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.
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