{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T04:54:36Z","timestamp":1781499276092,"version":"3.54.1"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Type 1 Diabetes Mellitus (T1DM) arises from a fundamental breakdown of central immune tolerance within the thymus. Medullary thymic epithelial cells (mTECs) express the Autoimmune Regulator (AIRE) protein, which drives the promiscuous transcription of peripheral tissue-restricted antigens \u2014 including insulin \u2014 thereby creating a \u201cgenetic mirror\u201d essential for the clonal deletion of autoreactive T-cells. Genetic susceptibility loci that reduce intrathymic insulin expression allow high-affinity insulin-reactive T-cells to escape negative selection and enter the periphery, where they ultimately orchestrate the progressive destruction of pancreatic \u03b2-cells. Despite decades of research, no therapeutic strategy has yet succeeded in restoring this upstream tolerogenic defect at its source.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Hypothesis<\/jats:title>\n                    <jats:p>\n                      I hypothesise that the thymic microenvironment can be bioelectronically reprogrammed to re-establish central immune tolerance in T1DM. Specifically, I propose that non-invasive application of 448 kHz radiofrequency (RF) fields, delivered via a wearable smart patch using subthermal Capacitive-Resistive Electric Transfer (CRET), can selectively upregulate\n                      <jats:italic>AIRE<\/jats:italic>\n                      -dependent insulin expression in mTECs, thereby restoring the intrathymic \u201cimmunological shadow\u201d of the pancreatic \u03b2-cell.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Proposed mechanism<\/jats:title>\n                    <jats:p>\n                      The 448 kHz RF field is hypothesised to interact with L-type voltage-gated calcium channels (Cav1.2\/Cav1.3) on mTEC membranes, inducing a controlled, subthermal Ca\u00b2\n                      <jats:sup>+<\/jats:sup>\n                      influx. This calcium signal is proposed to activate two parallel intracellular cascades: the MAPK\/ERK pathway and the calcineurin\/NFAT\u2013NF-\u03baB axis, both of which converge on transcriptional upregulation of\n                      <jats:italic>AIRE<\/jats:italic>\n                      and, consequently, enhanced intrathymic insulin (\n                      <jats:italic>Ins2<\/jats:italic>\n                      ) expression. Strengthened negative selection and the preferential generation of epigenetically stable Helios\n                      <jats:sup>+<\/jats:sup>\n                      Foxp3\n                      <jats:sup>+<\/jats:sup>\n                      thymus-derived regulatory T-cells (tTregs) are predicted as downstream immunological outcomes. The hypothesis is testable and falsifiable through a structured programme of preclinical experiments in the Non-Obese Diabetic (NOD) mouse model, incorporating pharmacological pathway dissection, live-cell calcium imaging and longitudinal immune phenotyping.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>This approach represents a conceptual shift from peripheral immunosuppression or symptomatic glycaemic management towards upstream, disease-modifying bioelectronic intervention. By targeting the embryologically conserved thymic\u2013pancreatic axis, the 448 kHz CRET strategy offers a non-invasive, paediatric-compatible platform to arrest the autoimmune cascade at its immunological origin, with potential implications for the prevention and early interception of T1DM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1851942","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T04:25:54Z","timestamp":1781497554000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Bioelectronic modulation of the thymic \u201cgenetic mirror\u201d: 448 kHz radiofrequency stimulation as a novel strategy for immune tolerance induction in type 1 diabetes"],"prefix":"10.3389","volume":"17","author":[{"given":"Natasha","family":"Yaneva","sequence":"first","affiliation":[{"name":"Clinic for Paediatric endocrinology, diabetes and metabolic diseases, University Children\u2019s Hospital \u201cProf. Ivan Mitev\u201d","place":["Sofia, Bulgaria"]},{"name":"Department of Paediatrics, Medical Faculty, Medical University of Sofia","place":["Sofia, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1001570303","article-title":"Development of thymus, parathyroids, and ultimo-branchial bodies in NMRI and nude mice","volume":"157","author":"Cordier","year":"1980","journal-title":"Am J Anat"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1997.8765","article-title":"Hox group 3 paralogous genes act synergistically in the formation of somitic and neural crest-derived structures","volume":"192","author":"Manley","year":"1997","journal-title":"Dev Biol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1146\/annurev.immunol.23.021704.115601","article-title":"A central role for central tolerance","volume":"24","author":"Kyewski","year":"2006","journal-title":"Annu Rev Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(22)00218-2","article-title":"Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040","volume":"10","author":"Gregory","year":"2022","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/ng0397-289","article-title":"Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus","volume":"15","author":"Vafiadis","year":"1997","journal-title":"Nat Genet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/ng0397-293","article-title":"The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes","volume":"15","author":"Pugliese","year":"1997","journal-title":"Nat Genet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2009.212","article-title":"Thymus-specific deletion of insulin induces autoimmune