese, B. Roep, M. Roncarolo, P. Savage, O. Simell, R. Sherwin, M. Siegelman, J. S. Skyler, A. Steck, J. Thomas, M. Trucco, J. Wagner, Manuela Battaglia

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Abstract

BACKGROUND. Neutrophils and their inflammatory mediators are key pathogenic componentsin multiple autoimmune diseases, while their role in human type 1 diabetes (T1D), a diseasethat progresses sequentially through identifable stages prior to the clinical onset, is not wellunderstood. We previously reported that the number of circulating neutrophils is reduced inpatients with T1D and in presymptomatic at-risk subjects. The aim of the present work was toidentify possible changes in circulating and pancreas-residing neutrophils throughout the diseasecourse to better elucidate neutrophil involvement in human T1D.METHODS. Data collected from 389 subjects at risk of developing T1D, and enrolled in 4 distinctstudies performed by TrialNet, were analyzed with comprehensive statistical approaches todetermine whether the number of circulating neutrophils correlates with pancreas function. Toobtain a broad analysis of pancreas-infltrating neutrophils throughout all disease stages, pancreassections collected worldwide from 4 different cohorts (i.e., nPOD, DiViD, Siena, and Exeter) wereanalyzed by immunohistochemistry and immunoffuorescence. Finally, circulating neutrophilswere purifed from unrelated nondiabetic subjects and donors at various T1D stages and theirtranscriptomic signature was determined by RNA sequencing.RESULTS. Here, we show that the decline in β cell function is greatest in individuals with the lowestperipheral neutrophil numbers. Neutrophils infltrate the pancreas prior to the onset of symptomsand they continue to do so as the disease progresses. Of interest, a fraction of these pancreasinfltrating neutrophils also extrudes neutrophil extracellular traps (NETs), suggesting a tissue-specifcpathogenic role. Whole-transcriptome analysis of purifed blood neutrophils revealed a uniquemolecular signature that is distinguished by an overabundance of IFN-associated genes; despite beinghealthy, said signature is already present in T1D-autoantibody-negative at-risk subjects.CONCLUSIONS. These results reveal an unexpected abnormality in neutrophil disposition both inthe circulation and in the pancreas of presymptomatic and symptomatic T1D subjects, implying thattargeting neutrophils might represent a previously unrecognized therapeutic modality.

Original language	English (US)
Article number	e122146
Journal	JCI Insight
Volume	3
Issue number	18
DOIs	https://doi.org/10.1172/jci.insight.122146
State	Published - Sep 20 2018

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© 2018 American Society for Clinical Investigation. All rights reserved.

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Vecchio, F., Lo Buono, N., Stabilini, A., Nigi, L., Dufort, M. J., Geyer, S., Rancoita, P. M., Cugnata, F., Mandelli, A., Valle, A., Leete, P., Mancarella, F., Linsley, P. S., Krogvold, L., Herold, K. C., Larsson, H. E., Richardson, S. J., Morgan, N. G., Dahl-Jørgensen, K., ... Battaglia, M. (2018). Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes. JCI Insight, 3(18), Article e122146. https://doi.org/10.1172/jci.insight.122146

Vecchio, F, Lo Buono, N, Stabilini, A, Nigi, L, Dufort, MJ, Geyer, S, Rancoita, PM, Cugnata, F, Mandelli, A, Valle, A, Leete, P, Mancarella, F, Linsley, PS, Krogvold, L, Herold, KC, Larsson, HE, Richardson, SJ, Morgan, NG, Dahl-Jørgensen, K, Sebastiani, G, Dotta, F, Bosi, E, Bianconi, E, Bonfanti, R, Bonura, C, De Pellegrin, M, Frontino, G, Grogan, P, Laurenzi, A, Meschi, F, Ragogna, F, Rigamonti, A, Greenbaum, CJ, Atkinson, M, Baidal, D, Becker, D, Bingley, P, Buckner, J, Clements, M, Colman, P, DiMeglio, L, Gitelman, S, Goland, R, Gottlieb, P, Knip, M, Krischer, J, Lernmark, A, Moore, W, Moran, A, Muir, A, Palmer, J, Peakman, M, Philipson, L, Raskin, P, Redondo, M, Rodriguez, H, Russell, W, Spain, L, Schatz, DA, Sosenko, J, Wentworth, J, Wherrett, D, Wilson, D, Winter, W, Ziegler, A, Anderson, M, Antinozzi, P, Benoist, C, Blum, J, Bourcier, K, Chase, P, Clare-Salzler, M, Clynes, R, Eisenbarth, G, Fathman, CG, Grave, G, Hering, B, Insel, R, Kaufman, F, Kay, T, Leschek, E, Mahon, J, Marks, JB, Nanto-Salonen, K, Nepom, G, Orban, T, Parkman, R, Pescovitz, M, Peyman, J, Pugliese, A, Roep, B, Roncarolo, M, Savage, P, Simell, O, Sherwin, R, Siegelman, M, Skyler, JS, Steck, A, Thomas, J, Trucco, M, Wagner, J & Battaglia, M 2018, 'Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes', JCI Insight, vol. 3, no. 18, e122146. https://doi.org/10.1172/jci.insight.122146

