Smoking-induced HLA-DQA1 overexpression in T cells: a novel pathway in thyroid eye disease development

Background: Smoking is an established risk factor for thyroid eye disease (TED), its immunopathological mechanisms remain elusive. This study investigates how smoking exacerbates TED through immune cell dysregulation. Methods: National Health and Nutrition Examination Survey (NHANES) data (1999-2010; n = 62,160) was used to compare leukocyte profiles between smokers and non-smokers using non-parametric tests and meta-analysis, with validation using retrospective clinical data. TED was characterized by orbital immune infiltration via CIBERSORT in the GEO dataset GSE58331 (27 patients vs. 23 controls). Linear regression linked lymphocyte levels with thyroid hormones with validation using retrospective clinical data. Summary-data-based Mendelian randomization (SMR) analyzed causal relationships between blood-derived gene expression and TED risk. Smoking-induced transcriptomic changes were validated using GSE4806 (T cells from smokers vs non-smokers) and RT-qPCR. Results: Smokers exhibited decreased leukocytes and neutrophils but elevated lymphocytes (p0.05). Smoking induced 406 upregulated genes (including HLA-DQA1/DQB1) and 31 downregulated genes in T cells. RT-qPCR confirmed that HLA-DQA1 expression was significantly upregulated in leukocytes from TED patients who smoke. Conclusion: Smoking exacerbates TED by elevating T cells and promoting HLA-DQA1 overexpression in peripheral T cells, provide a mechanistic justification for smoking cessation in TED management.