血友病A患者抑制剂发展的生物标志物探索

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis Pub Date : 2025-05-01 DOI:10.1016/j.rpth.2025.102877

Meng-Ni Fan , Tangliang Shen , Barbara A. Konkle , Xiaohe Cai , Ting-Yen Chao , Marilyn Manco-Johnson , Anna V. Faino , Junping Zhang , Shumin Bao , Weidong Xiao , Lei Li , Carol H. Miao

{"title":"血友病A患者抑制剂发展的生物标志物探索","authors":"Meng-Ni Fan , Tangliang Shen , Barbara A. Konkle , Xiaohe Cai , Ting-Yen Chao , Marilyn Manco-Johnson , Anna V. Faino , Junping Zhang , Shumin Bao , Weidong Xiao , Lei Li , Carol H. Miao","doi":"10.1016/j.rpth.2025.102877","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Inhibitor development remains a significant challenge for hemophilia A (HA) treatment. Cytokines and glycosylation play crucial roles in inducing and regulating immune responses. Cytokine and altered N-glycan profiles have the potential to be biomarkers in association with the presence of inhibitors in persons with HA.</div></div><div><h3>Objectives</h3><div>We investigated the association of cytokine and plasma N-glycan profiles with inhibitor presence.</div></div><div><h3>Methods</h3><div>In 60 persons with HA and 23 controls, we analyzed 10 cytokines and used multivariable regression to assess their association with inhibitor presence. Given the challenges of validating these findings in previously untreated patients, we employed an HA mouse model to explore the association between cytokine levels and inhibitors. We also examined the correlation between plasma N-glycan profiles and inhibitors in persons with HA, analyzing adult and pediatric groups separately due to age-dependent glycosylation.</div></div><div><h3>Results</h3><div>Elevated granulocyte colony-stimulating factor and interleukin (IL) 6 levels, coupled with decreased IL-10, were significantly associated with inhibitor presence in multivariable regression analysis. High-titer inhibitor was observed in factor (F)VIII-treated mice experiencing chronic inflammation with increased levels of granulocyte colony-stimulating factor, IL-6, and macrophage inflammatory protein-1β, a murine IL-8 homolog, but not in those receiving FVIII alone, consistent with our clinical observations. Inhibitor-positive adult patients exhibited higher biantennary <em>N</em>-glycan and reduced multiantennary <em>N</em>-glycan ratios compared with inhibitor-negative adults. Conversely, inhibitor-positive pediatric patients displayed decreased sialic acid ratios.</div></div><div><h3>Conclusion</h3><div>These findings highlight the association of inhibitor presence with altered plasma cytokine levels and <em>N-</em>glycosylation patterns. Prospective validation is crucial to confirm these associations, develop robust biomarkers, and improve inhibitor risk assessment for persons with HA.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 4","pages":"Article 102877"},"PeriodicalIF":3.4000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exploration of biomarkers for inhibitor development in persons with hemophilia A\",\"authors\":\"Meng-Ni Fan , Tangliang Shen , Barbara A. Konkle , Xiaohe Cai , Ting-Yen Chao , Marilyn Manco-Johnson , Anna V. Faino , Junping Zhang , Shumin Bao , Weidong Xiao , Lei Li , Carol H. Miao\",\"doi\":\"10.1016/j.rpth.2025.102877\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Inhibitor development remains a significant challenge for hemophilia A (HA) treatment. Cytokines and glycosylation play crucial roles in inducing and regulating immune responses. Cytokine and altered N-glycan profiles have the potential to be biomarkers in association with the presence of inhibitors in persons with HA.</div></div><div><h3>Objectives</h3><div>We investigated the association of cytokine and plasma N-glycan profiles with inhibitor presence.</div></div><div><h3>Methods</h3><div>In 60 persons with HA and 23 controls, we analyzed 10 cytokines and used multivariable regression to assess their association with inhibitor presence. Given the challenges of validating these findings in previously untreated patients, we employed an HA mouse model to explore the association between cytokine levels and inhibitors. We also examined the correlation between plasma N-glycan profiles and inhibitors in persons with HA, analyzing adult and pediatric groups separately due to age-dependent glycosylation.</div></div><div><h3>Results</h3><div>Elevated granulocyte colony-stimulating factor and interleukin (IL) 6 levels, coupled with decreased IL-10, were significantly associated with inhibitor presence in multivariable regression analysis. High-titer inhibitor was observed in factor (F)VIII-treated mice experiencing chronic inflammation with increased levels of granulocyte colony-stimulating factor, IL-6, and macrophage inflammatory protein-1β, a murine IL-8 homolog, but not in those receiving FVIII alone, consistent with our clinical observations. Inhibitor-positive adult patients exhibited higher biantennary <em>N</em>-glycan and reduced multiantennary <em>N</em>-glycan ratios compared with inhibitor-negative adults. Conversely, inhibitor-positive pediatric patients displayed decreased sialic acid ratios.</div></div><div><h3>Conclusion</h3><div>These findings highlight the association of inhibitor presence with altered plasma cytokine levels and <em>N-</em>glycosylation patterns. Prospective validation is crucial to confirm these associations, develop robust biomarkers, and improve inhibitor risk assessment for persons with HA.</div></div>\",\"PeriodicalId\":20893,\"journal\":{\"name\":\"Research and Practice in Thrombosis and Haemostasis\",\"volume\":\"9 4\",\"pages\":\"Article 102877\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Research and Practice in Thrombosis and Haemostasis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2475037925002018\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Research and Practice in Thrombosis and Haemostasis","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2475037925002018","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"HEMATOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

