Single-Cell Transcriptomic Profiling of Peripheral Blood in a Patient with Progressive Thyroid Eye Disease Following...

Thyroid eye disease (TED) is an autoimmune inflammatory disorder of the orbit closely associated with thyroid dysfunction. Total thyroidectomy is traditionally expected to attenuate the autoimmune cascade, yet some patients continue to progress after surgery, which challenges this paradigm and points to a potentially autonomous orbital immune response. To investigate this, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from a 47-year-old woman with severe, glucocorticoid-refractory TED, four years after total thyroidectomy, and compared her immune landscape with that of an age- and sex-matched healthy control. The patient's peripheral blood showed a clear shift toward an active, stress-associated inflammatory state: pro-inflammatory mediators, immediate-early response transcription factors (FOS, JUNB, FOSB, TNFAIP3), and survival-related genes (CXCR4, DDIT4) were all upregulated. Gene Set Enrichment Analysis (GSEA) pointed to different mechanisms across cell types-myeloid cells were enriched for IL-6/JAK/STAT3 and TNF-α signaling, activated T cells for oxidative phosphorylation and mTORC1 signaling-while B lymphocytes and NK cells showed the opposite pattern, with reduced inflammatory and metabolic activity. One possible explanation is a "tissue-drainage" effect, where the most pathogenic lymphocytes leave the bloodstream and migrate into the inflamed orbital tissue along chemokine gradients. Together, these findings point to the CXCR4/CXCL12 axis and cellular stress pathways as candidate therapeutic targets, though as a single-case observation this remains preliminary and requires validation in larger cohorts, at the protein level, and in functional in vitro/in vivo studies.