Context: Thyroid eye disease (TED) is an autoimmune disease characterized by orbital inflammation and tissue remodeling. TED pathogenesis is poorly understood but is linked to autoantibodies to thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor 1 receptor (IGF-1R). Objective: To explore the potential involvement of viral infections in TED pathogenesis. Methods: Using NCBI BLAST, we compared human TSHR and IGF-1R proteins to various viral proteomes, including Papillomaviridae, Paramyxoviridae, Herpesviridae, Enterovirus, Polyomaviridae, and Rhabdoviridae. Enzyme-linked immunoassays (ELISAs) were performed on orbital adipose tissue samples from 22 TED patients and controls to quantify antiviral antibody titers. Demographics and clinical data were reviewed. Results: Homology analysis revealed conserved motifs between TSHR and IGF-1R with several viral proteins, particularly the human papillomavirus 18 (HPV18) L1 capsid protein. Basic demographic and clinical information between the cohorts were comparable. ELISAs showed statistically significant differences in the average HPV18 L1 IgG normalized optical density levels among tissues of control (M = 0.9387, SD = 0.3548), chronic TED (M = 2.305, SD = 1.064), and active acute TED (M = 4.087, SD = 2.034) patients. These elevated HPV18 L1 IgG titers did not statistically correlate with TSH, T4, or TSI levels, and were elevated in TED patients irrespective of treatment with teprotumumab, indicating a direct immunological response to HPV. Conclusions: This study presents the first molecular evidence linking HPV and TED, highlighting molecular mimicry between HPV capsid protein and key autoimmunity targets in TED. This suggests an immunological link contributing to TED's pathogenesis, opening new avenues for understanding and managing the disease.

The authors have declared no competing interest.

This work was supported in part by the Dr. Nasser Al-Rashid Orbital Research Endowment (Miami, FL, USA). Bascom Palmer Eye Institute is supported by NIH Center Core Grant P30EY014801 and a Research to Prevent Blindness Unrestricted Grant (New York, NY, USA).

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IRB of the University of Miami gave ethical approval for this work.

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