Single-cell immune transcriptomics reveals an inflammatory-inhibitory set-point spectrum in autoimmune diabetes
Ivan I. Golodnikov, Elizaveta S. Podshivalova, Vadim I. Chechekhin, Anatoliy V. Zubritskiy, Alina A. Matrosova, Nikita A. Sergeev, Margarita D. Samsonova, Yaroslav V. Dvoryanchikov, Tatiana V. Nikonova, Ekaterina V. Bondarenko, Marina Yu. Loguinova, Yulia A. Medvedeva, Dmitry N. Laptev, Rita I. Khusainova, Ildar R. Minniakhmetov, Marina V. Shestakova, Natalia G. Mokrysheva, Ivan I. Dedov
Ivan I. Golodnikov, Elizaveta S. Podshivalova, Vadim I. Chechekhin, Anatoliy V. Zubritskiy, Alina A. Matrosova, Nikita A. Sergeev, Margarita D. Samsonova, Yaroslav V. Dvoryanchikov, Tatiana V. Nikonova, Ekaterina V. Bondarenko, Marina Yu. Loguinova, Yulia A. Medvedeva, Dmitry N. Laptev, Rita I. Khusainova, Ildar R. Minniakhmetov, Marina V. Shestakova, Natalia G. Mokrysheva, Ivan I. Dedov
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Research Article Endocrinology Genetics

Single-cell immune transcriptomics reveals an inflammatory-inhibitory set-point spectrum in autoimmune diabetes

Abstract

Autoimmune diabetes encompasses rapidly progressive type 1 diabetes mellitus (T1D) and indolent latent autoimmune diabetes in adults (LADA), which represent distinct inflammatory set points along a shared autoimmune spectrum. Yet, the immunological mechanisms that determine these divergent inflammatory states remain unresolved. We performed single-cell RNA sequencing with paired T and B cell receptor profiling on over 400,000 PBMCs from patients with LADA, newly diagnosed T1D, and individuals acting as healthy controls. PBMC composition was comparable across cohorts, indicating that qualitative rather than quantitative immune differences underlie disease heterogeneity. In T1D, pan-lineage activation of NF-κB, EGFR, MAPK, and hypoxia pathways, coupled with a TNF-centered communication hub, enhanced MHC signaling, disrupted adhesion, and promoted systemic inflammation. LADA, by contrast, exhibited global suppression of NF-κB/EGFR activity, retention of moderate JAK/STAT tone, reinforced NK cell inhibitory checkpoints via HLA-C–KIR2DL3/3DL1 interaction, and stabilized CD8+ T cell synapses through HLA-C–CD8 binding, collectively restraining effector activation. Single-cell V(D)J analysis revealed multiclonal, patient-unique adaptive repertoires, emphasizing the primacy of signaling context over receptor convergence. These findings define autoimmune diabetes as an inflammatory-inhibitory set-point continuum, positioning the NF-κB/EGFR–JAK/STAT gradient and HLA-C–KIR axis as potential therapeutic targets to preserve residual β cell function.

Authors

Ivan I. Golodnikov, Elizaveta S. Podshivalova, Vadim I. Chechekhin, Anatoliy V. Zubritskiy, Alina A. Matrosova, Nikita A. Sergeev, Margarita D. Samsonova, Yaroslav V. Dvoryanchikov, Tatiana V. Nikonova, Ekaterina V. Bondarenko, Marina Yu. Loguinova, Yulia A. Medvedeva, Dmitry N. Laptev, Rita I. Khusainova, Ildar R. Minniakhmetov, Marina V. Shestakova, Natalia G. Mokrysheva, Ivan I. Dedov

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Figure 4

Model of T1D and LADA pathogenesis based on published literature and our own findings.

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Model of T1D and LADA pathogenesis based on published literature and our...
(A) Illustration of the PBMC compartment, where heightened activity of CD4+ Th1/Th17, CD8+ cytotoxic T lymphocytes (CTLs) and NK cells, coupled with depletion of FOXP3+ Tregs and IL-10–producing B regulatory cells (Bregs), establishes a proinflammatory milieu and systemic production of disease-defining autoantibodies. (B) Depiction of the pancreatic draining lymph node: dendritic cells ferry β cell antigens, driving oligoclonal expansion of autoreactive T cell receptors (TCRs) without a universal public clonotype. (C) Illustration of the islet microenvironment, where upregulation of HLA class I molecules and endoplasmic reticulum stress in β cells result in their direct lysis by CD8+ CTLs and NK cells. In addition, β cells are subject to cytokine-mediated damage driven by Th1 and Th17 cells, antibody-dependent cellular cytotoxicity (ADCC), and the effects of innate cytokines released by macrophages and dendritic cells. The bottom left panel displays data generated in the present study. Integrated JAK-STAT1/3, NF-κB, PI3K-AKT-mTOR, MAPK p38/JNK pathways maintain chronic inflammation and propagate β cell apoptosis, leading to epitope spreading and progressive loss of insulin secretion. Created in BioRender. (Samsonova M, 2025; https://BioRender.com/tkecn1v).