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01-08-2020 | Cytokines | Article

Innate immune stimulation of whole blood reveals IFN-1 hyper-responsiveness in type 1 diabetes

Authors: Kameron B. Rodrigues, Matthew J. Dufort, Alba Llibre, Cate Speake, M. Jubayer Rahman, Vincent Bondet, Juan Quiel, Peter S. Linsley, Carla J. Greenbaum, Darragh Duffy, Kristin V. Tarbell

Published in: Diabetologia | Issue 8/2020

Abstract

Aims/hypothesis

Self-antigen-specific T cell responses drive type 1 diabetes pathogenesis, but alterations in innate immune responses are also critical and not as well understood. Innate immunity in human type 1 diabetes has primarily been assessed via gene-expression analysis of unstimulated peripheral blood mononuclear cells, without the immune activation that could amplify disease-associated signals. Increased responsiveness in each of the two main innate immune pathways, driven by either type 1 IFN (IFN-1) or IL-1, have been detected in type 1 diabetes, but the dominant innate pathway is still unclear. This study aimed to determine the key innate pathway in type 1 diabetes and assess the whole blood immune stimulation assay as a tool to investigate this.

Methods

The TruCulture whole blood ex vivo stimulation assay, paired with gene expression and cytokine measurements, was used to characterise changes in the stimulated innate immune response in type 1 diabetes. We applied specific cytokine-induced signatures to our data, pre-defined from the same assays measured in a separate cohort of healthy individuals. In addition, NOD mice were stimulated with CpG and monocyte gene expression was measured.

Results

Monocytes from NOD mice showed lower baseline vs diabetes-resistant B6.g7 mice, but higher induced IFN-1-associated gene expression. In human participants, ex vivo whole blood stimulation revealed higher induced IFN-1 responses in type 1 diabetes, as compared with healthy control participants. In contrast, neither the IL-1-induced gene signature nor response to the adaptive immune stimulant Staphylococcal enterotoxin B were significantly altered in type 1 diabetes samples vs healthy control participants. Targeted gene-expression analysis showed that this enhanced IFN response was specific to IFN-1, as IFN-γ-driven responses were not significantly different.

Conclusions/interpretation

Our study identifies increased responsiveness to IFN-1 as a feature of both the NOD mouse model of autoimmune diabetes and human established type 1 diabetes. A stimulated IFN-1 gene signature may be a potential biomarker for type 1 diabetes and used to evaluate the effects of therapies targeting this pathway.

Data availability

Mouse gene expression data are found in the gene expression omnibus (GEO) repository, accession GSE146452 (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE146452). Nanostring count data from the human experiments were deposited in the GEO repository, accession GSE146338 (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE146338). Data files and R code for all analyses are available at https://github.com/rodriguesk/T1D_truculture_diabetologia.

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Title: Innate immune stimulation of whole blood reveals IFN-1 hyper-responsiveness in type 1 diabetes
Authors: Kameron B. Rodrigues
Matthew J. Dufort
Alba Llibre
Cate Speake
M. Jubayer Rahman
Vincent Bondet
Juan Quiel
Peter S. Linsley
Carla J. Greenbaum
Darragh Duffy
Kristin V. Tarbell
Publication date: 01-08-2020
Publisher: Springer Berlin Heidelberg
Keywords: Cytokines
Type 1 Diabetes
Published in: Diabetologia / Issue 8/2020
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-020-05179-4

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Conclusions/interpretation

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