ORIGINAL RESEARCH article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1554570
This article is part of the Research TopicThe Innate Immune System as a Driver of Diabetes and its ComplicationsView all 4 articles
Effect Of The Autoimmune-associated Genetic Variant PTPN22 R620W On Neutrophil Activation And Function In Patients With Insulin-dependent Diabetes Mellitus
Provisionally accepted
Eugenia Belcastro
Annamaria Cudini
Stefania Petrini
Valentina D'Oria
RICCARDO SCHIAFFINIMarco ScarsellaAnna Lo Russo
Alessandra Fierabracci*- Bambino Gesù Children's Hospital (IRCCS), Rome, Italy
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Recent evidence highlights neutrophils' role in initiating/sustaining aberrant immune responses in Type 1 diabetes (T1D). The PTPN22 C1858T variant, a risk factor for several autoimmune conditions including T1D, affects T/B cell receptors signalling. This study investigates its contribution to the altered neutrophils activation and function in T1D.Neutrophils were isolated from peripheral blood mononuclear cells (PBMCs) of wild-type (WT) C1858C, heterozygous (HET) C1858T T1D patients and healthy controls (HD). ROS levels were assessed using a fluorogenic probe by FACS in TNF-α primed, unprimed-fMLP stimulated, and primed-stimulated neutrophils. Neutrophils adhesion/transmigration were evaluated by brightfield and epifluorescence microscopy on HUVECs.Results: Neutrophil counts were increased in female patients than in HD. ROS production was enhanced in neutrophils of HET patients versus WT controls under the different culture conditions. Further ROS levels were increased in HET(n=10) versus WT (n=6) patients (p < 0.05). Neutrophil adhesion on HUVECs and transmigration through monolayer was increased in HET(n=4) versus WT (n=6) patients both in basal and TNF-α conditions (p < 0.0001).Neutrophils from C1858T patients are more intrinsically active with increased ROS production and HUVECs adhesion/transmigration suggesting enhanced contribution to migration of other immunotypes from vessels into the pancreatic islets during T1D etiopathogenesis.
Keywords: type 1 diabetes, Variant PTPN22, Reactive Oxygen Species, Neutrophils activation, Endothelial Cells
Received: 02 Jan 2025; Accepted: 30 Jul 2025.
Copyright: © 2025 Belcastro, Cudini, Petrini, D'Oria, SCHIAFFINI, Scarsella, Russo and Fierabracci. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Alessandra Fierabracci, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy
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