diabetes","volume":"28","author":"Fan","year":"2009","journal-title":"EMBO J"},{"key":"B8","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/nrd4351","article-title":"Bioelectronic medicines: a research roadmap","volume":"13","author":"Birmingham","year":"2014","journal-title":"Nat Rev Drug Discov"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1159\/000366375","article-title":"Electric stimulation at 448 kHz promotes proliferation of human mesenchymal stem cells","volume":"34","author":"Hern\u00e1ndez-Bule","year":"2014","journal-title":"Cell Physiol Biochem"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0139644","article-title":"mTOR activation by PI3K\/Akt and ERK signaling in short ELF-EMF exposed human keratinocytes","volume":"10","author":"Patruno","year":"2015","journal-title":"PloS One"},{"key":"B11","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.neuint.2014.06.004","article-title":"Pulsed electromagnetic field enhances brain-derived neurotrophic factor expression through L-type voltage-gated calcium channel- and Erk-dependent signaling pathways in neonatal rat dorsal root ganglion neurons","volume":"75","author":"Li","year":"2014","journal-title":"Neurochem Int"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201545928","article-title":"A highly conserved NF-\u03baB-responsive enhancer is critical for thymic expression of Aire in mice","volume":"45","author":"Haljasorg","year":"2015","journal-title":"Eur J Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00699-2","article-title":"NFAT signaling: choreographing the social lives of cells","volume":"109","author":"Crabtree","year":"2002","journal-title":"Cell"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nri2818","article-title":"NFAT, immunity and cancer: a transcription factor comes of age","volume":"10","author":"M\u00fcller","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nri1632","article-title":"NFAT proteins: key regulators of T-cell development and function","volume":"5","author":"Macian","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100945","article-title":"NFATc1 affects mouse splenic B cell function by controlling the calcineurin\u2013NFAT signaling network","volume":"208","author":"Bhattacharyya","year":"2011","journal-title":"J Exp Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1150","article-title":"Regulation of cell death: the calcium\u2013apoptosis link","volume":"4","author":"Orrenius","year":"2003","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1155","article-title":"Calcium signalling: dynamics, homeostasis and remodelling","volume":"4","author":"Berridge","year":"2003","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006080","article-title":"Cell death signaling","volume":"7","author":"Green","year":"2015","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1088\/0031-9155\/55\/2\/N01","article-title":"The Virtual Family \u2014 development of surface-based anatomical models of two adults and two children for dosimetric simulations","volume":"55","author":"Christ","year":"2010","journal-title":"Phys Med Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1088\/0031-9155\/59\/18\/5287","article-title":"Development of a new generation of high-resolution anatomical models for medical device evaluation: the Virtual Population 3.0","volume":"59","author":"Gosselin","year":"2014","journal-title":"Phys Med Biol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084636","article-title":"Molecular mechanisms underlying the antiproliferative and differentiating responses of hepatocarcinoma cells to subthermal electric stimulation","volume":"9","author":"Hern\u00e1ndez-Bule","year":"2014","journal-title":"PloS One"},{"key":"B24","doi-asserted-by":"publisher","first-page":"21968","DOI":"10.1038\/s41598-020-78612-8","article-title":"Thermal and non-thermal effects of capacitive-resistive electric transfer application on different structures of the knee: a cadaveric study","volume":"10","author":"Rodr\u00edguez-Sanz","year":"2020","journal-title":"Sci Rep"},{"key":"B25","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1097\/HP.0000000000001210","article-title":"Guidelines for limiting exposure to electromagnetic fields (100 kHz to 300 GHz)","volume":"118","year":"2020","journal-title":"Health Phys"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1109\/IEEESTD.2019.8859679","article-title":"IEEE standard for safety levels with respect to human exposure to electric, magnetic, and electromagnetic fields, 0 hz to 300 GHz","year":"2019","journal-title":"IEEE Std C951-2019"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.33549\/physiolres.934425","article-title":"Radiofrequency electromagnetic field affects heart rate variability in rabbits","volume":"69","author":"Misek","year":"2020","journal-title":"Physiol Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3791\/63873","article-title":"Real-time electrocardiogram monitoring during treadmill training in mice","volume":"183","author":"Tomsits","year":"2022","journal-title":"J Vis Exp"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nri3667","article-title":"Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see)","volume":"14","author":"Klein","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.05.009","article-title":"Regulatory T cells and immune tolerance","volume":"133","author":"Sakaguchi","year":"2008","journal-title":"Cell"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1166135","article-title":"Opportunities for Treg cell therapy for the treatment of human disease","volume":"14","author":"Bluestone","year":"2023","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050038","article-title":"Epigenetic control of the foxp3 locus in regulatory T cells","volume":"5","author":"Floess","year":"2007","journal-title":"PloS Biol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200838105","article-title":"DNA methylation