Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
Webb Waring Summer Research Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; and.
J Immunol. 2018 Oct 15;201(8):2232-2243. doi: 10.4049/jimmunol.1800303. Epub 2018 Sep 5.
Metal-induced hypersensitivity is driven by dendritic cells (DCs) that migrate from the site of exposure to the lymph nodes, upregulate costimulatory molecules, and initiate metal-specific CD4 T cell responses. Chronic beryllium disease (CBD), a life-threatening metal-induced hypersensitivity, is driven by beryllium-specific CD4 Th1 cells that expand in the lung-draining lymph nodes (LDLNs) after beryllium exposure (sensitization phase) and are recruited back to the lung, where they orchestrate granulomatous lung disease (elicitation phase). To understand more about how beryllium exposures impact DC function during sensitization, we examined the early events in the lung and LDLNs after pulmonary exposure to different physiochemical forms of beryllium. Exposure to soluble or crystalline forms of beryllium induced alveolar macrophage death/release of IL-1α and DNA, enhanced migration of CD80 DCs to the LDLNs, and sensitized HLA-DP2 transgenic mice after single low-dose exposures, whereas exposures to insoluble particulate forms beryllium did not. IL-1α and DNA released by alveolar macrophages upregulated CD80 on immature BMDC via IL-1R1 and TLR9, respectively. Intrapulmonary exposure of mice to IL-1R and TLR9 agonists without beryllium was sufficient to drive accumulation of CD80 DCs in the LDLNs, whereas blocking both pathways prevented accumulation of CD80 DCs in the LDLNs of beryllium-exposed mice. Thus, in contrast to particulate forms of beryllium, which are poor sensitizers, soluble or crystalline forms of beryllium promote death of alveolar macrophages and their release of IL-1α and DNA, which act as damage-associated molecular pattern molecules to enhance DC function during beryllium sensitization.
金属诱导的超敏反应是由树突状细胞（DC）驱动的，这些细胞从暴露部位迁移到淋巴结，上调共刺激分子，并启动金属特异性 CD4 T 细胞反应。慢性铍病（CBD）是一种致命的金属诱导的超敏反应，由铍特异性 CD4 Th1 细胞驱动，这些细胞在铍暴露后（致敏阶段）在肺引流淋巴结（LDLN）中扩增，并被招募回肺部，在肺部它们协调肉芽肿性肺病（激发阶段）。为了更深入地了解铍暴露在致敏过程中如何影响 DC 功能，我们研究了肺部暴露于不同物理化学形式的铍后，肺部和 LDLN 中的早期事件。暴露于可溶性或结晶形式的铍会诱导肺泡巨噬细胞死亡/释放白细胞介素-1α和 DNA，增强 CD80 DC 向 LDLN 的迁移，并在单次低剂量暴露后使 HLA-DP2 转基因小鼠致敏，而暴露于不溶性颗粒形式的铍则不会。肺泡巨噬细胞释放的白细胞介素-1α和 DNA 通过白细胞介素-1R1 和 TLR9 分别上调未成熟 BMDC 上的 CD80。在没有铍的情况下，向肺部内给予小鼠白细胞介素-1R 和 TLR9 激动剂足以驱动 LDLN 中 CD80 DC 的积累，而阻断这两个途径则防止了暴露于铍的小鼠 LDLN 中 CD80 DC 的积累。因此，与颗粒形式的铍不同，可溶性或结晶形式的铍促进肺泡巨噬细胞的死亡及其释放白细胞介素-1α和 DNA，这些物质作为损伤相关分子模式分子，在铍致敏过程中增强 DC 功能。
