Diagnostic and Immunopathological Significance of Serum IL-4 and IL-21 in Graves' Disease

Abstract

Graves’ disease (GD) is an organ-specific autoimmune hyperthyroid disorder in which loss of tolerance to thyroid antigens promotes autoantibody production and persistent immune activation. Cytokine imbalance is increasingly viewed as a measurable component of this process. Objective: This study evaluated serum interleukin-4 (IL-4) and interleukin-21 (IL-21) in GD patients, assessed their diagnostic performance by receiver operating characteristic (ROC) analysis, and examined their relationships with thyroid-function parameters. Methods: A case-control design included 50 patients with GD and 50 healthy controls. The serum IL-4 and IL-21 were measured using ELISA according to the manufacturers’ procedures. Group comparisons were performed using an independent-samples t-test, diagnostic accuracy was evaluated using ROC curve analysis, and Spearman’s rank correlation was used to assess associations with TSH, FT3, and FT4 among GD patients. Results: IL-4 was significantly higher in GD patients than controls (16.70 ± 2.17 vs. 3.40 ± 0.69 pg/mL; P < 0.001). IL-21 was also markedly elevated (47.81 ± 3.15 vs. 20.20 ± 3.53 pg/mL; P < 0.001). IL-4 had a cutoff of 9.5 pg/mL with 100% sensitivity, 100% specificity, and AUC 1.000; IL-21 had a cutoff of 40.1 pg/mL with 98% sensitivity, 100% specificity, and AUC 1.000. IL-4 was not significantly correlated with TSH, FT3, or FT4. IL-21 showed a significant positive correlation with TSH (r = 0.368, P = 0.008), but not with FT3 or FT4. Conclusion: IL-4 and IL-21 are strongly elevated in GD and show high diagnostic accuracy. The correlation pattern does not support a direct relationship between cytokine elevation and the biochemical severity of hyperthyroidism, because neither cytokine was associated with FT3 or FT4.