Department of Immunology, University Medicine Greifswald, Greifswald, Germany.
Upper Airways Research Laboratory, Ghent University, Ghent, Belgium.
J Allergy Clin Immunol. 2017 Feb;139(2):492-500.e8. doi: 10.1016/j.jaci.2016.03.045. Epub 2016 May 10.
A substantial subgroup of asthmatic patients have "nonallergic" or idiopathic asthma, which often takes a severe course and is difficult to treat. The cause might be allergic reactions to the gram-positive pathogen Staphylococcus aureus, a frequent colonizer of the upper airways. However, the driving allergens of S aureus have remained elusive.
We sought to search for potentially allergenic S aureus proteins and characterize the immune response directed against them.
S aureus extracellular proteins targeted by human serum IgG were identified by means of immunoblotting to screen for potential bacterial allergens. Candidate antigens were expressed as recombinant proteins and used to analyze the established cellular and humoral immune responses in healthy adults and asthmatic patients. The ability to induce a type 2 immune response in vivo was tested in a mouse asthma model.
We identified staphylococcal serine protease-like proteins (Spls) as dominant IgG-binding S aureus proteins. SplA through SplF are extracellular proteases of unknown function expressed by S aureus in vivo. Spls elicited IgE antibody responses in most asthmatic patients. In healthy S aureus carriers and noncarriers, peripheral blood T cells elaborated T2 cytokines after stimulation with Spls, as is typical for allergens. In contrast, T1/T17 cytokines, which dominated the response to S aureus α-hemolysin, were of low concentration or absent. In mice inhalation of SplD without adjuvant induced lung inflammation characterized by T2 cytokines and eosinophil infiltration.
We identify Spls as triggering allergens released by S aureus, opening prospects for diagnosis and causal therapy of asthma.
大量哮喘患者属于“非过敏性”或特发性哮喘，此类患者的病情通常较为严重，且治疗难度较大。其病因可能是对革兰阳性病原体金黄色葡萄球菌的过敏反应，金黄色葡萄球菌是上呼吸道的常见定植菌。然而，金黄色葡萄球菌的致敏原一直难以确定。
我们试图寻找金黄色葡萄球菌潜在的变应原蛋白，并对其免疫反应进行特征分析。
通过免疫印迹法筛选人血清 IgG 靶向的金黄色葡萄球菌细胞外蛋白，以寻找潜在的细菌变应原。选择候选抗原并将其表达为重组蛋白，用于分析健康成年人和哮喘患者中已建立的细胞和体液免疫反应。在小鼠哮喘模型中测试其诱导 2 型免疫反应的能力。
我们确定葡萄球菌丝氨酸蛋白酶样蛋白（Spl）为金黄色葡萄球菌中主要与 IgG 结合的蛋白。SplA 至 SplF 是金黄色葡萄球菌在体内表达的未知功能的细胞外蛋白酶。Spl 在大多数哮喘患者中引发 IgE 抗体反应。在健康的金黄色葡萄球菌携带者和非携带者中，Spl 刺激外周血 T 细胞产生 T2 细胞因子，这是变应原的典型特征。相比之下，主导金黄色葡萄球菌α-溶血素反应的 T1/T17 细胞因子浓度较低或不存在。在没有佐剂的情况下，小鼠吸入 SplD 可诱导以 T2 细胞因子和嗜酸性粒细胞浸润为特征的肺部炎症。
我们确定 Spl 是金黄色葡萄球菌释放的触发变应原，为哮喘的诊断和因果治疗开辟了前景。
