Reduction of Circulating Neutrophils Precedes and Accompanies Type 1 Diabetes

Valle, Andrea; Giamporcaro, Gian Maria; Scavini, Marina; Stabilini, Angela; Grogan, Pauline; Bianconi, Eleonora; Sebastiani, Guido; Masini, Matilde; Maugeri, Norma; Porretti, Laura; Bonfanti, Riccardo; Meschi, Franco; Pellegrin, Maurizio De; Lesma, Arianna; Rossini, Silvano; Piemonti, Lorenzo; Marchetti, Piero; Dotta, Francesco; Bosi, Emanuele; Battaglia, Manuela

doi:10.2337/db12-1345

Cited by 182 publications

(224 citation statements)

References 19 publications

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“…4 and Supplementary Table 1). For example, the neutrophil module, including granule proteins such as lipocalin 2 and matrix metalloprotease 9, was first activated, after which the neutrophil-associated transcripts were suppressed before diagnosis, consistent with a recent report on reduced numbers of circulating neutrophils during the autoantibody-positive phase as well as at the diagnosis of T1D in humans (32). Also, the erythrocyterelated module was activated at early time windows and before diagnosis.…”

Section: Discussionsupporting

confidence: 70%

Innate Immune Activity Is Detected Prior to Seroconversion in Children With HLA-Conferred Type 1 Diabetes Susceptibility

et al. 2014

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The insult leading to autoantibody development in children who will progress to develop type 1 diabetes (T1D) has remained elusive. To investigate the genes and molecular pathways in the pathogenesis of this disease, we performed genome-wide transcriptomics analysis on a unique series of prospective whole-blood RNA samples from at-risk children collected in the Finnish Type 1 Diabetes Prediction and Prevention study. We studied 28 autoantibody-positive children, out of which 22 progressed to clinical disease. Collectively, the samples covered the time span from before the development of autoantibodies (seroconversion) through the diagnosis of diabetes. Healthy control subjects matched for date and place of birth, sex, and HLA-DQB1 susceptibility were selected for each case. Additionally, we genotyped the study subjects with Immunochip to identify potential genetic variants associated with the observed transcriptional signatures. Genes and pathways related to innate immunity functions, such as the type 1 interferon (IFN) response, were active, and IFN response factors were identified as central mediators of the IFN-related transcriptional changes. Importantly, this signature was detected already before the T1D-associated autoantibodies were detected. Together, these data provide a unique resource for new hypotheses explaining T1D biology.

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Section: Discussionsupporting

confidence: 70%

Innate Immune Activity Is Detected Prior to Seroconversion in Children With HLA-Conferred Type 1 Diabetes Susceptibility

et al. 2014

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“…However, as these markers are products of neutrophils, we thought the findings could be related to a reduction in neutrophil numbers, which has been reported previously by multiple groups [7,8]. Consistent with these reports, the RO T1D subgroup had reduced numbers of neutrophils compared to controls (3Á2 6 0Á9 3 10 3 /ll versus 4Á4 6 1Á8 3 10 3 /ll; mean 6 s.d.)…”

Section: Association Of Netosis Markers With Neutrophil Countsupporting

confidence: 79%

“…In contrast to our original hypothesis, the primary finding was that of reduced circulating PR3 and NE levels in those with recently diagnosed T1D, reflecting a mild neutropenia occurring consistent with previous reports [7,8]. The reason for these neutrophil reductions is still not clear.…”

Section: Discussioncontrasting

confidence: 55%

“…For instance, the frequency of natural killer (NK) T cells and a subpopulation of myeloid dendritic cells has been reported to correlate with C-peptide loss [5,6]. In addition, multiple laboratories have reported a reduction in the number of circulating neutrophils near the time of T1D diagnosis as well as prior to onset [7,8]. Somewhat paradoxically considering these findings, a recent study has raised a significant amount of interest in the field, showing extremely high levels of neutrophil-derived enzymes in the serum of newly diagnosed T1D patients [9].…”

Section: Introductionmentioning

confidence: 99%

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NETosis-associated serum biomarkers are reduced in type 1 diabetes in association with neutrophil count

