TH2/TH17优势型与TH2/TH17低型中性粒细胞内型哮喘的机制研究
2017/12/13
摘要
背景：TH2/TH17优势型哮喘和TH2/TH17低型哮喘的发病机制尚不明确。
目的：我们旨在研究TH2/TH17优势型哮喘和TH2/TH17低型哮喘的免疫学机制。
方法：受试者为先前队列研究中的60例哮喘患者，其中TH2/TH17优势型16例、TH2/TH17低型22例。检测这些患者支气管肺泡灌洗液中（bronchoalveolar lavage, BAL）的白细胞、细胞因子、调节介质和上皮细胞的功能。
结果：TH2/TH17优势型哮喘患者的BAL液中IL-1β、IL-6、IL-23、C3α和血清淀粉酶A的水平增高，其升高与IL-1β、C3α水平相关。TH2/TH17细胞高表达IL-I受体和磷酸化P38丝裂原活化蛋白激酶。阿那白滞素作为一种IL-1受体拮抗剂，可以抑制支气管肺泡灌洗液中TH2/TH17的细胞生成。TH2/TH17低型哮喘有两个不同的亚组：中性粒细胞型（45%）和寡细胞型（55%）。这与TH2/TH17优势型（仅有6%中性粒细胞型哮喘）哮喘及TH2优势型（0%中性粒细胞型哮喘）哮喘患者截然不同。BAL液中中性粒细胞与BAL液中髓过氧化物酶、IL-8、IL-1α、IL-6、粒细胞集落刺激因子（granulocyte colony-stimulating factor, G-CFS）、GM-CFS水平密切相关。60%的中性粒细胞型哮喘患者在BAL液中培养出病原微生物，提示这些患者存在亚临床感染。
结论：我们揭示了IL-1β这条通路在TH2/TH17优势型哮喘患者中的关键作用。TH2/TH17低型哮喘的一个亚组为中性粒细胞型哮喘，且在BAL液中IL-1α、IL-6、G-CFS、GM-CFS均升高。IL-1α直接参与IL-8的生成，并可能导致中性粒细胞型哮喘。60%的中性粒细胞型哮喘存在亚临床感染。
Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma
J Allergy Clin Immunol;2017;139:1548-58.
Abstract
Background: The mechanism of TH2/TH17-predominant andTH2/TH17-low asthma is unknown.
Objective: We sought to study the immune mechanism ofTH2/TH17-predominant and TH2/TH17-low asthma.
Methods: In a previously reported cohort of 60 asthmatic patients,16 patients were immunophenotyped with TH2/TH17-predominant asthma and 22 patients with TH2/TH17-low asthma. We examined bronchoalveolar lavage (BAL) fluid leukocytes, cytokines, mediators, and epithelial cell function for these asthma subgroups.
Results: Patients with TH2/TH17-predominant asthma had increased IL-1b, IL-6, IL-23, C3a, and serum amyloid A levels in BAL fluid, and these correlated with IL-1b and C3a levels.TH2/TH17 cells expressed higher levels of the IL-1 receptor and phospho-p38 mitogen-activated protein kinase. Anakinra, an IL-1receptor antagonist protein, inhibited BALTH2/TH17 cell counts. TH2/TH17-low asthma had 2 distinct subgroups: neutrophilic asthma (45%) and pauci-inflammatory asthma (55%). This contrasted with patients with TH2/TH17-predominant and TH2-predominant asthma, which included neutrophilic asthma in 6% and 0% of patients, respectively. BAL fluid neutrophils strongly correlated with BAL fluid myeloperoxidase, IL-8, IL-1a, IL-6,
granulocyte colony-stimulating factor, and GM-CSF levels. Sixty percent of the patients with neutrophilic asthma had a pathogenic microorganism in BAL culture, which suggested a subclinical infection.
Conclusion: We uncovered a critical role for the IL-1b pathway in patients with TH2/TH17-predminant asthma. A subgroup ofpatients with TH2/TH17-low asthma had neutrophilic asthma and increased BAL fluid IL-1a, IL-6, IL-8, granulocyte colony-stimulating factor, and GM-CSF levels. IL-1a was directly involved in IL-8 production and likely contributed to neutrophilic asthma. Sixty percent of neutrophilic patients had a subclinical infection.
