大规模激发研究发现，对普遍存在的空气过敏原适应不良与严重过敏性鼻结膜炎及哮喘相关
2021/10/20
摘要
背景：过敏性哮喘（AA）和过敏性鼻结膜炎（ARC）是常见的环境引发的共患病。我们假设严重的AA/ARC反映了对普遍存在的空气过敏原的不适应或不受限制的反应。
方法：我们进行了激发研究，其中6个单独的ARC人群（总人数n=217），有或没有AA，在空气过敏原激发室（ACC）中用固定浓度的季节性或常年性空气过敏原激发一次或多次。
结果：空气过敏原激发引起完全/部分抑制或非抑制诱发症状反应，分别对应于快速恢复/适应性或适应不良AA/ARC表型。与地方性季节性空气变应原相比，非流行性季节性空气变应原激发时更容易诱发适应不良表型。在一个AA队列中，屋尘螨（HDM）激发后诱发的症状反应与自然环境中记录的症状反应相比，更准确和精确的预测哮喘严重程度和控制水平、肺功能（FEV1）以及适应不良的机制相关性。相关性包括外周血CD4+和CD8+T细胞，嗜酸性粒细胞和T细胞活化水平升高，以及无效上皮损伤修复反应的基因表达替代物。与嗜酸性粒细胞、中性粒细胞或HDM特异性IgE相比，HDM激发后的诱发症状严重程度似乎与CD4+和CD8+T细胞水平更密切相关。
结论：激发研究支持对环境疾病的快速恢复、适应和不适应触发标定AA/ARC严重性的概念。尽管空气过敏原无处不在，但在受控环境（即ACC）中对这些疾病触发因素的反应，大多数特应性患者表现出快速恢复或适应性表型。因此，ARC/AA疾病进展可能反映了未能保持快速恢复/适应性的表型。CD8+T细胞活化、气道上皮损伤/修复过程和适应不良在介导AA疾病严重程度方面的三角关系需要更多的研究。
Large-scale provocation studies identify maladaptive responses to ubiquitous aeroallergens as a correlate of severe allergic rhinoconjunctivitis and asthma
Alisha M Smith, Robert M Ramirez, Nathan Harper, Fabio Jimenez, Anne P Branum, Justin A Meunier, Lavanya Pandranki, Andrew Carrillo, Caitlyn Winter, Lauryn Winter, Cynthia G Rather, Daniel A Ramirez, Charles P Andrews, Marcos I Restrepo, Diego J Maselli, Jacqueline A Pugh, Robert A Clark, Grace C Lee, Alvaro G Moreira, Muthu Saravanan Manoharan, Jason F Okulicz, Robert L Jacobs, Sunil K Ahuja
Abstract
Background: Allergic asthma (AA) and allergic rhinoconjunctivitis (ARC) are common comorbid environmentally triggered diseases. We hypothesized that severe AA/ARC reflects a maladaptive or unrestrained response to ubiquitous aeroallergens.
Methods: We performed provocation studies wherein six separate cohorts of persons (total n=217) with ARC, with or without AA, were challenged once or more with fixed concentrations of seasonal or perennial aeroallergens in an aeroallergen challenge chamber (ACC).
Results: Aeroallergen challenges elicited fully or partially restrained vs. unrestrained evoked symptom responsiveness, corresponding to the resilient and adaptive vs. maladaptive AA/ARC phenotypes, respectively. The maladaptive phenotype was evoked more commonly during challenge with a nonendemic versus endemic seasonal aeroallergen. In an AA cohort, symptom responses evoked after house dust mite (HDM) challenges vs. recorded in the natural environment were more accurate and precise predictors of asthma severity and control, lung function (FEV1), and mechanistic correlates of maladaptation. Correlates included elevated levels of peripheral blood CD4+ and CD8+ T-cells, eosinophils, and T-cell activation, as well as gene expression proxies for ineffectual epithelial injury-repair responses. Evoked symptom severity after HDM challenge appeared to be more closely related to levels of CD4+ and CD8+ T-cells than eosinophils, neutrophils, or HDM-specific IgE.
Conclusions: Provocation studies support the concept that resilience, adaptation, and maladaptation to environmental disease triggers calibrate AA/ARC severity. Despite the ubiquity of aeroallergens, in response to these disease triggers in controlled settings (i.e., ACC), most atopic persons manifest the resilient or adaptive phenotype. Thus, ARC/AA disease progression may reflect the failure to preserve the resilient/adaptive phenotype. The triangulation of CD8+ T-cell activation, airway epithelial injury/repair processes and maladaptation in mediating AA disease severity needs more investigation.