@article{34167276d6e644debb4fc99b828a2147,

title = "Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes",

abstract = "BACKGROUND. Neutrophils and their inflammatory mediators are key pathogenic componentsin multiple autoimmune diseases, while their role in human type 1 diabetes (T1D), a diseasethat progresses sequentially through identifable stages prior to the clinical onset, is not wellunderstood. We previously reported that the number of circulating neutrophils is reduced inpatients with T1D and in presymptomatic at-risk subjects. The aim of the present work was toidentify possible changes in circulating and pancreas-residing neutrophils throughout the diseasecourse to better elucidate neutrophil involvement in human T1D.METHODS. Data collected from 389 subjects at risk of developing T1D, and enrolled in 4 distinctstudies performed by TrialNet, were analyzed with comprehensive statistical approaches todetermine whether the number of circulating neutrophils correlates with pancreas function. Toobtain a broad analysis of pancreas-infltrating neutrophils throughout all disease stages, pancreassections collected worldwide from 4 different cohorts (i.e., nPOD, DiViD, Siena, and Exeter) wereanalyzed by immunohistochemistry and immunoffuorescence. Finally, circulating neutrophilswere purifed from unrelated nondiabetic subjects and donors at various T1D stages and theirtranscriptomic signature was determined by RNA sequencing.RESULTS. Here, we show that the decline in β cell function is greatest in individuals with the lowestperipheral neutrophil numbers. Neutrophils infltrate the pancreas prior to the onset of symptomsand they continue to do so as the disease progresses. Of interest, a fraction of these pancreasinfltrating neutrophils also extrudes neutrophil extracellular traps (NETs), suggesting a tissue-specifcpathogenic role. Whole-transcriptome analysis of purifed blood neutrophils revealed a uniquemolecular signature that is distinguished by an overabundance of IFN-associated genes; despite beinghealthy, said signature is already present in T1D-autoantibody-negative at-risk subjects.CONCLUSIONS. These results reveal an unexpected abnormality in neutrophil disposition both inthe circulation and in the pancreas of presymptomatic and symptomatic T1D subjects, implying thattargeting neutrophils might represent a previously unrecognized therapeutic modality.",

author = "Federica Vecchio and {Lo Buono}, Nicola and Angela Stabilini and Laura Nigi and Dufort, {Matthew J.} and Susan Geyer and Rancoita, {Paola Maria} and Federica Cugnata and Alessandra Mandelli and Andrea Valle and Pia Leete and Francesca Mancarella and Linsley, {Peter S.} and Lars Krogvold and Herold, {Kevan C.} and Larsson, {Helena Elding} and Richardson, {Sarah J.} and Morgan, {Noel G.} and Knut Dahl-J{\o}rgensen and Guido Sebastiani and Francesco Dotta and Emanuele Bosi and Eleonora Bianconi and Riccardo Bonfanti and Clara Bonura and {De Pellegrin}, Maurizio and Giulio Frontino and Pauline Grogan and Andrea Laurenzi and Franco Meschi and Francesca Ragogna and Andrea Rigamonti and Greenbaum, {C. J.} and M. Atkinson and D. Baidal and D. Becker and P. Bingley and J. Buckner and M. Clements and P. Colman and L. DiMeglio and S. Gitelman and R. Goland and P. Gottlieb and M. Knip and J. Krischer and A. Lernmark and W. Moore and A. Moran and A. Muir and J. Palmer and M. Peakman and L. Philipson and P. Raskin and M. Redondo and H. Rodriguez and W. Russell and L. Spain and Schatz, {D. A.} and J. Sosenko and J. Wentworth and D. Wherrett and D. Wilson and W. Winter and A. Ziegler and M. Anderson and P. Antinozzi and C. Benoist and J. Blum and K. Bourcier and P. Chase and M. Clare-Salzler and R. Clynes and G. Eisenbarth and Fathman, {C. G.} and G. Grave and B. Hering and R. Insel and F. Kaufman and T. Kay and E. Leschek and J. Mahon and Marks, {J. B.} and K. Nanto-Salonen and G. Nepom and T. Orban and R. Parkman and M. Pescovitz and J. Peyman and A. Pugliese and B. Roep and M. Roncarolo and P. Savage and O. Simell and R. Sherwin and M. Siegelman and Skyler, {J. S.} and A. Steck and J. Thomas and M. Trucco and J. Wagner and Manuela Battaglia",

