血中性粒细胞遗传学揭示中性粒细胞在儿童早期哮喘和病毒性呼吸道疾病中的作用
2026/04/28
摘要
背景：中性粒细胞在清除细菌和真菌病原体中起关键作用，但对病毒的防御效果较差。过度的中性粒细胞活性可能提示在儿童哮喘和病毒性呼吸道疾病发生前存在免疫调节失调。
目的：探讨遗传易感导致的过度中性粒细胞活化是否与儿童哮喘和病毒性呼吸道疾病相关。
方法：我们计算了儿童的多基因风险评分（PRS）——即与血中性粒细胞计数相关的遗传变异的加权总和。这些儿童来自哥本哈根儿童哮喘前瞻性研究2010队列（COPSAC2010）以及两个基于登记处的、因哮喘在6岁前住院的队列（iPSYCH 和 COPSACsevere）。采用孟德尔随机化（MR）检验遗传预测的中性粒细胞计数是否对儿童哮喘风险具有因果影响。在COPSAC2010队列中，检测了18月龄儿童在体外经病毒模拟配体（R848 和 Poly(I:C)）刺激后的血细胞因子水平，并整合为与中性粒细胞PRS相关的免疫特征评分，以代表与遗传相关的先天免疫反应变异。对儿童急性疾病期间的鼻咽样本进行呼吸道病毒和细菌分析。
结果：中性粒细胞PRS与因哮喘住院的风险增加相关（比值比：1.09，95%置信区间：1.05-1.13，p = 8.7e-6）。孟德尔随机化分析提示存在因果关系。在COPSAC2010队列中，中性粒细胞PRS与病毒刺激后17型免疫反应增强相关，尤其表现为CXCL8、IL-6和IL-18水平升高。与中性粒细胞PRS相关的细胞因子特征评分与3岁内病毒性呼吸道疾病以及6岁时哮喘的发生风险增加相关。
结论：遗传倾向导致的中性粒细胞升高可能驱动生命早期的抗病毒免疫失调，从而增加呼吸道疾病和儿童哮喘的风险。这支持将中性粒细胞通路作为潜在的预防或治疗靶点。
Blood neutrophil genetics highlight the role of neutrophils in early childhood asthma and viral respiratory illnesses
Luo Y, Eliasen AU, Fischer-Rasmussen K, et al.
Abstract
BACKGROUND:Neutrophils are key in eliminating bacterial and fungal pathogens, but are less effective against viruses. Excessive neutrophil activity may indicate dysregulated immunity preceding childhood asthma and viral respiratory illnesses.
OBJECTIVE:To investigate if genetic predisposition to an excessive neutrophil activation is linked to childhood asthma and viral respiratory illnesses.
METHODS:Polygenic Risk Scores (PRS)-calculated as the weighted sum of genetic variants associated with blood neutrophil counts-were derived for children in the COpenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort and two registry-based cohorts hospitalized for asthma by age 6 years (iPSYCH and COPSACsevere). Mendelian randomization (MR) was used to test whether genetically predicted neutrophil counts causally influence childhood asthma risk. In COPSAC2010, blood cytokines were measured at 18 months upon ex vivo stimulation with viral-mimicking ligands (R848 and Poly(I:C)) and then combined into neutrophil PRS-associated immune signature scores representing genetically linked variation in innate immune responsiveness. Nasopharyngeal samples from children during acute illness were analysed for pathogenic viruses and bacteria.
RESULTS:The neutrophil PRS was associated with an increased risk of hospitalization for asthma (Odds Ratio [OR] 1.09, 95% Confidence Interval [CI]:1.05-1.13, p=8.7e-6). MR suggested causality. In COPSAC2010, neutrophil PRS was associated with an increased Type 17 immune response to viral stimulation, notably CXCL8, IL-6, and IL-18. The neutrophil PRS-associated cytokine signature scores were associated with increased risk of viral respiratory illnesses by age three and asthma by age six.
CONCLUSIONS:Genetic predisposition to elevated neutrophils may drive early-life antiviral immune dysregulation, increasing the risk of respiratory illness and childhood asthma. This supports neutrophil pathways as potential preventive or therapeutic targets.