背景：过敏性哮喘（AA）和过敏性鼻结膜炎（ARC）是常见的环境引发的共患病。我们假设严重的AA/ARC反映了对普遍存在的空气过敏原的不适应或不受限制的反应。
方法：我们进行了激发研究，其中6个单独的ARC人群（总人数n=217），有或没有AA，在空气过敏原激发室（ACC）中用固定浓度的季节性或常年性空气过敏原激发一次或多次。
结果：空气过敏原激发引起完全/部分抑制或非抑制诱发症状反应，分别对应于快速恢复/适应性或适应不良AA/ARC表型。与地方性季节性空气变应原相比，非流行性季节性空气变应原激发时更容易诱发适应不良表型。在一个AA队列中，屋尘螨（HDM）激发后诱发的症状反应与自然环境中记录的症状反应相比，更准确和精确的预测哮喘严重程度和控制水平、肺功能（FEV1）以及适应不良的机制相关性。相关性包括外周血CD4+和CD8+T细胞，嗜酸性粒细胞和T细胞活化水平升高，以及无效上皮损伤修复反应的基因表达替代物。与嗜酸性粒细胞、中性粒细胞或HDM特异性IgE相比，HDM激发后的诱发症状严重程度似乎与CD4+和CD8+T细胞水平更密切相关。
结论：激发研究支持对环境疾病的快速恢复、适应和不适应触发标定AA/ARC严重性的概念。尽管空气过敏原无处不在，但在受控环境（即ACC）中对这些疾病触发因素的反应，大多数特应性患者表现出快速恢复或适应性表型。因此，ARC/AA疾病进展可能反映了未能保持快速恢复/适应性的表型。CD8+T细胞活化、气道上皮损伤/修复过程和适应不良在介导AA疾病严重程度方面的三角关系需要更多的研究。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(13.140 Allergy. 2021 Oct 4. doi: 10.1111/all.15124.)
(13.140 Allergy. 2021 Oct 4. doi: 10.1111/all.15124.)
Large-scale provocation studies identify maladaptive responses to ubiquitous aeroallergens as a correlate of severe allergic rhinoconjunctivitis and asthma
Alisha M Smith, Robert M Ramirez, Nathan Harper, Fabio Jimenez, Anne P Branum, Justin A Meunier, Lavanya Pandranki, Andrew Carrillo, Caitlyn Winter, Lauryn Winter, Cynthia G Rather, Daniel A Ramirez, Charles P Andrews, Marcos I Restrepo, Diego J Maselli, Jacqueline A Pugh, Robert A Clark, Grace C Lee, Alvaro G Moreira, Muthu Saravanan Manoharan, Jason F Okulicz, Robert L Jacobs, Sunil K Ahuja
Abstract
Background: Allergic asthma (AA) and allergic rhinoconjunctivitis (ARC) are common comorbid environmentally triggered diseases. We hypothesized that severe AA/ARC reflects a maladaptive or unrestrained response to ubiquitous aeroallergens.
Methods: We performed provocation studies wherein six separate cohorts of persons (total n=217) with ARC, with or without AA, were challenged once or more with fixed concentrations of seasonal or perennial aeroallergens in an aeroallergen challenge chamber (ACC).
Results: Aeroallergen challenges elicited fully or partially restrained vs. unrestrained evoked symptom responsiveness, corresponding to the resilient and adaptive vs. maladaptive AA/ARC phenotypes, respectively. The maladaptive phenotype was evoked more commonly during challenge with a nonendemic versus endemic seasonal aeroallergen. In an AA cohort, symptom responses evoked after house dust mite (HDM) challenges vs. recorded in the natural environment were more accurate and precise predictors of asthma severity and control, lung function (FEV1), and mechanistic correlates of maladaptation. Correlates included elevated levels of peripheral blood CD4+ and CD8+ T-cells, eosinophils, and T-cell activation, as well as gene expression proxies for ineffectual epithelial injury-repair responses. Evoked symptom severity after HDM challenge appeared to be more closely related to levels of CD4+ and CD8+ T-cells than eosinophils, neutrophils, or HDM-specific IgE.
Conclusions: Provocation studies support the concept that resilience, adaptation, and maladaptation to environmental disease triggers calibrate AA/ARC severity. Despite the ubiquity of aeroallergens, in response to these disease triggers in controlled settings (i.e., ACC), most atopic persons manifest the resilient or adaptive phenotype. Thus, ARC/AA disease progression may reflect the failure to preserve the resilient/adaptive phenotype. The triangulation of CD8+ T-cell activation, airway epithelial injury/repair processes and maladaptation in mediating AA disease severity needs more investigation.
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具有缓解的儿童期哮喘病史的成人肺功能加速下降
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哮喘的不同表型：临床发现和实验动物模型
