University of Pennsylvania, Philadelphia.
Bristol-Myers Squibb, Wallingford, Connecticut.
Arthritis Rheumatol. 2018 Dec;70(12):2077-2086. doi: 10.1002/art.40655. Epub 2018 Oct 22.
To examine the association between macrophage migration inhibitory factor (MIF) promoter polymorphisms and granulomatosis with polyangiitis (GPA) in human subjects, and to assess the role of MIF in a murine model of granulomatous vasculitis.
The human study involved 1,077 patients with GPA and healthy controls whose serum was genotyped by capillary electrophoresis for the MIF -794 CATT promoter microsatellite (rs5844572). MIF promoter, CATT-length-dependent gene expression in response to β-glucan was assessed by gene reporter assays. In mouse studies, granulomatous disease was induced by injection of Candida albicans β-glucan into wild-type (WT) or Mif-knockout (Mif-KO) C57BL/6 mice and C57BL/6 mice transgenically overexpressing Mif in lung epithelium (Mif lung-Tg2.1). Mice were treated with a neutralizing anti-MIF antibody and analyzed for the density of pulmonary granulomas, expression of inflammatory chemokines, and frequency of mortality.
The percentage of human subjects carrying >5 CATT repeats in each MIF allele (high genotypic MIF expressers) was 60.2% among patients with GPA and 53.9% among healthy controls (adjusted P = 0.049). In response to granulomatous stimulation, human MIF gene expression increased proportionally with CATT length. Mif lung-Tg2.1 mice exhibited more pulmonary granulomas than WT mice, which in turn showed more granulomas than Mif-KO mice. A significantly higher percentage of Mif lung-Tg2.1 mice, compared to Mif-KO or WT mice, died when injected with Candida albicans β-glucan, and treatment of these mice with an anti-MIF monoclonal antibody protected against a lethal outcome. Levels of MIF-dependent neutrophil/macrophage chemokines were elevated in the bronchoalveolar lavage fluid or plasma of Mif lung-Tg2.1 mice.
Patients with GPA have an increased frequency of high MIF expression CATT alleles. Higher Mif expression increases the incidence of mortality and pulmonary granulomas in Mif lung-Tg2.1 mice, while anti-MIF treatment protects these mice against death. Blockade of MIF in high genotypic MIF expressers may therefore offer a selective pharmacologic therapy for GPA.
研究巨噬细胞移动抑制因子（MIF）启动子多态性与人类肉芽肿性多血管炎（GPA）之间的关联，并评估 MIF 在肉芽肿性血管炎的小鼠模型中的作用。
本项人类研究纳入了 1077 例 GPA 患者和健康对照者，通过毛细管电泳对他们的血清进行 MIF-794 CATT 启动子微卫星（rs5844572）的基因分型。通过基因报告基因检测评估 MIF 启动子和 CATT 长度依赖性基因表达对β-葡聚糖的反应。在小鼠研究中，通过向野生型（WT）或 Mif 敲除（Mif-KO）C57BL/6 小鼠以及肺上皮细胞中过表达 Mif 的 C57BL/6 小鼠（Mif 肺-Tg2.1）中注射白色念珠菌β-葡聚糖诱导肉芽肿性疾病。用中和抗 MIF 抗体处理这些小鼠，并分析其肺部肉芽肿的密度、炎症趋化因子的表达和死亡率。
GPA 患者中每个 MIF 等位基因携带＞5 个 CATT 重复的患者百分比为 60.2%，健康对照者中为 53.9%（调整后 P=0.049）。在对肉芽肿刺激的反应中，人类 MIF 基因表达随 CATT 长度成比例增加。与 WT 小鼠相比，Mif 肺-Tg2.1 小鼠的肺部肉芽肿更多，而与 Mif-KO 小鼠相比，WT 小鼠的肺部肉芽肿更多。与 Mif-KO 或 WT 小鼠相比，Mif 肺-Tg2.1 小鼠在注射白色念珠菌β-葡聚糖时死亡的比例显著更高，而用抗 MIF 单克隆抗体治疗这些小鼠可防止致死结局。与 Mif-KO 或 WT 小鼠相比，Mif 肺-Tg2.1 小鼠的支气管肺泡灌洗液或血浆中的 MIF 依赖性中性粒细胞/巨噬细胞趋化因子水平升高。
GPA 患者高 MIF 表达 CATT 等位基因的频率增加。更高的 Mif 表达增加了 Mif 肺-Tg2.1 小鼠的死亡率和肺部肉芽肿的发生率，而抗 MIF 治疗可保护这些小鼠免受死亡。因此，在高 MIF 表达的患者中阻断 MIF 可能为 GPA 提供一种选择性的药物治疗。
