Systematic immune cell dysregulation and molecular subtypes revealed by single-cell RNA-seq of subjects with type 1 diabetes

• Published in: Genome medicine Vol. 16; no. 1; pp. 45 - 24
• Main Authors: Honardoost, Mohammad Amin, Adinatha, Andreas, Schmidt, Florian, Ranjan, Bobby, Ghaeidamini, Maryam, Arul Rayan, Nirmala, Gek Liang Lim, Michelle, Joanito, Ignasius, Xiao Xuan Lin, Quy, Rajagopalan, Deepa, Qi Mok, Shi, Hwang, You Yi, Larbi, Anis, Khor, Chiea Chuen, Foo, Roger, Boehm, Bernhard Otto, Prabhakar, Shyam
• Format: Journal Article
• Language: English
• Published: London BioMed Central 27.03.2024; BioMed Central Ltd; BMC
• Subjects: Antigen presentation; Antigens; Autoimmune Diseases; B cells; Beta cells; Bioinformatics; Biological response modifiers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell activation; Cells; Clinical trials; Cross-Sectional Studies; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Ethylenediaminetetraacetic acid; Gene expression; Genes; Haplotypes; Health risk assessment; Human Genetics; Humans; Insulin; Interferon; Leukocyte migration; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Medicine/Public Health; Metabolomics; Monocytes; Pancreas; Penicillin; Peptides; Peripheral blood mononuclear cells; Peripheral blood mononuclear cells (PBMCs); Phenotypes; RNA; RNA sequencing; Single-Cell Gene Expression Analysis; Single-cell RNA sequencing (scRNA-seq); Systemic lupus erythematosus; Systems Biology; Transcriptomics; Type 1 diabetes; Type 1 diabetes mellitus (T1DM); Wnt protein; Germany; Single-cell RNA sequencing (scRNA-seq); Type 1 diabetes mellitus (T1DM); Peripheral blood mononuclear cells (PBMCs)
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-024-01300-z

Background Type 1 diabetes mellitus (T1DM) is a prototypic endocrine autoimmune disease resulting from an immune-mediated destruction of pancreatic insulin-secreting β  cells. A comprehensive immune cell phenotype evaluation in T1DM has not been performed thus far at the single-cell level. Methods In this cross-sectional analysis, we generated a single-cell transcriptomic dataset of peripheral blood mononuclear cells (PBMCs) from 46 manifest T1DM (stage 3) cases and 31 matched controls. Results We surprisingly detected profound alterations in circulatory immune cells (1784 dysregulated genes in 13 immune cell types), far exceeding the count in the comparator systemic autoimmune disease SLE. Genes upregulated in T1DM were involved in WNT signaling, interferon signaling and migration of T/NK cells, antigen presentation by B cells, and monocyte activation. A significant fraction of these differentially expressed genes were also altered in T1DM pancreatic islets. We used the single-cell data to construct a T1DM metagene z-score (TMZ score) that distinguished cases and controls and classified patients into molecular subtypes. This score correlated with known prognostic immune markers of T1DM, as well as with drug response in clinical trials. Conclusions Our study reveals a surprisingly strong systemic dimension at the level of immune cell network in T1DM, defines disease-relevant molecular subtypes, and has the potential to guide non-invasive test development and patient stratification.