背景：TH2/TH17优势型哮喘和TH2/TH17低型哮喘的发病机制尚不明确。
目的：我们旨在研究TH2/TH17优势型哮喘和TH2/TH17低型哮喘的免疫学机制。
方法：受试者为先前队列研究中的60例哮喘患者，其中TH2/TH17优势型16例、TH2/TH17低型22例。检测这些患者支气管肺泡灌洗液中（bronchoalveolar lavage, BAL）的白细胞、细胞因子、调节介质和上皮细胞的功能。
结果：TH2/TH17优势型哮喘患者的BAL液中IL-1β、IL-6、IL-23、C3α和血清淀粉酶A的水平增高，其升高与IL-1β、C3α水平相关。TH2/TH17细胞高表达IL-I受体和磷酸化P38丝裂原活化蛋白激酶。阿那白滞素作为一种IL-1受体拮抗剂，可以抑制支气管肺泡灌洗液中TH2/TH17的细胞生成。TH2/TH17低型哮喘有两个不同的亚组：中性粒细胞型（45%）和寡细胞型（55%）。这与TH2/TH17优势型（仅有6%中性粒细胞型哮喘）哮喘及TH2优势型（0%中性粒细胞型哮喘）哮喘患者截然不同。BAL液中中性粒细胞与BAL液中髓过氧化物酶、IL-8、IL-1α、IL-6、粒细胞集落刺激因子（granulocyte colony-stimulating factor, G-CFS）、GM-CFS水平密切相关。60%的中性粒细胞型哮喘患者在BAL液中培养出病原微生物，提示这些患者存在亚临床感染。
结论：我们揭示了IL-1β这条通路在TH2/TH17优势型哮喘患者中的关键作用。TH2/TH17低型哮喘的一个亚组为中性粒细胞型哮喘，且在BAL液中IL-1α、IL-6、G-CFS、GM-CFS均升高。IL-1α直接参与IL-8的生成，并可能导致中性粒细胞型哮喘。60%的中性粒细胞型哮喘存在亚临床感染。
(袁雨来1 张红萍1 王刚1 四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（J Allergy Clin Immunol;2017;139:1548-58.）
（J Allergy Clin Immunol;2017;139:1548-58.）
Mechanism of TH2/TH17-predominant and neutrophilic TH2/TH17-low subtypes of asthma
J Allergy Clin Immunol;2017;139:1548-58.
Abstract
Background: The mechanism of TH2/TH17-predominant andTH2/TH17-low asthma is unknown.
Objective: We sought to study the immune mechanism ofTH2/TH17-predominant and TH2/TH17-low asthma.
Methods: In a previously reported cohort of 60 asthmatic patients,16 patients were immunophenotyped with TH2/TH17-predominant asthma and 22 patients with TH2/TH17-low asthma. We examined bronchoalveolar lavage (BAL) fluid leukocytes, cytokines, mediators, and epithelial cell function for these asthma subgroups.
Results: Patients with TH2/TH17-predominant asthma had increased IL-1b, IL-6, IL-23, C3a, and serum amyloid A levels in BAL fluid, and these correlated with IL-1b and C3a levels.TH2/TH17 cells expressed higher levels of the IL-1 receptor and phospho-p38 mitogen-activated protein kinase. Anakinra, an IL-1receptor antagonist protein, inhibited BALTH2/TH17 cell counts. TH2/TH17-low asthma had 2 distinct subgroups: neutrophilic asthma (45%) and pauci-inflammatory asthma (55%). This contrasted with patients with TH2/TH17-predominant and TH2-predominant asthma, which included neutrophilic asthma in 6% and 0% of patients, respectively. BAL fluid neutrophils strongly correlated with BAL fluid myeloperoxidase, IL-8, IL-1a, IL-6,
granulocyte colony-stimulating factor, and GM-CSF levels. Sixty percent of the patients with neutrophilic asthma had a pathogenic microorganism in BAL culture, which suggested a subclinical infection.
Conclusion: We uncovered a critical role for the IL-1b pathway in patients with TH2/TH17-predminant asthma. A subgroup ofpatients with TH2/TH17-low asthma had neutrophilic asthma and increased BAL fluid IL-1a, IL-6, IL-8, granulocyte colony-stimulating factor, and GM-CSF levels. IL-1a was directly involved in IL-8 production and likely contributed to neutrophilic asthma. Sixty percent of neutrophilic patients had a subclinical infection.
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哮喘中气道重塑及炎症依赖于细胞外基质蛋白fibulin-1c
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