State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health; Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
Sino-French Hoffmann Institute, School of Basic Medical Sciences, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.
Front Immunol. 2024 Jul 18;15:1423764. doi: 10.3389/fimmu.2024.1423764. eCollection 2024.
Sputum immunoglobulin G (Sp-IgG) has been discovered to induce cytolytic extracellular trap cell death in eosinophils, suggesting a potential autoimmune mechanism contributing to asthma. This study aimed to explore the potential origin of Sp-IgG and identify clinically relevant subtypes of Sp-IgG that may indicate autoimmune events in asthma.
This study included 165 asthmatic patients and 38 healthy volunteers. We measured Sp-IgG and its five subtypes against eosinophil inflammatory proteins (Sp-IgG), including eosinophil peroxidase, eosinophil major basic protein, eosinophil-derived neurotoxin, eosinophil cationic protein, and Charcot-Leyden Crystal protein in varying asthma severity. Clinical and Mendelian randomization (MR) analyses were conducted. A positive Sp-IgG signature (Sp-IgG) was defined when any of the five Sp-IgG values exceeded the predefined cutoff thresholds, calculated as the mean values of healthy controls plus twice the standard deviation.
The levels of Sp-IgG and Sp-IgG were significantly elevated in moderate/severe asthma than those in mild asthma/healthy groups (all p < 0.05). Sp-IgG levels were positively correlated with airway eosinophil and Sp-IgG. MR analysis showed causality between eosinophil and IgG (OR = 1.02, 95%CI = 1.00-1.04, p = 0.020), and elevated IgG was a risk factor for asthma (OR = 2.05, 95%CI = 1.00-4.17, p = 0.049). Subjects with Sp-IgG exhibited worse disease severity and served as an independent risk factor contributing to severe asthma (adjusted-OR = 5.818, adjusted-95% CI = 2.193-15.431, adjusted-p < 0.001). Receiver operating characteristic curve analysis demonstrated that the combination of Sp-IgG with non-allergic status, an ACT score < 15, and age ≥ 45 years, effectively predicted severe asthma (AUC = 0.84, sensitivity = 86.20%, specificity = 67.80%).
This study identifies a significant association between airway eosinophilic inflammation, Sp-IgG, and asthma severity. The Sp-IgG panel potentially serves as the specific biomarker reflecting airway autoimmune events in asthma.
已发现痰免疫球蛋白 G（Sp-IgG）可诱导嗜酸性粒细胞细胞外细胞杀伤陷阱细胞死亡，提示哮喘中存在潜在的自身免疫机制。本研究旨在探讨 Sp-IgG 的潜在来源，并确定可能提示哮喘自身免疫事件的临床相关 Sp-IgG 亚型。
本研究纳入 165 例哮喘患者和 38 名健康志愿者。我们测量了 Sp-IgG 及其五种亚型针对嗜酸性粒细胞炎症蛋白（Sp-IgG）的水平，包括嗜酸性粒细胞过氧化物酶、嗜酸性粒细胞主要碱性蛋白、嗜酸性粒细胞衍生神经毒素、嗜酸性粒细胞阳离子蛋白和夏科-莱登晶体蛋白，根据哮喘严重程度不同进行分组。进行了临床和孟德尔随机化（MR）分析。当任何一种 Sp-IgG 值超过预定义的截止阈值时，定义为阳性 Sp-IgG 特征（Sp-IgG），该阈值计算为健康对照组的平均值加上两倍标准差。
中度/重度哮喘患者的 Sp-IgG 和 Sp-IgG 水平明显高于轻度哮喘/健康组（均 p<0.05）。Sp-IgG 水平与气道嗜酸性粒细胞和 Sp-IgG 呈正相关。MR 分析显示嗜酸性粒细胞与 IgG 之间存在因果关系（OR=1.02，95%CI=1.00-1.04，p=0.020），并且升高的 IgG 是哮喘的危险因素（OR=2.05，95%CI=1.00-4.17，p=0.049）。具有 Sp-IgG 的受试者表现出更严重的疾病严重程度，并作为导致严重哮喘的独立危险因素（调整后 OR=5.818，调整后 95%CI=2.193-15.431，调整后 p<0.001）。受试者工作特征曲线分析表明，Sp-IgG 与非变应性状态、ACT 评分<15 和年龄≥45 岁相结合，可有效预测严重哮喘（AUC=0.84，灵敏度=86.20%，特异性=67.80%）。
本研究确定了气道嗜酸性粒细胞炎症、Sp-IgG 和哮喘严重程度之间的显著相关性。Sp-IgG 谱可能作为反映哮喘气道自身免疫事件的特异性生物标志物。
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