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已发表论文
血清焦亡相关细胞因子作为诊断评估和风险分层眼部移植物抗宿主病的生物标志物：一项病例对照研究
Authors Lou J , Xu Y , Zhuang X, Zhao Y, Pan H, Chen Y, Zhang X , Lu P
Received 18 July 2025
Accepted for publication 11 December 2025
Published 19 December 2025 Volume 2025:18 Pages 17825—17841
DOI https://doi.org/10.2147/JIR.S552170
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 4
Editor who approved publication: Professor Ning Quan
Jing Lou,1,2 Yue Xu,2 Xinyu Zhuang,2 Ye Zhao,1 Hui Pan,2 Yingjie Chen,2 Xiaofeng Zhang,2 Peirong Lu1
1Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Ophthalmology, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, People’s Republic of China
Correspondence: Xiaofeng Zhang, Department of Ophthalmology, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu Province, People’s Republic of China, Email zhangxiaofeng@suda.edu.cn Peirong Lu, Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China, Email lupeirong@suda.edu.cn
Background: Ocular graft-versus-host disease (oGVHD) often presents with subtle and nonspecific symptoms following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Current diagnostic methods primarily depend on subjective clinical evaluations with limited sensitivity. This study aimed to identify serum pyroptosis-related cytokines associated with oGVHD and to develop a cytokine-based diagnostic model.
Methods: In this prospective case–control study, 116 allo-HSCT recipients (61 with oGVHD and 55 without) and 47 healthy controls were enrolled. A sandwich antibody array was used to screen differentially expressed proteins in a pilot cohort (n = 4 per group), followed by pathway enrichment analysis. Ocular surface parameters and serum levels of NLRP3, TLR4, CCL2, IL-18, IL-6, and TNF-α were measured. Linear correlation, logistic regression, receiver operating characteristic (ROC) analyses, and internal bootstrap validation were performed to evaluate diagnostic performance. A cytokine-based risk score model was established.
Results: Thirty-four upregulated proteins were enriched in immune and inflammatory pathways. Patients with oGVHD exhibited severe dry eye features and significantly higher serum levels of NLRP3, TLR4, CCL2, IL-18, and IL-6 (all p < 0.001), which inversely correlated with ocular surface parameters. A logistic model combining these five cytokines achieved excellent diagnostic accuracy (AUC = 0.960). Internal 10-fold cross-validation with 1,000 bootstrap iterations yielded a consistent mean AUC of 0.953, confirming model robustness. A simplified risk score stratified patients into low-, intermediate-, and high-risk categories with strong discriminatory power (p < 0.001).
Conclusion: A serum panel of NLRP3, TLR4, CCL2, IL-18, and IL-6 demonstrates high diagnostic accuracy and stability for oGVHD. As the diagnostic cutoffs were derived from the same dataset, potential overfitting cannot be excluded, and independent validation in larger multicenter cohorts is warranted.
Keywords: ocular graft-versus-host disease, pyroptosis, cytokines, dry eye, case-control study
1Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Ophthalmology, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, People’s Republic of China
Correspondence: Xiaofeng Zhang, Department of Ophthalmology, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu Province, People’s Republic of China, Email zhangxiaofeng@suda.edu.cn Peirong Lu, Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China, Email lupeirong@suda.edu.cn
Background: Ocular graft-versus-host disease (oGVHD) often presents with subtle and nonspecific symptoms following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Current diagnostic methods primarily depend on subjective clinical evaluations with limited sensitivity. This study aimed to identify serum pyroptosis-related cytokines associated with oGVHD and to develop a cytokine-based diagnostic model.
Methods: In this prospective case–control study, 116 allo-HSCT recipients (61 with oGVHD and 55 without) and 47 healthy controls were enrolled. A sandwich antibody array was used to screen differentially expressed proteins in a pilot cohort (n = 4 per group), followed by pathway enrichment analysis. Ocular surface parameters and serum levels of NLRP3, TLR4, CCL2, IL-18, IL-6, and TNF-α were measured. Linear correlation, logistic regression, receiver operating characteristic (ROC) analyses, and internal bootstrap validation were performed to evaluate diagnostic performance. A cytokine-based risk score model was established.
Results: Thirty-four upregulated proteins were enriched in immune and inflammatory pathways. Patients with oGVHD exhibited severe dry eye features and significantly higher serum levels of NLRP3, TLR4, CCL2, IL-18, and IL-6 (all p < 0.001), which inversely correlated with ocular surface parameters. A logistic model combining these five cytokines achieved excellent diagnostic accuracy (AUC = 0.960). Internal 10-fold cross-validation with 1,000 bootstrap iterations yielded a consistent mean AUC of 0.953, confirming model robustness. A simplified risk score stratified patients into low-, intermediate-, and high-risk categories with strong discriminatory power (p < 0.001).
Conclusion: A serum panel of NLRP3, TLR4, CCL2, IL-18, and IL-6 demonstrates high diagnostic accuracy and stability for oGVHD. As the diagnostic cutoffs were derived from the same dataset, potential overfitting cannot be excluded, and independent validation in larger multicenter cohorts is warranted.
Keywords: ocular graft-versus-host disease, pyroptosis, cytokines, dry eye, case-control study