与病毒感染相关的1型免疫反应影响哮喘中的皮质类固醇反应
2025/03/03
摘要
背景：皮质类固醇反应的2型（T2）炎症是T2-high哮喘内型的基础。然而，我们假设1型（T1）炎症，可能与病毒感染相关，也可能影响皮质类固醇反应。本研究旨在确定T1-high、T2-high和T1/T2-high哮喘内型的频率和患者内部变异性，以及病毒影响的T1-high疾病是否影响哮喘中的皮质类固醇反应。
方法：SARP-3（重度哮喘研究计划-3）中的患者在基线、肌内注射（曲安奈德）皮质类固醇治疗后以及1年和3年随访时收集了痰液。痰液细胞RNA用于全转录组基因网络和病毒宏基因组分析。然后，我们将患者分析为高度表达T1和/或T2基因网络，并确定这些内型对皮质类固醇反应性的影响以及气道中病毒转录物检测的可能性。
结果：我们发现，22%和35%的哮喘患者分别高度表达T1和T2网络基因，8.5%的患者高度表达这两种网络。与T1-high哮喘相比，T2-high哮喘的严重程度结果更差，而T1-high/T2-high亚组的严重程度最高。皮质类固醇治疗强烈抑制了T2基因表达，但对T1基因表达的抑制效果较差，且皮质类固醇相关的FEV1改善仅发生在T1-low/T2-high疾病患者中，而在T1-high/T2-high疾病患者中未发生。病毒宏基因组分析发现，24%的哮喘痰液样本检测出呼吸道病毒阳性，高病毒携带与T1-high疾病风险增加14倍相关。
结论：气道T1免疫反应在哮喘中相对常见，对皮质类固醇具有较大的抵抗性，并与亚临床病毒感染相关。
背景：皮质类固醇反应的2型（T2）炎症是T2-high哮喘内型的基础。然而，我们假设1型（T1）炎症，可能与病毒感染相关，也可能影响皮质类固醇反应。本研究旨在确定T1-high、T2-high和T1/T2-high哮喘内型的频率和患者内部变异性，以及病毒影响的T1-high疾病是否影响哮喘中的皮质类固醇反应。
方法：SARP-3（重度哮喘研究计划-3）中的患者在基线、肌内注射（曲安奈德）皮质类固醇治疗后以及1年和3年随访时收集了痰液。痰液细胞RNA用于全转录组基因网络和病毒宏基因组分析。然后，我们将患者分析为高度表达T1和/或T2基因网络，并确定这些内型对皮质类固醇反应性的影响以及气道中病毒转录物检测的可能性。
结果：我们发现，22%和35%的哮喘患者分别高度表达T1和T2网络基因，8.5%的患者高度表达这两种网络。与T1-high哮喘相比，T2-high哮喘的严重程度结果更差，而T1-high/T2-high亚组的严重程度最高。皮质类固醇治疗强烈抑制了T2基因表达，但对T1基因表达的抑制效果较差，且皮质类固醇相关的FEV1改善仅发生在T1-low/T2-high疾病患者中，而在T1-high/T2-high疾病患者中未发生。病毒宏基因组分析发现，24%的哮喘痰液样本检测出呼吸道病毒阳性，高病毒携带与T1-high疾病风险增加14倍相关。
结论：气道T1免疫反应在哮喘中相对常见，对皮质类固醇具有较大的抵抗性，并与亚临床病毒感染相关。
（中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校）
（Am J Respir Crit Care Med. 2025 Feb; DOI: 10.1164/rccm.202402-0403OC）
Type 1 Immune Responses Related to Viral Infection Influence Corticosteroid Response in Asthma
Fahy JV, Jackson ND, Sajuthi SP, Pruesse E, Moore CM, Everman JL, Rios C, Tang M, Gauthier M, Wenzel SE, Bleecker ER, Castro M, Comhair SA, Erzurum SC, Hastie AT, Moore W, Israel E, Levy BD, Denlinger L, Jarjour NN, Johansson MW, Mauger DT, Phillips BR, Sumino K, Woodruff PG, Peters MC, Seibold MA
Abstract
BACKGROUND:Corticosteroid-responsive type 2 (T2) inflammation underlies the T2-high asthma endotype. However, we hypothesized that type 1 (T1) inflammation, possibly related to viral infection, may also influence corticosteroid response. To determine the frequency and within-patient variability of T1-high, T2-high, and T1/T2-high asthma endotypes and whether virally influenced T1-high disease influences corticosteroid response in asthma.
