Back to Search Start Over

A novel subpopulation of monocytes with a strong interferon signature indicated by SIGLEC-1 is present in patients with in recent-onset type 1 diabetes.

Authors :
Guo, Mengqi
Guo, Han
Zhu, Jingjing
Wang, Fei
Chen, Jianni
Wan, Chuan
Deng, Yujie
Wang, Fang
Xu, Lili
Chen, Ying
Li, Ran
Liu, Shikai
Zhang, Lin
Wang, Yangang
Zhou, Jing
Li, Shufa
Source :
Diabetologia; Apr2024, Vol. 67 Issue 4, p623-640, 18p
Publication Year :
2024

Abstract

Aims/hypothesis: Type 1 diabetes is a T cell-mediated autoimmune disease characterised by pancreatic beta cell destruction. In this study, we explored the pathogenic immune responses in initiation of type 1 diabetes and new immunological targets for type 1 diabetes prevention and treatment. Methods: We obtained peripheral blood samples from four individuals with newly diagnosed latent autoimmune diabetes in adults (LADA) and from four healthy control participants. Single-cell RNA-sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells to uncover transcriptomic profiles of early LADA. Validation was performed through flow cytometry in a cohort comprising 54 LADA, 17 adult-onset type 2 diabetes, and 26 healthy adults, matched using propensity score matching (PSM) based on age and sex. A similar PSM method matched 15 paediatric type 1 diabetes patients with 15 healthy children. Further flow cytometry analysis was performed in both peripheral blood and pancreatic tissues of non-obese diabetic (NOD) mice. Additionally, cell adoptive transfer and clearance assays were performed in NOD mice to explore the role of this monocyte subset in islet inflammation and onset of type 1 diabetes. Results: The scRNA-seq data showed that upregulated genes in peripheral T cells and monocytes from early-onset LADA patients were primarily enriched in the IFN signalling pathway. A new cluster of classical monocytes (cluster 4) was identified, and the proportion of this cluster was significantly increased in individuals with LADA compared with healthy control individuals (11.93% vs 5.93%, p=0.017) and that exhibited a strong IFN signature marked by SIGLEC-1 (encoding sialoadhesin). These SIGLEC-1<superscript>+</superscript> monocytes expressed high levels of genes encoding C-C chemokine receptors 1 or 2, as well as genes for chemoattractants for T cells and natural killer cells. They also showed relatively low levels of genes for co-stimulatory and HLA molecules. Flow cytometry analysis verified the elevated levels of SIGLEC-1<superscript>+</superscript> monocytes in the peripheral blood of participants with LADA and paediatric type 1 diabetes compared with healthy control participants and those with type 2 diabetes. Interestingly, the proportion of SIGLEC-1<superscript>+</superscript> monocytes positively correlated with disease activity and negatively with disease duration in the LADA patients. In NOD mice, the proportion of SIGLEC-1<superscript>+</superscript> monocytes in the peripheral blood was highest at the age of 6 weeks (16.88%), while the peak occurred at 12 weeks in pancreatic tissues (23.65%). Adoptive transfer experiments revealed a significant acceleration in diabetes onset in the SIGLEC-1<superscript>+</superscript> group compared with the SIGLEC-1<superscript>−</superscript> or saline control group. Conclusions/interpretation: Our study identified a novel group of SIGLEC-1<superscript>+</superscript> monocytes that may serve as an important indicator for early diagnosis, activity assessment and monitoring of therapeutic efficacy in type 1 diabetes, and may also be a novel target for preventing and treating type 1 diabetes. Data availability: RNA-seq data have been deposited in the GSA human database (https://ngdc.cncb.ac.cn/gsa-human/) under accession number HRA003649. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
0012186X
Volume :
67
Issue :
4
Database :
Complementary Index
Journal :
Diabetologia
Publication Type :
Academic Journal
Accession number :
175759132
Full Text :
https://doi.org/10.1007/s00125-024-06098-4