选择性产生 IL-33 中和自身抗体可改善哮喘反应和严重程度
2024/06/26
摘要
背景：天然抗细胞因子自身抗体可调节感染性和炎症性疾病的平衡。抗细胞因子自身抗体的特征及其与哮喘发病机制的相关性尚不清楚。我们旨在确定哮喘患者的主要抗细胞因子自身抗体，并揭示其免疫学功能和临床意义。
方法：使用荧光素酶免疫沉淀系统筛查过敏性哮喘患者和健康供体血清中针对 11 种关键细胞因子的自身抗体。通过ELISA、qPCR、中和试验和统计分析，分别确定了抗细胞因子自身抗体的抗原特异性、免疫调节功能和临床意义。体外免疫法揭示了诱导自身抗体的潜在条件。
结果：在检测的 11 种细胞因子中，与健康对照组相比，只有抗 IL-33 自身抗体在哮喘患者中明显升高，而且轻中度过敏性哮喘患者的阳性比例高于重度过敏性哮喘患者。在过敏性哮喘患者中，抗IL-33自身抗体水平与血清中致病细胞因子（如IL-4、IL-13、IL-25和IL-33）、IgE和血液中嗜酸性粒细胞计数呈负相关，但与呼气中期流量FEF25-75%呈正相关。自身抗体主要是 IgG 同型、多克隆抗体，可中和 IL-33 在体外和体内诱导的致病反应。体外诱导血液 B 细胞中的抗 IL-33 自身抗体需要多肽 IL-33 抗原以及 TLR9 激动剂和细胞因子 IL-2、IL-4 或 IL-21 刺激剂混合物。
结论：在一些哮喘患者中选择性诱导血清天然抗 IL-33 自身抗体。它们可以改善关键的哮喘炎症反应，并可能改善过敏性哮喘的肺功能。
Selective production of IL-33-neutralizing autoantibody ameliorates asthma responses and severity
Ji Y, Wang E, Mohammed MT, Hameed N, Christodoulou MI, Liu X, Zhou W, Fang Z, Jia N, Yu H, Zhou Z, Sun Y, Huang SK, McSharry C, Zhong NS, Xiao X, Li J, Xu D.
Abstract
Background:Natural anti-cytokine autoantibodies can regulate homeostasis of infectious and inflammatory diseases. The anti-cytokine autoantibody profile and relevance to the pathogenesis of asthma are unknown. We aim to identify key anti-cytokine autoantibodies in asthma patients, and reveal their immunological function and clinical significance.
Methods:A Luciferase Immunoprecipitation System was used to screen serum autoantibodies against 11 key cytokines in patients with allergic asthma and healthy donors. The antigen-specificity, immunomodulatory functions and clinical significance of anti-cytokine autoantibodies were determined by ELISA, qPCR, neutralization assays and statistical analysis, respectively. Potential conditions for autoantibody induction were revealed by in vitro immunization.
Results:Of 11 cytokines tested, only anti-IL-33 autoantibody was significantly increased in asthma, compare to healthy controls, and the proportion positive was higher in patients with mild-to-moderate than severe allergic asthma. In allergic asthma patients, the anti-IL-33 autoantibody level correlated negatively with serum concentration of pathogenic cytokines (e.g., IL-4, IL-13, IL-25 and IL-33), IgE, and blood eosinophil count, but positively with mid-expiratory flow FEF25-75%. The autoantibodies were predominantly IgG isotype, polyclonal and could neutralize IL-33-induced pathogenic responses in vitro and in vivo. The induction of the anti-IL-33 autoantibody in blood B-cells in vitro required peptide IL-33 antigen along with a stimulation cocktail of TLR9 agonist and cytokines IL-2, IL-4 or IL-21.
Conclusion:Serum natural anti-IL-33 autoantibodies are selectively induced in some asthma patients. They ameliorate key asthma inflammatory responses, and may improve lung function of allergic asthma.
