{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:52:32Z","timestamp":1791474752261,"version":"4.3.4"},"reference-count":124,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100016299","name":"Al-Ahliyya Amman University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100016299","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00xddhq60","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Autoimmune endocrine diseases constitute a group of disorders characterized by immune-mediated destruction or dysfunction of hormone-producing glands. The pathogenesis of these diseases reflects a breakdown of immune tolerance in which regulatory T cells (Tregs) play a key role. The transcription factor forkhead box P3 (FOXP3) is a master regulator of Treg differentiation and suppressive function. Also, it is central to maintaining self-tolerance. Genetic mutations in FOXP3, including those responsible for immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome, highlight the critical role of FOXP3 in endocrine immune tolerance. Emerging evidence suggests that autoimmune endocrine disorders may reflect organ-specific destabilization of FOXP3 expression rather than complete Treg deficiency. The reversibility or irreversible loss of FOXP3 gene expression represents a key determinant of Treg plasticity and the persistence of autoimmune inflammation. This review proposes an integrated genetic\u2013epigenetic model of FOXP3 instability and examines how the endocrine microenvironment shapes Treg plasticity. Genetic or epigenetic alterations affecting FOXP3 expression can impair Treg activity and precipitate endocrine organ-specific autoimmunity. Epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNA-mediated regulation that modulate FOXP3 transcriptional activity are discussed. From a translational perspective, the potential of FOXP3 as a biomarker for endocrine disease susceptibility and progression was summarized. Furthermore, therapeutic strategies employed for expanding or engineering functional FOXP3+ Tregs using antigen-specific vaccines, chimeric antigen receptors (CAR)-Tregs, gene therapy, or low-dose interleukin-2 (IL-2) were described.<\/jats:p>","DOI":"10.3390\/ijms27135778","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:55:11Z","timestamp":1782780911000},"page":"5778","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["FOXP3 Mutations and Instability as Determinants of Regulatory T-Cell Plasticity in Endocrine Autoimmunity"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8962-1879","authenticated-orcid":false,"given":"Manal A.","family":"Abbas","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19111, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2853","DOI":"10.1210\/clinem\/dgaf049","article-title":"Searching for Monogenic Autoimmune Etiology in Patients With Type 1 Diabetes Onset Before 30 Months of Age","volume":"110","author":"Urrutia","year":"2025","journal-title":"J. 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