期刊
DIABETES
卷 68, 期 10, 页码 2024-2034出版社
AMER DIABETES ASSOC
DOI: 10.2337/db19-0287
关键词
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资金
- JDRF
- Academy of Finland (AoF) Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) [250114]
- AoF Personalized Medicine Program [292482]
- AoF [294337, 292335, 319280, 314444, 311081]
- Sigrid Juselius Foundation
- Diabetes Research Foundation (Diabetestutkimussaatio)
- Novo Nordisk Foundation Innovative Medicines Initiative 2 Joint Undertaking [115797]
- Union's Horizon 2020 research and innovation programme
- EFPIA
- Leona M. and Harry B. Helmsley Charitable Trust
- European Union [202063]
The appearance of type 1 diabetes (T1D)-associated autoantibodies is the first and only measurable parameter to predict progression toward T1D in genetically susceptible individuals. However, autoantibodies indicate an active autoimmune reaction, wherein the immune tolerance is already broken. Therefore, there is a clear and urgent need for new biomarkers that predict the onset of the autoimmune reaction preceding autoantibody positivity or reflect progressive beta-cell destruction. Here we report the mRNA sequencing-based analysis of 306 samples including fractionated samples of CD4(+) and CD8(+) T cells as well as CD4(-)CD8(-) cell fractions and unfractionated peripheral blood mononuclear cell samples longitudinally collected from seven children who developed beta-cell autoimmunity (case subjects) at a young age and matched control subjects. We identified transcripts, including interleukin 32 (IL32), that were upregulated before T1D-associated autoantibodies appeared. Single-cell RNA sequencing studies revealed that high IL32 in case samples was contributed mainly by activated T cells and NK cells. Further, we showed that IL32 expression can be induced by a virus and cytokines in pancreatic islets and beta-cells, respectively. The results provide a basis for early detection of aberrations in the immune system function before T1D and suggest a potential role for IL32 in the pathogenesis of T1D.
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