Korf Johanna E, Pynaert Gwenda, Tournoy Kurt, Boonefaes Tom, Van Oosterhout Antoon, Ginneberge Daisy, Haegeman Anuschka, Verschoor Jan A, De Baetselier Patrick, Grooten Johan
Department for Molecular Biomedical Research (DMBR), VIB-Ghent University, "Fiers-Schell-Van Montagu" Building, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium.
Am J Respir Crit Care Med. 2006 Jul 15;174(2):152-60. doi: 10.1164/rccm.200507-1175OC. Epub 2006 May 4.
Mycolic acid (MA) constitutes a major and distinguishing cell wall biolipid from Mycobacterium tuberculosis. MA interferes with the lipid homeostasis of alveolar macrophages, inducing differentiation into foamy macrophages exhibiting increased proinflammatory function.
We verified the interference of this altered macrophage function with inhaled antigen-triggered allergic airway inflammation and underlying Th2 lymphocyte reactivity.
Using ovalbumin (OVA) as model allergen, C57BL/6 or BALB/C mice were sensitized by OVA-alum immunization. Experimental asthma, triggered subsequently by repetitive nebulized OVA inhalation, was assessed, using as readout parameters eosinophilia, peribronchial inflammation, and Th2 cytokine function.
A single intratracheal treatment of sensitized mice with MA, inserted into liposomes as carriers, prevented the onset of OVA-triggered allergic airway inflammation and promoted unresponsiveness to a secondary set of allergen exposures. The development of this tolerant condition required an 8-d lapse after MA instillation, coinciding with the appearance of foamy alveolar macrophages. MA-conditioned CD11b(+)F4/80(+) macrophages, transferred to the airways, mimicked the tolerogenic function of instilled MA; however, without the 8-d lapse requirement. Indicative of a macrophage-mediated tolerogenic antigen-presenting function, major histocompatibility complex (MHC)-mismatched donor macrophages failed to promote tolerance. Furthermore, Treg markers were strongly increased and established tolerance was lost after in situ depletion of CD25(+) Treg cells. Contrary to the interleukin-10 dependence of tolerogenic dendritic cells, IFN-gamma deficiency but not interleukin-10 deficiency abrogated the tolerogenic capacity of MA-conditioned macrophages.
These results document an innate-driven Mycobacterium tuberculosis MA-triggered immune regulatory mechanism in control of pulmonary allergic responses by converting macrophages into IFN-gamma-dependent tolerogenic antigen-presenting cells.
分枝菌酸（MA）是结核分枝杆菌细胞壁的一种主要且独特的生物脂质。MA干扰肺泡巨噬细胞的脂质稳态，诱导其分化为具有增强促炎功能的泡沫巨噬细胞。
我们验证了这种改变的巨噬细胞功能对吸入抗原引发的过敏性气道炎症及潜在Th2淋巴细胞反应性的干扰作用。
以卵清蛋白（OVA）作为模型变应原，通过OVA-明矾免疫对C57BL/6或BALB/C小鼠进行致敏。随后通过反复雾化吸入OVA引发实验性哮喘，并以嗜酸性粒细胞增多、支气管周围炎症和Th2细胞因子功能作为读数参数进行评估。
将MA作为载体包裹于脂质体中，对致敏小鼠进行单次气管内治疗，可预防OVA引发的过敏性气道炎症的发生，并促进对二次变应原暴露的无反应性。这种耐受状态的形成需要在MA滴注后间隔8天，这与泡沫肺泡巨噬细胞的出现相一致。将经MA处理的CD11b(+)F4/80(+)巨噬细胞转移至气道，可模拟滴注MA的致耐受功能；然而，无需间隔8天。主要组织相容性复合体（MHC）不匹配的供体巨噬细胞无法促进耐受，这表明存在巨噬细胞介导的致耐受抗原呈递功能。此外，在原位耗尽CD25(+)调节性T细胞后，Treg标志物显著增加，且已建立的耐受性丧失。与致耐受性树突状细胞对白介素-10的依赖性相反，IFN-γ缺乏而非白介素-10缺乏消除了经MA处理的巨噬细胞的致耐受能力。
这些结果证明了一种由结核分枝杆菌MA触发的先天性免疫调节机制，该机制通过将巨噬细胞转化为IFN-γ依赖性致耐受抗原呈递细胞来控制肺部过敏反应。
