重症哮喘患者呼吸道感染自身抗体介导的巨噬细胞功能障碍
2022/11/22
摘要
背景：已有报道在以嗜酸性粒细胞脱颗粒和呼吸道感染为特征的严重嗜酸性哮喘患者中出现局部自身免疫反应。
目的：探讨呼吸道内抗巨噬细胞清道夫受体自身抗体的存在及其对巨噬细胞功能和感染易感性的影响。
方法：对143例重症哮喘患者221例痰标本进行抗嗜酸性粒细胞过氧化物酶(EPX)、抗巨噬细胞胶原性结构受体(MARCO)、免疫球蛋G(IgG)滴度和1/2型(T1/T2)细胞因子检测。用免疫沉淀免疫球蛋白(IP-Igs)处理健康人外周血单核细胞和单核细胞来源的巨噬细胞(MDMs)，以评估肺炎链球菌的摄取或对细菌产物脂多糖(LPS)的反应。
结果：36%的患者检测到抗MARCO抗体，混合型粒细胞痰的抗体滴度显著升高(高达1：16)，提示呼吸道感染。多因素回归分析证实，脱颗粒(游离嗜酸性粒细胞)、外周血嗜酸粒细胞增多(T2负荷高)、痰细胞总数增加、外周血白细胞数(感染标志)和淋巴细胞减少与抗MARCO抗体滴度升高有关；IL-15(OR：1.79；CI-1.19~2.70)、IL-13(OR：1.06；CI-1.02~1.12)和IL-12p70(OR：3.34；CI 1.32~8.40)是相关细胞因子。具有抗MARCO抗体的患者与嗜酸性粒细胞恶化相比，有更高的机会继发感染性疾病(P=0.01)。经IP-Igs(抗MARCO+sputa)处理的MDMs细菌摄取减少39±15%，IL-10和GM-CSF的释放显著减少(P<0.05)。
结论：嗜酸性哮喘气道巨噬细胞清道夫受体的自身抗体可能阻碍有效的宿主防御，导致反复发作性感染性支气管炎。
Autoantibody-mediated Macrophage Dysfunction in Severe Asthma Patients with Airway Infections
Kiho Son, Kate Miyasaki, Brittany Salter
Abstrast
Background：Localised autoimmune responses have been reported in patients with severe eosinophilic asthma, characterised by eosinophil degranulation and airway infections.
Objective：To determine the presence of autoantibodies against macrophage scavenger receptors within the airways and their effects on macrophage function and susceptibility to infection.
Methods：Anti-eosinophil peroxidase (EPX), anti-macrophage receptor with collagenous structure (MARCO) immunoglobulin G (IgG) titers, and type 1/2 (T1/T2) cytokines were measured in 221 sputa from 143 well-characterized patients with severe asthma. Peripheral monocytes and monocyte-derived macrophages (MDMs) isolated from healthy controls were treated with immunoprecipitated immunoglobulins (IP-Igs) from sputa with high anti-MARCO titers or non-specific IgG to assess uptake of Streptococcus pneumoniae or response to the bacterial product lipopolysaccharide (LPS).
Results：Anti-MARCO IgG was detected in 36% of patients, with significantly higher titers (up to 1:16) in patients with mixed granulocytic sputa, indicative of airway infections. Multivariate regression analysis confirmed increased frequency of degranulation (free eosinophil granules), increased blood eosinophils (indicative of high T2 burden), increased sputum total cell count, peripheral blood leukocytes (indicative of infection) and lymphopenia were associated with increased anti-MARCO IgG titers; IL-15 (OR:1.79; CI-1.19-2.70), IL-13 (OR:1.06; CI-1.02-1.12) and IL-12p70 (OR:3.34; CI 1.32-8.40) were the associated cytokines. Patients with anti-MARCO antibodies had higher chances of subsequent infective vs. eosinophilic exacerbations (P=0.01). MDMs treated with IP-Igs (anti-MARCO+ sputa) had reduced bacterial uptake by 39±15% and significantly reduced release of IL-10 and GM-CSF (P<0.05) in response to a lipopolysaccharide stimulus.
Conclusions：Autoantibodies against macrophage scavenger receptors in eosinophilic asthma airways may impede effective host defenses and lead to recurrent infective bronchitis.