year = "2018",

month = sep,

day = "20",

doi = "10.1172/jci.insight.122146",

language = "English (US)",

volume = "3",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "American Society for Clinical Investigation",

number = "18",

}

TY - JOUR

T1 - Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes

AU - Vecchio, Federica

AU - Lo Buono, Nicola

AU - Stabilini, Angela

AU - Nigi, Laura

AU - Dufort, Matthew J.

AU - Geyer, Susan

AU - Rancoita, Paola Maria

AU - Cugnata, Federica

AU - Mandelli, Alessandra

AU - Valle, Andrea

AU - Leete, Pia

AU - Mancarella, Francesca

AU - Linsley, Peter S.

AU - Krogvold, Lars

AU - Herold, Kevan C.

AU - Larsson, Helena Elding

AU - Richardson, Sarah J.

AU - Morgan, Noel G.

AU - Dahl-Jørgensen, Knut

AU - Sebastiani, Guido

AU - Dotta, Francesco

AU - Bosi, Emanuele

AU - Bianconi, Eleonora

AU - Bonfanti, Riccardo

AU - Bonura, Clara

AU - De Pellegrin, Maurizio

AU - Frontino, Giulio

AU - Grogan, Pauline

AU - Laurenzi, Andrea

AU - Meschi, Franco

AU - Ragogna, Francesca

AU - Rigamonti, Andrea

AU - Greenbaum, C. J.

AU - Atkinson, M.

AU - Baidal, D.

AU - Becker, D.

AU - Bingley, P.

AU - Buckner, J.

AU - Clements, M.

AU - Colman, P.

AU - DiMeglio, L.

AU - Gitelman, S.

AU - Goland, R.

AU - Gottlieb, P.

AU - Knip, M.

AU - Krischer, J.

AU - Lernmark, A.

AU - Moore, W.

AU - Moran, A.

AU - Muir, A.

AU - Palmer, J.

AU - Peakman, M.

AU - Philipson, L.

AU - Raskin, P.

AU - Redondo, M.

AU - Rodriguez, H.

AU - Russell, W.

AU - Spain, L.

AU - Schatz, D. A.

AU - Sosenko, J.

AU - Wentworth, J.

AU - Wherrett, D.

AU - Wilson, D.

AU - Winter, W.

AU - Ziegler, A.

AU - Anderson, M.

AU - Antinozzi, P.

AU - Benoist, C.

AU - Blum, J.

AU - Bourcier, K.

AU - Chase, P.

AU - Clare-Salzler, M.

AU - Clynes, R.

AU - Eisenbarth, G.

AU - Fathman, C. G.

AU - Grave, G.

AU - Hering, B.

AU - Insel, R.

AU - Kaufman, F.

AU - Kay, T.

AU - Leschek, E.

AU - Mahon, J.

AU - Marks, J. B.

AU - Nanto-Salonen, K.

AU - Nepom, G.

AU - Orban, T.

AU - Parkman, R.

AU - Pescovitz, M.

AU - Peyman, J.

AU - Pugliese, A.

AU - Roep, B.

AU - Roncarolo, M.

AU - Savage, P.

AU - Simell, O.

AU - Sherwin, R.

AU - Siegelman, M.

AU - Skyler, J. S.

AU - Steck, A.

AU - Thomas, J.

AU - Trucco, M.

AU - Wagner, J.

