Pattern recognition pathways leading to a Th2 cytokine bias in allergic bronchopulmonary aspergillosis patients
Pattern recognition pathways leading to a Th2 cytokine bias in allergic bronchopulmonary aspergillosis patients
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DOI：
10.1111/cea.12354
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发表时间：
2015-02-01
影响因子：
6.1
通讯作者：
van de Veerdonk, F. L.
中科院分区：
文献类型：
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作者：
Becker, K. L.;Gresnigt, M. S.;van de Veerdonk, F. L.
背景变应性支气管肺曲霉病（ABPA）的特征是对烟曲霉的Th 2应答增强，目的本研究的目的是阐明参与曲霉特异性Th 2应答的模式识别受体（PRRs）和细胞因子，并研究曲霉-方法用热灭活的曲霉菌分生孢子、各种其他病原体或PRR配体刺激外周血单核细胞（PBMC）。PRR和细胞因子通路用PRR阻断剂、抗TNF（依那西普或阿达木单抗）、IL-1 Ra（阿那白滞素）或IFN-γ（IFN-γ）阻断。结果曲霉菌是唯一能刺激Th 2细胞因子IL-5和IL-13的病原菌，而革兰氏阴性菌、革兰氏阳性菌、白色念珠菌、几丁质、β-葡聚糖和Toll样受体（TLR）配体均不能刺激Th 2细胞因子IL-5和IL-13。CD 4（+）细胞的耗竭可抑制IL-13的产生。阻断补体受体3（CR 3）可显著降低IL-5和IL-13，而阻断TLR 2、TLR 4或dectin-1则无影响。与健康对照组相比，ABPA患者显示白细胞介素诱导的IL-5和IL-13增加，IFN γ产生减少。所有的生物制剂测试表明，抑制Th 2反应的能力，但也降低了曲霉诱导的IFN γ。结论和临床相关性曲霉分生孢子是独特的触发Th 2反应在人PBMC中，通过CR 3依赖性途径。ABPA患者显示出显著增加的阿曲库铵诱导的Th 2/Th 1比值，可通过生物制剂调节。这些数据提供了一个理论基础，探索IFN γ治疗ABPA作为皮质类固醇保留治疗的选择，通过抑制Th 2反应，并补充IFN γ的缺陷，在同一时间。
Background Allergic bronchopulmonary aspergillosis (ABPA) is characterised by an exaggerated Th2 response to Aspergillus fumigatus, but the immunological pathways responsible for this effect are unknown.Objective The aim of this study was to decipher the pattern recognition receptors (PRRs) and cytokines involved in the Aspergillus-specific Th2 response and to study Aspergillus-induced responses in healthy controls and ABPA patients.Methods Peripheral blood mononuclear cells (PBMCs) were stimulated with heat-killed Aspergillus conidia, various other pathogens, or PRR ligands. PRRs and cytokine pathways were blocked with PRR-blocking reagents, anti-TNF (Etanercept or Adalimumab), IL-1Ra (Anakinra) or IFN gamma (IFN-gamma). ELISA and FACS were used to analyse cytokine responses.Results Aspergillus was the only pathogen that stimulated the Th2 cytokines IL-5 and IL-13, while Gram-negative bacteria, Gram-positive bacteria, Candida albicans, chitin, beta-glucan or Toll-like receptor (TLR) ligands did not. Depletion of CD4(+) cells abolished IL-13 production. Blocking complement receptor 3 (CR3) significantly reduced IL-5 and IL-13, while blocking TLR2, TLR4 or dectin-1 had no effect. ABPA patients displayed increased Aspergillus-induced IL-5 and IL-13 and decreased IFN gamma production compared with healthy controls. All biological agents tested showed the capability to inhibit Th2 responses, but also decreased Aspergillus-induced IFN gamma.Conclusions and Clinical Relevance Aspergillus conidia are unique in triggering Th2 responses in human PBMCs, through a CR3-dependent pathway. ABPA patients display a significantly increased Aspergillus-induced Th2/Th1 ratio that can be modulated by biologicals. These data provide a rationale to explore IFN gamma therapy in ABPA as a corticosteroid- sparing treatment option, by dampening Th2 responses and supplementing the IFN gamma deficiency at the same time.