Researchers at the University of Miami Miller School of Medicine have uncovered molecular evidence suggesting a link between human papillomavirus (HPV) infection and the development of thyroid eye disease (TED). Their findings, published in JAMA Ophthalmology, point to molecular mimicry involving HPV capsid proteins and key autoimmune targets as a potential mechanism driving TED pathogenesis.
TED is a complex autoimmune condition characterized by a range of ocular symptoms, including proptosis (eye bulging), double vision, pain, dryness, and redness. Severe cases can lead to vision loss in approximately 2% to 5% of patients. Among individuals with Graves’ disease, TED occurs in 25% to 50% of cases, while 3% to 5% of those with Hashimoto thyroiditis also develop TED. The disease can also manifest in individuals who are euthyroid or hypothyroid, suggesting that mechanisms beyond thyroid dysfunction contribute to its development.
Autoantibodies targeting the insulin-like growth factor-1 receptor (IGF-1R) and thyroid-stimulating hormone receptor (TSHR) have been primarily implicated in TED. However, TED cases without thyroid abnormalities have fueled hypotheses that external triggers, such as infections, might initiate autoimmune responses through molecular mimicry. The recent reports of TED following COVID-19 infection further support this theory.
Researchers collected orbital adipose tissue samples from 11 patients undergoing decompression surgery for TED and 11 control patients undergoing blepharoplasty in their experimental study. The study population had a mean age of 58.6 years (ranging from 37.4 to 74.4 years), with females accounting for 86.4% of participants.
Using the publicly available Basic Local Alignment Search Tool (BLAST) from the National Center for Biotechnology Information (NCBI), the researchers conducted protein homology analyses comparing IGF-1R and TSHR sequences against viral proteomes. They found significant homology between IGF-1R, TSHR, and the major capsid proteins of the Papillomaviridae family, including HPV, as well as other viral families such as Paramyxoviridae, Herpesviridae, Enteroviruses, Polyomaviridae, and Rhabdoviridae. Two conserved motifs, FGXV and IXEXT+NP, were consistently identified across all HPV serotypes and the autoimmune targets.
The researchers also performed enzyme-linked immunosorbent assays (ELISAs) to measure HPV type 18 (HPV18) L1 immunoglobulin G (IgG) levels in the tissue samples. Optical density (OD) readings from the ELISA indicated the extent of antibody binding. Analysis showed that mean normalized OD values were significantly elevated in TED patients compared with controls. Controls had a mean OD of 0.94, whereas patients with chronic TED had a mean OD of approximately 2.31. The highest levels were observed in patients with acute active TED, with a mean OD of around 4.09.
However, no correlations were found between HPV18 L1 IgG levels and thyroid hormone levels, thyroid-stimulating immunoglobulin, radioactive iodine treatment, or thyroidectomy status. Elevated antibody titers also appeared independent of treatment with teprotumumab, a therapeutic antibody used in TED management.
The researchers concluded that molecular mimicry between HPV and key autoimmune receptors could play a role in triggering TED. Elevated HPV18 L1 antibody levels in TED patients support the possibility that viral exposure may contribute to disease development. The findings open new avenues for exploring viral contributions to TED and could inform future strategies for prevention, diagnosis, and treatment.
References
- Human Papillomavirus and Thyroid Eye Disease | Ophthalmology | JAMA Ophthalmology | JAMA Network [Internet]. [cited 2025 Apr 29]. Available from: https://jamanetwork.com/journals/jamaophthalmology/article-abstract/2832966
- Hodgson NM, Rajaii F. Current Understanding of the Progression and Management of Thyroid Associated Orbitopathy: A Systematic Review. Ophthalmol Ther. 2020 Mar 1;9(1):21–33.
- Allam MM, El-Zawawy HT, Ahmed SM, Aly Abdelhamid M. Thyroid disease and covid-19 infection: Case series. Clinical Case Reports. 2021 Jun;9(6):e04225.