背景：中性粒细胞在清除细菌和真菌病原体中起关键作用，但对病毒的防御效果较差。过度的中性粒细胞活性可能提示在儿童哮喘和病毒性呼吸道疾病发生前存在免疫调节失调。
目的：探讨遗传易感导致的过度中性粒细胞活化是否与儿童哮喘和病毒性呼吸道疾病相关。
方法：我们计算了儿童的多基因风险评分（PRS）——即与血中性粒细胞计数相关的遗传变异的加权总和。这些儿童来自哥本哈根儿童哮喘前瞻性研究2010队列（COPSAC2010）以及两个基于登记处的、因哮喘在6岁前住院的队列（iPSYCH 和 COPSACsevere）。采用孟德尔随机化（MR）检验遗传预测的中性粒细胞计数是否对儿童哮喘风险具有因果影响。在COPSAC2010队列中，检测了18月龄儿童在体外经病毒模拟配体（R848 和 Poly(I:C)）刺激后的血细胞因子水平，并整合为与中性粒细胞PRS相关的免疫特征评分，以代表与遗传相关的先天免疫反应变异。对儿童急性疾病期间的鼻咽样本进行呼吸道病毒和细菌分析。
结果：中性粒细胞PRS与因哮喘住院的风险增加相关（比值比：1.09，95%置信区间：1.05-1.13，p = 8.7e-6）。孟德尔随机化分析提示存在因果关系。在COPSAC2010队列中，中性粒细胞PRS与病毒刺激后17型免疫反应增强相关，尤其表现为CXCL8、IL-6和IL-18水平升高。与中性粒细胞PRS相关的细胞因子特征评分与3岁内病毒性呼吸道疾病以及6岁时哮喘的发生风险增加相关。
结论：遗传倾向导致的中性粒细胞升高可能驱动生命早期的抗病毒免疫失调，从而增加呼吸道疾病和儿童哮喘的风险。这支持将中性粒细胞通路作为潜在的预防或治疗靶点。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（J Allergy Clin Immunol. 2026 Apr 7:S0091-6749(26)00250-2.DOI: 10.1016/j.jaci.2026.03.019）
（J Allergy Clin Immunol. 2026 Apr 7:S0091-6749(26)00250-2.DOI: 10.1016/j.jaci.2026.03.019）
Blood neutrophil genetics highlight the role of neutrophils in early childhood asthma and viral respiratory illnesses
Luo Y, Eliasen AU, Fischer-Rasmussen K, et al.
Abstract
BACKGROUND:Neutrophils are key in eliminating bacterial and fungal pathogens, but are less effective against viruses. Excessive neutrophil activity may indicate dysregulated immunity preceding childhood asthma and viral respiratory illnesses.
OBJECTIVE:To investigate if genetic predisposition to an excessive neutrophil activation is linked to childhood asthma and viral respiratory illnesses.
METHODS:Polygenic Risk Scores (PRS)-calculated as the weighted sum of genetic variants associated with blood neutrophil counts-were derived for children in the COpenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort and two registry-based cohorts hospitalized for asthma by age 6 years (iPSYCH and COPSACsevere). Mendelian randomization (MR) was used to test whether genetically predicted neutrophil counts causally influence childhood asthma risk. In COPSAC2010, blood cytokines were measured at 18 months upon ex vivo stimulation with viral-mimicking ligands (R848 and Poly(I:C)) and then combined into neutrophil PRS-associated immune signature scores representing genetically linked variation in innate immune responsiveness. Nasopharyngeal samples from children during acute illness were analysed for pathogenic viruses and bacteria.
RESULTS:The neutrophil PRS was associated with an increased risk of hospitalization for asthma (Odds Ratio [OR] 1.09, 95% Confidence Interval [CI]:1.05-1.13, p=8.7e-6). MR suggested causality. In COPSAC2010, neutrophil PRS was associated with an increased Type 17 immune response to viral stimulation, notably CXCL8, IL-6, and IL-18. The neutrophil PRS-associated cytokine signature scores were associated with increased risk of viral respiratory illnesses by age three and asthma by age six.
CONCLUSIONS:Genetic predisposition to elevated neutrophils may drive early-life antiviral immune dysregulation, increasing the risk of respiratory illness and childhood asthma. This supports neutrophil pathways as potential preventive or therapeutic targets.
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