AU - Battaglia, Manuela

PY - 2018/9/20

Y1 - 2018/9/20

N2 - BACKGROUND. Neutrophils and their inflammatory mediators are key pathogenic componentsin multiple autoimmune diseases, while their role in human type 1 diabetes (T1D), a diseasethat progresses sequentially through identifable stages prior to the clinical onset, is not wellunderstood. We previously reported that the number of circulating neutrophils is reduced inpatients with T1D and in presymptomatic at-risk subjects. The aim of the present work was toidentify possible changes in circulating and pancreas-residing neutrophils throughout the diseasecourse to better elucidate neutrophil involvement in human T1D.METHODS. Data collected from 389 subjects at risk of developing T1D, and enrolled in 4 distinctstudies performed by TrialNet, were analyzed with comprehensive statistical approaches todetermine whether the number of circulating neutrophils correlates with pancreas function. Toobtain a broad analysis of pancreas-infltrating neutrophils throughout all disease stages, pancreassections collected worldwide from 4 different cohorts (i.e., nPOD, DiViD, Siena, and Exeter) wereanalyzed by immunohistochemistry and immunoffuorescence. Finally, circulating neutrophilswere purifed from unrelated nondiabetic subjects and donors at various T1D stages and theirtranscriptomic signature was determined by RNA sequencing.RESULTS. Here, we show that the decline in β cell function is greatest in individuals with the lowestperipheral neutrophil numbers. Neutrophils infltrate the pancreas prior to the onset of symptomsand they continue to do so as the disease progresses. Of interest, a fraction of these pancreasinfltrating neutrophils also extrudes neutrophil extracellular traps (NETs), suggesting a tissue-specifcpathogenic role. Whole-transcriptome analysis of purifed blood neutrophils revealed a uniquemolecular signature that is distinguished by an overabundance of IFN-associated genes; despite beinghealthy, said signature is already present in T1D-autoantibody-negative at-risk subjects.CONCLUSIONS. These results reveal an unexpected abnormality in neutrophil disposition both inthe circulation and in the pancreas of presymptomatic and symptomatic T1D subjects, implying thattargeting neutrophils might represent a previously unrecognized therapeutic modality.

AB - BACKGROUND. Neutrophils and their inflammatory mediators are key pathogenic componentsin multiple autoimmune diseases, while their role in human type 1 diabetes (T1D), a diseasethat progresses sequentially through identifable stages prior to the clinical onset, is not wellunderstood. We previously reported that the number of circulating neutrophils is reduced inpatients with T1D and in presymptomatic at-risk subjects. The aim of the present work was toidentify possible changes in circulating and pancreas-residing neutrophils throughout the diseasecourse to better elucidate neutrophil involvement in human T1D.METHODS. Data collected from 389 subjects at risk of developing T1D, and enrolled in 4 distinctstudies performed by TrialNet, were analyzed with comprehensive statistical approaches todetermine whether the number of circulating neutrophils correlates with pancreas function. Toobtain a broad analysis of pancreas-infltrating neutrophils throughout all disease stages, pancreassections collected worldwide from 4 different cohorts (i.e., nPOD, DiViD, Siena, and Exeter) wereanalyzed by immunohistochemistry and immunoffuorescence. Finally, circulating neutrophilswere purifed from unrelated nondiabetic subjects and donors at various T1D stages and theirtranscriptomic signature was determined by RNA sequencing.RESULTS. Here, we show that the decline in β cell function is greatest in individuals with the lowestperipheral neutrophil numbers. Neutrophils infltrate the pancreas prior to the onset of symptomsand they continue to do so as the disease progresses. Of interest, a fraction of these pancreasinfltrating neutrophils also extrudes neutrophil extracellular traps (NETs), suggesting a tissue-specifcpathogenic role. Whole-transcriptome analysis of purifed blood neutrophils revealed a uniquemolecular signature that is distinguished by an overabundance of IFN-associated genes; despite beinghealthy, said signature is already present in T1D-autoantibody-negative at-risk subjects.CONCLUSIONS. These results reveal an unexpected abnormality in neutrophil disposition both inthe circulation and in the pancreas of presymptomatic and symptomatic T1D subjects, implying thattargeting neutrophils might represent a previously unrecognized therapeutic modality.

UR - http://www.scopus.com/inward/record.url?scp=85056037710&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056037710&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.122146

DO - 10.1172/jci.insight.122146

M3 - Article

C2 - 30232284

AN - SCOPUS:85056037710

SN - 2379-3708

VL - 3

JO - JCI Insight

JF - JCI Insight

IS - 18

M1 - e122146

ER -

Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes

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