背景：抑制剂的开发仍然是血友病a （HA）治疗的一个重大挑战。细胞因子和糖基化在诱导和调节免疫应答中起重要作用。细胞因子和改变的n -聚糖谱有可能成为与HA患者抑制剂存在相关的生物标志物。目的探讨细胞因子和血浆n -聚糖谱与抑制剂存在的关系。方法在60例HA患者和23例对照组中，我们分析了10种细胞因子，并使用多变量回归来评估它们与抑制剂存在的关系。考虑到在未经治疗的患者中验证这些发现的挑战，我们采用了HA小鼠模型来探索细胞因子水平和抑制剂之间的关系。我们还检查了血凝素患者血浆n -聚糖谱和抑制剂之间的相关性，由于年龄依赖性糖基化，分别分析了成人和儿童组。结果在多变量回归分析中，粒细胞集落刺激因子和白细胞介素（IL） 6水平升高以及IL-10水平降低与抑制剂存在显著相关。高滴度抑制剂在因子(F) viii治疗的慢性炎症小鼠中观察到，粒细胞集落刺激因子、IL-6和巨噬细胞炎症蛋白-1β（小鼠IL-8同源物）水平升高，但在单独接受FVIII治疗的小鼠中没有，与我们的临床观察一致。与抑制剂阴性的成人相比，抑制剂阳性的成人患者表现出更高的双天线n -聚糖比率和更低的多天线n -聚糖比率。相反，抑制剂阳性的儿科患者唾液酸比率下降。结论这些发现强调了抑制剂的存在与血浆细胞因子水平和n -糖基化模式的改变有关。前瞻性验证对于确认这些关联、开发强大的生物标志物和改善HA患者抑制剂风险评估至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Exploration of biomarkers for inhibitor development in persons with hemophilia A

Background

Inhibitor development remains a significant challenge for hemophilia A (HA) treatment. Cytokines and glycosylation play crucial roles in inducing and regulating immune responses. Cytokine and altered N-glycan profiles have the potential to be biomarkers in association with the presence of inhibitors in persons with HA.

Objectives

We investigated the association of cytokine and plasma N-glycan profiles with inhibitor presence.

Methods

In 60 persons with HA and 23 controls, we analyzed 10 cytokines and used multivariable regression to assess their association with inhibitor presence. Given the challenges of validating these findings in previously untreated patients, we employed an HA mouse model to explore the association between cytokine levels and inhibitors. We also examined the correlation between plasma N-glycan profiles and inhibitors in persons with HA, analyzing adult and pediatric groups separately due to age-dependent glycosylation.

Results

Elevated granulocyte colony-stimulating factor and interleukin (IL) 6 levels, coupled with decreased IL-10, were significantly associated with inhibitor presence in multivariable regression analysis. High-titer inhibitor was observed in factor (F)VIII-treated mice experiencing chronic inflammation with increased levels of granulocyte colony-stimulating factor, IL-6, and macrophage inflammatory protein-1β, a murine IL-8 homolog, but not in those receiving FVIII alone, consistent with our clinical observations. Inhibitor-positive adult patients exhibited higher biantennary N-glycan and reduced multiantennary N-glycan ratios compared with inhibitor-negative adults. Conversely, inhibitor-positive pediatric patients displayed decreased sialic acid ratios.

Conclusion

These findings highlight the association of inhibitor presence with altered plasma cytokine levels and N-glycosylation patterns. Prospective validation is crucial to confirm these associations, develop robust biomarkers, and improve inhibitor risk assessment for persons with HA.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