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. 2013 Jun;62(6):2072-7.
doi: 10.2337/db12-1345. Epub 2013 Jan 24.

Reduction of circulating neutrophils precedes and accompanies type 1 diabetes

Andrea Valle  1 , Gian Maria Giamporcaro, Marina Scavini, Angela Stabilini, Pauline Grogan, Eleonora Bianconi, Guido Sebastiani, Matilde Masini, Norma Maugeri, Laura Porretti, Riccardo Bonfanti, Franco Meschi, Maurizio De Pellegrin, Arianna Lesma, Silvano Rossini, Lorenzo Piemonti, Piero Marchetti, Francesco Dotta, Emanuele Bosi, Manuela Battaglia
Affiliations

Reduction of circulating neutrophils precedes and accompanies type 1 diabetes

Andrea Valle et al. Diabetes. 2013 Jun.

Abstract

Human type 1 diabetes (T1D) is an autoimmune disease associated with major histocompatibility complex polymorphisms, β-cell autoantibodies, and autoreactive T cells. However, there is increasing evidence that innate cells may also play critical roles in T1D. We aimed to monitor peripheral immune cells in early stages of T1D (i.e., in healthy autoantibody-positive subjects) and in more advanced phases of the disease (i.e., at disease onset and years after diagnosis). We found a mild but significant and reproducible peripheral neutropenia that both precedes and accompanies the onset of T1D. This reduction was not due to peripheral neutrophil cell death, impaired differentiation, or the presence of anti-neutrophil antibodies. Neutrophils were observed by electron microscopy and immunohistochemical analysis in the exocrine pancreas of multiorgan donors with T1D (both at onset and at later stages of the disease) and not in that of multiorgan donors with type 2 diabetes or nondiabetic donors. These pancreas-infiltrating neutrophils mainly localized at the level of very small blood vessels. Our findings suggest the existence of a hitherto unrecognized clinical phenotype that might reflect unexplored pathogenic pathways underlying T1D.

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Figures

FIG. 1.
FIG. 1.
A: Neutrophil and platelet counts in pediatric healthy controls (n = 198) and autoAbNEG (n = 138) and autoAbPOS (n = 25) relatives of patients with T1D, and patients with T1D at onset (n = 238); **P < 0.005, ***P < 0.0001 vs. healthy controls, ANOVA and Tukey WSD test. The lower normal laboratory range is shown by the dotted line. B: Neutrophil and platelet counts in pediatric autoAbNEG relatives (n = 138) and autoAbPOS relatives at low (n = 15) and high risk (n = 10), as defined in the research design and methods section. The nonparametric test for trend is significant for both neutrophil (P < 0.001) and platelet (P = 0.023) counts. Means and SDs of neutrophil and platelet counts for each group also are reported. C: Neutrophil and platelet counts in pediatric patients studied at the onset of T1D and measured during clinical follow-up. Filled circles represent mean values, and bars represent 95% CIs. Numbers in parentheses on the x-axis represent the number of patients analyzed. D: Neutrophil and platelet counts in adult healthy controls (n = 511), patients with T1D at onset (n = 45), individuals with ≥5 years of T1D (n = 67), and individuals with T2D (n = 60) aged ≥18 years; **P < 0.005 vs. healthy controls, ANOVA and Tukey WSD test. The lower normal laboratory range is shown by the dotted line. Square dots that appear above the whiskers are outliers, i.e., individual observations that are above the upper fence of the distribution (i.e., above the 75th percentile).
FIG. 2.
FIG. 2.
A: Neutrophils are detected by immunoperoxidase in the exocrine pancreas. Representative neutrophil stainings of sections from donor no. 1 with T1D (I and II), donor no. 3 with T1D (III), and a nondiabetic donor (IV) are shown. These pancreas-infiltrating neutrophils localize mainly at the level of very small blood vessels (panels I and III) and, to a lesser extent, adjacent to acinar cells (panel II). B: Representative sections of the pancreas collected from donor no. 1 with T1D, analyzed using electron microscopy, and showing a granulocyte (GN) and a lymphocyte (L) in a microvessel of the exocrine tissue (left panel), and a GN adjacent to acinar cells (right panel). In both panels, red stars identify pancreatic acinar cells. C: The frequency of pancreatic neutrophils is determined by immunoperoxidase on pancreatic paraffin sections. The numbers of myeloperoxidase positive cells per square millimeter in the pancreas (left panel) and within the small blood vessels (right panel) are shown. At least 20 fields per donor have been examined. D: A representative section of the pancreas collected from donor no. 1 with T1D, analyzed using electron microscopy and showing GNs adjacent to β-cells (β).
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