背景：已有报道在以嗜酸性粒细胞脱颗粒和呼吸道感染为特征的严重嗜酸性哮喘患者中出现局部自身免疫反应。
目的：探讨呼吸道内抗巨噬细胞清道夫受体自身抗体的存在及其对巨噬细胞功能和感染易感性的影响。
方法：对143例重症哮喘患者221例痰标本进行抗嗜酸性粒细胞过氧化物酶(EPX)、抗巨噬细胞胶原性结构受体(MARCO)、免疫球蛋G(IgG)滴度和1/2型(T1/T2)细胞因子检测。用免疫沉淀免疫球蛋白(IP-Igs)处理健康人外周血单核细胞和单核细胞来源的巨噬细胞(MDMs)，以评估肺炎链球菌的摄取或对细菌产物脂多糖(LPS)的反应。
结果：36%的患者检测到抗MARCO抗体，混合型粒细胞痰的抗体滴度显著升高(高达1：16)，提示呼吸道感染。多因素回归分析证实，脱颗粒(游离嗜酸性粒细胞)、外周血嗜酸粒细胞增多(T2负荷高)、痰细胞总数增加、外周血白细胞数(感染标志)和淋巴细胞减少与抗MARCO抗体滴度升高有关；IL-15(OR：1.79；CI-1.19~2.70)、IL-13(OR：1.06；CI-1.02~1.12)和IL-12p70(OR：3.34；CI 1.32~8.40)是相关细胞因子。具有抗MARCO抗体的患者与嗜酸性粒细胞恶化相比，有更高的机会继发感染性疾病(P=0.01)。经IP-Igs(抗MARCO+sputa)处理的MDMs细菌摄取减少39±15%，IL-10和GM-CSF的释放显著减少(P<0.05)。
结论：嗜酸性哮喘气道巨噬细胞清道夫受体的自身抗体可能阻碍有效的宿主防御，导致反复发作性感染性支气管炎。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(Am J Respir Crit Care Med. 2022 Oct 26. doi: 10.1164/rccm.202206-1183OC. Online ahead of print. IF: 17.452)
(Am J Respir Crit Care Med. 2022 Oct 26. doi: 10.1164/rccm.202206-1183OC. Online ahead of print. IF: 17.452)
Autoantibody-mediated Macrophage Dysfunction in Severe Asthma Patients with Airway Infections
Kiho Son, Kate Miyasaki, Brittany Salter
Abstrast
Background：Localised autoimmune responses have been reported in patients with severe eosinophilic asthma, characterised by eosinophil degranulation and airway infections.
Objective：To determine the presence of autoantibodies against macrophage scavenger receptors within the airways and their effects on macrophage function and susceptibility to infection.
Methods：Anti-eosinophil peroxidase (EPX), anti-macrophage receptor with collagenous structure (MARCO) immunoglobulin G (IgG) titers, and type 1/2 (T1/T2) cytokines were measured in 221 sputa from 143 well-characterized patients with severe asthma. Peripheral monocytes and monocyte-derived macrophages (MDMs) isolated from healthy controls were treated with immunoprecipitated immunoglobulins (IP-Igs) from sputa with high anti-MARCO titers or non-specific IgG to assess uptake of Streptococcus pneumoniae or response to the bacterial product lipopolysaccharide (LPS).
Results：Anti-MARCO IgG was detected in 36% of patients, with significantly higher titers (up to 1:16) in patients with mixed granulocytic sputa, indicative of airway infections. Multivariate regression analysis confirmed increased frequency of degranulation (free eosinophil granules), increased blood eosinophils (indicative of high T2 burden), increased sputum total cell count, peripheral blood leukocytes (indicative of infection) and lymphopenia were associated with increased anti-MARCO IgG titers; IL-15 (OR:1.79; CI-1.19-2.70), IL-13 (OR:1.06; CI-1.02-1.12) and IL-12p70 (OR:3.34; CI 1.32-8.40) were the associated cytokines. Patients with anti-MARCO antibodies had higher chances of subsequent infective vs. eosinophilic exacerbations (P=0.01). MDMs treated with IP-Igs (anti-MARCO+ sputa) had reduced bacterial uptake by 39±15% and significantly reduced release of IL-10 and GM-CSF (P<0.05) in response to a lipopolysaccharide stimulus.
Conclusions：Autoantibodies against macrophage scavenger receptors in eosinophilic asthma airways may impede effective host defenses and lead to recurrent infective bronchitis.
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