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

Golodnikov, I.I.; Podshivalova, E.S.; Chechekhin, V.I.; Zubritskiy, A.V.; Matrosova, A.A.; Sergeev, N.A.; Samsonova, M.D.; Dvoryanchikov, Y.V.; Nikonova, T.V.; Bondarenko, E.V.; Loguinova, M.Y.; Medvedeva, Y.A.; Laptev, D.N.; Khusainova, R.I.; Minniakhmetov, I.R.; Shestakova, M.V.; Mokrysheva, N.G.; Dedov, I.I.

Авторы: Golodnikov Ivan I., Podshivalova Elizaveta S., Chechekhin Vadim I., Zubritskiy Anatoliy V., Matrosova Alina A., Sergeev Nikita A., Samsonova Margarita D., Dvoryanchikov Yaroslav V., Nikonova Tatiana V., Bondarenko Ekaterina V., Loguinova Marina Yu, Medvedeva Yulia A., Laptev Dmitry N., Khusainova Rita I., Minniakhmetov Ildar R., Shestakova Marina V., Mokrysheva Natalia G., Dedov Ivan I.
Журнал: JCI INSIGHT
Том: 11
Номер: 1
Год издания: 2026
Номер статьи: e199050
DOI: 10.1172/jci.insight.199050.
Аннотация: Autoimmune diabetes encompasses rapidly progressive type 1 diabetes mellitus (T1D) and indolent latent autoimmunediabetes 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 performedsingle-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-lineageactivation of NF-κB, EGFR, MAPK, and hypoxia pathways, coupled with a TNF-centered communication hub, enhancedMHC signaling, disrupted adhesion, and promoted systemic inflammation. LADA, by contrast, exhibited globalsuppression of NF-κB/EGFR activity, retention of moderate JAK/STAT tone, reinforced NK cell inhibitory checkpoints viaHLA-C–KIR2DL3/3DL1 interaction, and stabilized CD8+ T cell synapses through HLA-C–CD8 binding, collectivelyrestraining 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 asan inflammatory-inhibitory set-point continuum, positioning the NF-κB/EGFR–JAK/STAT gradient and HLA-C–KIR axis aspotential therapeutic targets to preserve residual β cell function.
Добавил в систему: Голодников Иван Иванович

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