Upregulation of ADAM19 in dendritic cells is associated with immune features and lower C-peptide levels in type 1 diabetes mellitus.

内容摘要

Type 1 diabetes mellitus (T1DM) is a chronic metabolic disorder characterized by the autoimmune destruction of insulin-producing β-cells in the pancreas, leading to absolute insulin deficiency and persistent hyperglycemia. The immune system plays a pivotal role in the development of T1DM, with dendritic cells (DCs) acting as crucial modulators of immune responses. Despite this, the specific role of ADAM19 within the T1DM immune microenvironment remains poorly understood, particularly its expression in DCs and potential effects on pancreatic β-cell function. Further research is needed to explore these aspects in peripheral blood mononuclear cells (PBMCs) and pancreatic tissues. This study aims to investigate the association between ADAM19 expression in DCs and immune features in T1DM. Among the genes consistently upregulated across four independent PBMC transcriptomic datasets and previously implicated in immune regulation, ADAM19 exhibited the most pronounced differential expression in dendritic cell subsets. We therefore focused on ADAM19 to determine whether it influences DC function, thereby disrupting the immune microenvironment and exacerbating pancreatic β-cell damage. Additionally, the study evaluates the potential of ADAM19 as a candidate biomarker for T1DM. This study analyzed public bulk RNA-seq data from peripheral blood mononuclear cells (PBMCs) derived from three datasets (GSE156035, GSE55100, GSE9006), comprising a total of 129 samples (75 T1DM patients and 54 healthy controls). For discovery, an additional in-house PBMC RNA-seq cohort of 20 samples (13 T1DM, 7 controls) was included. Single-cell RNA-seq (scRNA-seq) data were obtained from PBMCs and pancreatic islets, comprising a total of 117 samples (55 from T1DM patients and 62 from healthy controls), with detailed distributions including 46 T1DM and 31 controls from PBMCs, and 9 T1DM and 31 controls from pancreas samples. By integrating transcriptomic and single-cell data, we evaluated the expression patterns of ADAM19 in DCs from T1DM patients. Analytical approaches included partial least squares discriminant analysis (PLS-DA), differential expression analysis (DEG), Gene Set Enrichment Analysis (GSEA), pseudotime trajectory analysis, and cell-cell communication inference to explore the potential involvement of ADAM19 in immune responses. For validation, an independent in-house cohort of PBMC samples (44 samples: 29 T1DM, 15 controls) was examined using RT-qPCR to assess the correlation between ADAM19 expression and C-peptide levels. ADAM19 expression was consistently elevated in PBMCs of T1DM patients across all datasets, with the highest levels observed in DCs in single-cell RNA-seq data. Receiver operating characteristic (ROC) analysis demonstrated AUC values greater than 0.7 in all cohorts, reaching 0.93 in the in-house dataset. Elevated ADAM19 expression in DCs was associated with altered immune cell proportions and reduced fasting C-peptide levels in T1DM patients. This study identifies an association between elevated ADAM19 expression in DCs and T1DM immune features, suggesting potential links to immune dysregulation and β-cell dysfunction. ADAM19 shows promise as a candidate biomarker, warranting further validation for diagnostic and therapeutic applications.