Distinct mutations in the autoimmune regulator gene differentially affect transcriptional and functional properties of medullary thymic epithelial cells - PubMed
8 days ago
- #central tolerance
- #mTEC biology
- #AIRE mutations
- Autoimmune Polyendocrine Syndrome Type 1 (APS-1) is caused by mutations in the AIRE gene, affecting central immune tolerance.
- Distinct AIRE mutations differentially impact medullary thymic epithelial cells (mTECs) at transcriptional and functional levels.
- Single-cell RNA sequencing (scRNA-seq) of mTECs with a heterozygous Aire c.735delG mutation showed reduced transcriptional heterogeneity and decreased expression of tissue-restricted antigens (TRAs).
- Key mTEC lineage markers (Epcam, Cldn4, Krt14) were downregulated in mutant cells.
- Mutant mTECs exhibited altered expression of genes involved in chemokine-mediated migration, extracellular matrix, cell adhesion, and actin cytoskeleton organization.
- Functional assays revealed mutation-dependent changes in mTEC morphology, thymocyte migration, and adhesion, with the p.C313Y variant having the strongest effects.
- The study provides mechanistic insights into how AIRE mutations lead to immune tolerance failure in APS-1.