ИСТИНА

Background and Aims: Latent autoimmune diabetes in adults (LADA) progresses more slowly than type 1 diabetes mellitus (T1DM); the molecular determinants of this attenuated β-cell destruction are incompletely understood. We compared JAK/STAT and TRAIL signaling activities in circulating immune subsets to delineate immunopathogenic differences between LADA and T1DM. Methods: Peripheral blood mononuclear cells from 15 LADA patients, 21 T1DM patients and 22 age-matched healthy controls underwent 5′ single-cell RNA sequencing (10× Genomics). After quality control and batch correction, PROGENy pathway scores quantified JAK/STAT and TRAIL activities across T-cell and NK-cell subpopulations. Results: In T1DM, CD4⁺ and CD8⁺ T-cells exhibited pronounced JAK/STAT hyperactivation (median 12-fold vs controls) accompanied by marked TRAIL repression (median 0.4-fold). LADA displayed intermediate JAK/STAT elevation (median 4-fold vs controls) while maintaining significantly higher TRAIL signaling than T1DM (2.3-fold, p < 0.001). Similar but less marked trends were observed in CD56dim NK-cells. These findings for T-cell, visualized in the accompanying pathway heat-map (Figure), indicate a distinct immune-signaling milieu in LADA that may temper effector lymphocyte activity. Conclusions: Single-cell transcriptomics reveals that LADA is characterised by moderated JAK/STAT activation coupled with retained TRAIL signaling, contrasting with the pro-inflammatory, apoptosis-deficient profile of T1DM. Therapeutic strategies simultaneously limiting JAK/STAT-driven inflammation and preserving TRAIL-dependent apoptosis warrant investigation for β-cell preservation in LADA. Funding: This research was funded by the Ministry of Science and Higher Education of the Russian Federation (agreement No. 075-15-2024-645 from 12 July 2024).