controls Foxp3 gene expression","volume":"38","author":"Polansky","year":"2008","journal-title":"Eur J Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.09.010","article-title":"T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development","volume":"37","author":"Ohkura","year":"2012","journal-title":"Immunity"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02382","article-title":"Dynamic imprinting of the Treg cell-specific epigenetic signature in developing thymic regulatory T cells","volume":"10","author":"Herppich","year":"2019","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003099","article-title":"Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes","volume":"186","author":"McClymont","year":"2011","journal-title":"J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.10.015","article-title":"Regulatory T-cell therapy for autoimmune and autoinflammatory diseases: the next frontier","volume":"142","author":"Esensten","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2023.103057","article-title":"Supraphysiological FOXP3 expression in human CAR-Tregs results in improved stability, efficacy, and safety of CAR-Treg products for clinical application","volume":"136","author":"Henschel","year":"2023","journal-title":"J Autoimmun"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz3866","article-title":"Functional effects of chimeric antigen receptor co-receptor signaling domains in human regulatory T cells","volume":"12","author":"Dawson","year":"2020","journal-title":"Sci Transl Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.09.003","article-title":"Bioelectronic medicine: preclinical insights and clinical advances","volume":"110","author":"Pavlov","year":"2022","journal-title":"Neuron"},{"key":"B41","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1146\/annurev.immunol.25.022106.141532","article-title":"Aire","volume":"27","author":"Mathis","year":"2009","journal-title":"Annu Rev Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20062497","article-title":"RANK signals from CD4+3- inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla","volume":"204","author":"Rossi","year":"2007","journal-title":"J Exp Med"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.06.018","article-title":"The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator","volume":"29","author":"Hikosaka","year":"2008","journal-title":"Immunity"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1902226","article-title":"An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes","volume":"381","author":"Herold","year":"2019","journal-title":"N Engl J Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.2337\/dc15-1419","article-title":"Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association","volume":"38","author":"Insel","year":"2015","journal-title":"Diabetes Care"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.6285","article-title":"Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children","volume":"309","author":"Ziegler","year":"2013","journal-title":"JAMA"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7558","article-title":"Analysis of the human thymic perivascular space during aging","volume":"104","author":"Flores","year":"1999","journal-title":"J Clin Invest"},{"key":"B48","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.anndiagpath.2003.11.006","article-title":"Histologic and molecular assessment of human thymus","volume":"8","author":"Hale","year":"2004","journal-title":"Ann Diagn Pathol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/25374","article-title":"Changes in thymic function with age and during the treatment of HIV infection","volume":"396","author":"Douek","year":"1998","journal-title":"Nature"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2009.04.003","article-title":"Thymic involution and immune reconstitution","volume":"30","author":"Lynch","year":"2009","journal-title":"Trends Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2009.05.001","article-title":"An evolutionary perspective on the mechanisms of immunosenescence","volume":"30","author":"Shanley","year":"2009","journal-title":"Trends Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00249","article-title":"Regulations of gene expression in medullary thymic epithelial cells required for preventing the onset of autoimmune diseases","volume":"4","author":"Akiyama","year":"2013","journal-title":"Front Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0904028","article-title":"Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells","volume":"184","author":"Thornton","year":"2010","journal-title":"J Immunol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201379","article-title":"Helios+ and Helios- cells coexist within the natural FOXP3+ T regulatory cell subset in humans","volume":"190","author":"Himmel","year":"2013","journal-title":"J Immunol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1002\/eji.201847935","article-title":"Helios+ and Helios- Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires","volume":"49","author":"Thornton","year":"2019","journal-title":"Eur J Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.873560","article-title":"Human CD4+CD25+CD226- Tregs demonstrate increased purity, lineage stability, and suppressive capacity versus CD4+CD25+CD127lo\/- Tregs for adoptive cell therapy","volume":"13","author":"Brown","year":"2022","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1851942\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T04:25:57Z","timestamp":1781497557000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1851942\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,15]]},"references-count":56,"alternative-id":["10.3389\/fimmu.2026.1851942"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1851942","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,15]]},"article-number":"1851942"}}