背景：天然抗细胞因子自身抗体可调节感染性和炎症性疾病的平衡。抗细胞因子自身抗体的特征及其与哮喘发病机制的相关性尚不清楚。我们旨在确定哮喘患者的主要抗细胞因子自身抗体，并揭示其免疫学功能和临床意义。
方法：使用荧光素酶免疫沉淀系统筛查过敏性哮喘患者和健康供体血清中针对 11 种关键细胞因子的自身抗体。通过ELISA、qPCR、中和试验和统计分析，分别确定了抗细胞因子自身抗体的抗原特异性、免疫调节功能和临床意义。体外免疫法揭示了诱导自身抗体的潜在条件。
结果：在检测的 11 种细胞因子中，与健康对照组相比，只有抗 IL-33 自身抗体在哮喘患者中明显升高，而且轻中度过敏性哮喘患者的阳性比例高于重度过敏性哮喘患者。在过敏性哮喘患者中，抗IL-33自身抗体水平与血清中致病细胞因子（如IL-4、IL-13、IL-25和IL-33）、IgE和血液中嗜酸性粒细胞计数呈负相关，但与呼气中期流量FEF25-75%呈正相关。自身抗体主要是 IgG 同型、多克隆抗体，可中和 IL-33 在体外和体内诱导的致病反应。体外诱导血液 B 细胞中的抗 IL-33 自身抗体需要多肽 IL-33 抗原以及 TLR9 激动剂和细胞因子 IL-2、IL-4 或 IL-21 刺激剂混合物。
结论：在一些哮喘患者中选择性诱导血清天然抗 IL-33 自身抗体。它们可以改善关键的哮喘炎症反应，并可能改善过敏性哮喘的肺功能。
(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)
(Clin Immunol. 2024 Jul; DOI: 10.1016/j.clim.2024.110234)
(Clin Immunol. 2024 Jul; DOI: 10.1016/j.clim.2024.110234)
Selective production of IL-33-neutralizing autoantibody ameliorates asthma responses and severity
Ji Y, Wang E, Mohammed MT, Hameed N, Christodoulou MI, Liu X, Zhou W, Fang Z, Jia N, Yu H, Zhou Z, Sun Y, Huang SK, McSharry C, Zhong NS, Xiao X, Li J, Xu D.
Abstract
Background:Natural anti-cytokine autoantibodies can regulate homeostasis of infectious and inflammatory diseases. The anti-cytokine autoantibody profile and relevance to the pathogenesis of asthma are unknown. We aim to identify key anti-cytokine autoantibodies in asthma patients, and reveal their immunological function and clinical significance.
Methods:A Luciferase Immunoprecipitation System was used to screen serum autoantibodies against 11 key cytokines in patients with allergic asthma and healthy donors. The antigen-specificity, immunomodulatory functions and clinical significance of anti-cytokine autoantibodies were determined by ELISA, qPCR, neutralization assays and statistical analysis, respectively. Potential conditions for autoantibody induction were revealed by in vitro immunization.
Results:Of 11 cytokines tested, only anti-IL-33 autoantibody was significantly increased in asthma, compare to healthy controls, and the proportion positive was higher in patients with mild-to-moderate than severe allergic asthma. In allergic asthma patients, the anti-IL-33 autoantibody level correlated negatively with serum concentration of pathogenic cytokines (e.g., IL-4, IL-13, IL-25 and IL-33), IgE, and blood eosinophil count, but positively with mid-expiratory flow FEF25-75%. The autoantibodies were predominantly IgG isotype, polyclonal and could neutralize IL-33-induced pathogenic responses in vitro and in vivo. The induction of the anti-IL-33 autoantibody in blood B-cells in vitro required peptide IL-33 antigen along with a stimulation cocktail of TLR9 agonist and cytokines IL-2, IL-4 or IL-21.
Conclusion:Serum natural anti-IL-33 autoantibodies are selectively induced in some asthma patients. They ameliorate key asthma inflammatory responses, and may improve lung function of allergic asthma.
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探讨成人重度哮喘生物制剂治疗后临床缓解的定义和预测因素
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