Fan Meng-Ni, Shen Tangliang, Konkle Barbara A, Cai Xiaohe, Chao Ting-Yen, Manco-Johnson Marilyn, Faino Anna V, Zhang Junping, Bao Shumin, Xiao Weidong, Li Lei, Miao Carol H
Center for Immunity & Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA.
Department of Chemistry, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, Georgia, USA.
Res Pract Thromb Haemost. 2025 Apr 27;9(4):102877. doi: 10.1016/j.rpth.2025.102877. eCollection 2025 May.
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.
We investigated the association of cytokine and plasma N-glycan profiles with inhibitor presence.
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.
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 -glycan and reduced multiantennary -glycan ratios compared with inhibitor-negative adults. Conversely, inhibitor-positive pediatric patients displayed decreased sialic acid ratios.
These findings highlight the association of inhibitor presence with altered plasma cytokine levels and glycosylation patterns. Prospective validation is crucial to confirm these associations, develop robust biomarkers, and improve inhibitor risk assessment for persons with HA.
抑制剂的产生仍然是A型血友病（HA）治疗面临的重大挑战。细胞因子和糖基化在诱导和调节免疫反应中起着关键作用。细胞因子和改变的N-聚糖谱有可能成为与HA患者体内抑制剂存在相关的生物标志物。
我们研究了细胞因子和血浆N-聚糖谱与抑制剂存在之间的关联。
在60例HA患者和23名对照中，我们分析了10种细胞因子，并使用多变量回归评估它们与抑制剂存在的关联。鉴于在先前未治疗的患者中验证这些发现存在挑战，我们采用HA小鼠模型来探索细胞因子水平与抑制剂之间的关联。我们还检查了HA患者血浆N-聚糖谱与抑制剂之间的相关性，由于糖基化存在年龄依赖性，因此分别分析了成人和儿童组。
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，同时IL-10降低，与抑制剂的存在显著相关。在经历慢性炎症且粒细胞集落刺激因子、IL-6和巨噬细胞炎性蛋白-1β（一种小鼠IL-8同源物）水平升高的因子（F）VIII治疗小鼠中观察到高滴度抑制剂，但在仅接受FVIII的小鼠中未观察到，这与我们的临床观察结果一致。与抑制剂阴性的成年人相比，抑制剂阳性的成年患者表现出更高的双天线-N-聚糖和更低的多天线-N-聚糖比例。相反，抑制剂阳性的儿科患者唾液酸比例降低。
这些发现突出了抑制剂存在与血浆细胞因子水平改变和糖基化模式之间的关联。前瞻性验证对于确认这些关联、开发可靠的生物标志物以及改善HA患者的抑制剂风险评估至关重要。
