{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T02:47:15Z","timestamp":1771123635698,"version":"3.50.1"},"reference-count":46,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,13]],"date-time":"2025-09-13T00:00:00Z","timestamp":1757721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: The pathogenesis of thyroid eye disease (TED) is driven by interactions between orbital fibroblasts and immune cells. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint molecule with a similar structure to the T lymphocyte CD4 receptor but with higher affinity for MHC class II, and LAG-3\u2013MHC class II interaction inhibits T lymphocyte activity. Lymphocytes shed LAG-3, generating soluble LAG-3 (sLAG-3), whose function is unclear. We investigated sLAG-3 involvement in Graves\u2019 disease (GD) and GD-associated TED pathogenesis. Materials and Methods: Patients with GD-associated TED (n = 47) and GD without TED (n = 35) were enrolled alongside 37 healthy controls (HCs). Peripheral blood serum sLAG-3 levels were measured using enzyme-linked immunosorbent assays and compared across the three groups. The effect of intravenous glucocorticosteroid (IVGC) treatment (12 weeks) on sLAG-3 concentrations in patients with GD-associated TED was monitored, and associations of sLAG-3 levels with clinical characteristics were analyzed. Disease activity before and after IVGC treatment was assessed using Clinical Activity Score. Results: Relative to those in HCs, serum sLAG-3 levels were significantly higher in GD patients both with (p &lt; 0.001) and without (p = 0.0129) TED. No significant difference in sLAG-3 levels was observed between the two patient groups (p = 1.000), and no significant change in sLAG-3 levels was detected in patients with TED after IVGC therapy (p = 0.0536). Conclusions: The higher sLAG-3 levels in patients compared to HCs suggest that sLAG-3 dysregulation may contribute to GD and GD with orbitopathy development and the pathomechanisms underlying these conditions. Metalloproteinase-mediated cleavage of LAG-3 from the lymphocyte surface enables T lymphocyte proliferation and activation, while released sLAG-3 may enhance the immune response. Further studies of sLAG-3\u2019s mechanisms of action are needed to establish clear cut-off values and to define the diagnostic role of sLAG-3 in GD diagnosis.<\/jats:p>","DOI":"10.3390\/medicina61091664","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T07:56:51Z","timestamp":1757923011000},"page":"1664","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Elevated Levels of sLAG-3 as a Possible Biomarker in Graves\u2019 Disease With and Without Thyroid Eye Disease: A Prospective Observational Case\u2013Control Study"],"prefix":"10.3390","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5703-5448","authenticated-orcid":false,"given":"Katarzyna","family":"Ciepli\u0144ska","sequence":"first","affiliation":[{"name":"Department of Tumor Markers, Holy Cross Cancer Center, 25-734 Kielce, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5481-8071","authenticated-orcid":false,"given":"Emilia","family":"Niedziela","sequence":"additional","affiliation":[{"name":"Collegium Medicum, Jan Kochanowski University in Kielce, 25-317 Kielce, Poland"},{"name":"Department of Endocrinology, Holy Cross Cancer Center, 25-734 Kielce, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edyta","family":"Jagielska","sequence":"additional","affiliation":[{"name":"Department of Tumor Markers, Holy Cross Cancer Center, 25-734 Kielce, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iwona","family":"Pa\u0142yga","sequence":"additional","affiliation":[{"name":"Collegium Medicum, Jan Kochanowski University in Kielce, 25-317 Kielce, Poland"},{"name":"Department of Endocrinology, Holy Cross Cancer Center, 25-734 Kielce, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"S\u0142uszniak","sequence":"additional","affiliation":[{"name":"Department of Tumor Markers, Holy Cross Cancer Center, 25-734 Kielce, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5647-5898","authenticated-orcid":false,"given":"Aldona","family":"Kowalska","sequence":"additional","affiliation":[{"name":"Collegium Medicum, Jan Kochanowski University in Kielce, 25-317 Kielce, Poland"},{"name":"Department of Endocrinology, Holy Cross Cancer Center, 25-734 Kielce, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1159\/000490384","article-title":"2018 European Thyroid Association Guideline for the Management of Graves\u2019 Hyperthyroidism","volume":"7","author":"Kahaly","year":"2018","journal-title":"Eur. 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