Qin¹,

Song²,

Speake³

et al. 2016

Clinical and Experimental Immunology

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1These authors contributed equally to this study. SummaryAs the immune pathways involved in the pathogenesis of type 1 diabetes (T1D) are not fully understood, biomarkers implicating novel mechanisms of disease are of great interest and call for independent evaluation. Recently, it was reported that individuals with T1D display dramatic elevations in circulating components of neutrophil extracellular traps (NETs), indicating a potential role for NETosis in T1D. Our aim was to evaluate further the potential of NET-associated proteins as novel circulating biomarkers in T1D. We tested serum from subjects with T1D (n 5 44) with a median age of 26Á5 years and a median duration of 2Á2 years, along with 38 age-matched controls. T1D subjects did not show elevations in either neutrophil elastase (NE) or proteinase 3 (PR3), as reported previously. In fact, both NE and PR3 levels were reduced significantly in T1D subjects, particularly in subjects within 3 years of diagnosis, consistent with the known reduction in neutrophil counts in recent-onset T1D. Indeed, levels of both NE and PR3 correlated with absolute neutrophil counts. Therefore, while not ruling out potential local or transient spikes in NETosis activity, the levels of these serum markers do not support a role for systemically elevated NETosis in the T1D population we studied. Rather, a modest reduction in these markers may reflect other important aspects of disease activity associated with reduced neutrophil numbers.

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“…CXCL1 is important in the recruitment of neutrophils, which infiltrate the pancreas and are present in low numbers in the periphery in diabetic patients [45]. CCL2 expression is increased in the islets of prediabetic female NOD mice [7], and transgenic overexpression of CCL2 in beta cells stimulates insulitis and progression to diabetes in mice with a B6D2 background [46].…”

Section: Discussionmentioning

confidence: 99%

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

et al. 2013

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Aims/hypothesis Cytotoxic T cells and macrophages contribute to beta cell destruction in type 1 diabetes at least in part through the production of cytokines such as IL-1β, IFN-γ and TNF-α. We have recently shown the IL-17 pathway to be activated in circulating T cells and pancreatic islets of type 1 diabetes patients. Here, we studied whether IL-17A upregulates the production of chemokines by human pancreatic islets, thus contributing to the build-up of insulitis. Methods Human islets (from 18 donors), INS-1E cells and islets from wild-type and Stat1 knockout mice were studied. Dispersed islet cells were left untreated, or were treated with IL-17A alone or together with IL-1β+IFN-γ or TNF-α+IFN-γ.RNA interference was used to knock down signal transducer and activator of transcription 1 (STAT1). Chemokine expression was assessed by quantitative RT-PCR, ELISA and histology. Cell viability was evaluated with nuclear dyes. Results IL-17A augmented IL-1β+IFN-γ-and TNF-α+IFN-γ-induced chemokine mRNA and protein expression, and apoptosis in human islets. Beta cells were at least in part the source of chemokine production. Knockdown of STAT1 in human islets prevented cytokine-or IL-17A+cytokine-induced apoptosis and the expression of particular chemokines, e.g. chemokine (C-X-C motif) ligands 9 and 10. Similar observations were made in islets isolated from Stat1 knockout mice. Conclusions/interpretation Our findings indicate that IL-17A exacerbates proinflammatory chemokine expression and secretion by human islets exposed to cytokines. This suggests that IL-17A contributes to the pathogenesis of type 1 diabetes by two mechanisms, namely the exacerbation of beta cell apoptosis and increased local production of chemokines, thus potentially aggravating insulitis.

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Reduction of Circulating Neutrophils Precedes and Accompanies Type 1 Diabetes

Cited by 182 publications

References 19 publications

Innate Immune Activity Is Detected Prior to Seroconversion in Children With HLA-Conferred Type 1 Diabetes Susceptibility

Innate Immune Activity Is Detected Prior to Seroconversion in Children With HLA-Conferred Type 1 Diabetes Susceptibility

NETosis-associated serum biomarkers are reduced in type 1 diabetes in association with neutrophil count

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

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