METHODS:Patients in SARP-3 (Severe Asthma Research Program-3) had sputum collected at baseline, after intramuscular (triamcinolone acetonide) corticosteroid treatment, and at 1- and 3-year follow-ups. Sputum cell RNA was used for whole-transcriptome gene network and viral metagenomic analyses. We then profiled patients as highly expressing T1 and/or T2 gene networks and established the influence of these endotypes on corticosteroid responsiveness and the likelihood of viral transcript detection in the airways.
RESULTS:We found that 22% and 35% of patients with asthma highly expressed T1 and T2 network genes, respectively, and that 8.5% highly expressed both networks. Asthma severity outcomes were worse in T2-high compared with T1-high asthma and most severe in the T1-high/T2-high subgroup. Corticosteroid treatment strongly suppressed T2 but poorly suppressed T1 gene expression, and corticosteroid-associated improvements in FEV1 occurred only in patients with T1-low/T2-high disease and not in patients with T1-high/T2-high disease. Viral metagenomic analyses uncovered that 24% of asthma sputum samples tested positive for a respiratory virus, and high viral carriage was associated with 14-fold increased risk of T1-high disease.
CONCLUSION:Airway T1 immune responses are relatively common in asthma, are largely corticosteroid resistant, and are associated with subclinical viral infection.
Fahy JV, Jackson ND, Sajuthi SP, Pruesse E, Moore CM, Everman JL, Rios C, Tang M, Gauthier M, Wenzel SE, Bleecker ER, Castro M, Comhair SA, Erzurum SC, Hastie AT, Moore W, Israel E, Levy BD, Denlinger L, Jarjour NN, Johansson MW, Mauger DT, Phillips BR, Sumino K, Woodruff PG, Peters MC, Seibold MA
Abstract
BACKGROUND:Corticosteroid-responsive type 2 (T2) inflammation underlies the T2-high asthma endotype. However, we hypothesized that type 1 (T1) inflammation, possibly related to viral infection, may also influence corticosteroid response. To determine the frequency and within-patient variability of T1-high, T2-high, and T1/T2-high asthma endotypes and whether virally influenced T1-high disease influences corticosteroid response in asthma.
METHODS:Patients in SARP-3 (Severe Asthma Research Program-3) had sputum collected at baseline, after intramuscular (triamcinolone acetonide) corticosteroid treatment, and at 1- and 3-year follow-ups. Sputum cell RNA was used for whole-transcriptome gene network and viral metagenomic analyses. We then profiled patients as highly expressing T1 and/or T2 gene networks and established the influence of these endotypes on corticosteroid responsiveness and the likelihood of viral transcript detection in the airways.
RESULTS:We found that 22% and 35% of patients with asthma highly expressed T1 and T2 network genes, respectively, and that 8.5% highly expressed both networks. Asthma severity outcomes were worse in T2-high compared with T1-high asthma and most severe in the T1-high/T2-high subgroup. Corticosteroid treatment strongly suppressed T2 but poorly suppressed T1 gene expression, and corticosteroid-associated improvements in FEV1 occurred only in patients with T1-low/T2-high disease and not in patients with T1-high/T2-high disease. Viral metagenomic analyses uncovered that 24% of asthma sputum samples tested positive for a respiratory virus, and high viral carriage was associated with 14-fold increased risk of T1-high disease.
CONCLUSION:Airway T1 immune responses are relatively common in asthma, are largely corticosteroid resistant, and are associated with subclinical viral infection.
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