Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Science, Tokyo, Japan.
Ann Allergy Asthma Immunol. 2012 Mar;108(3):188-94. doi: 10.1016/j.anai.2012.01.009.
A large body of evidence has demonstrated that treatment with omalizumab is clinically effective for the management of moderate to severe allergic asthma, emphasizing the importance of IgE in the pathogenesis of allergic asthma. We hypothesized that IgE accelerates FcεRI-mediated responsiveness of "immature" human mast cells (MCs) and that omalizumab downregulates the acceleration.
To examine when MC progenitors acquired the ability to degranulate following FcεRI aggregation, whether IgE accelerates the responsiveness of immature MCs following FcεRI aggregation, and whether omalizumab regulates such an acceleration.
Gene expression was examined using a microarray and quantitative reverse transcription polymerase chain reaction. Protein expression was investigated using FACS. Histamine release was examined using an EIA.
The time-course analysis of the mRNA expression of MC-related genes, including FcεRI, in Kit(+) sorted cells during the differentiation and histamine experiments revealed that the expression level of FcεRI in 5 week (w)-cultured MCs was not sufficient to induce degranulation following FcεRI aggregation but that 5 w-cultured MCs were fully responsive to calcium ionophore. By addition of IgE in culture medium FcεRI expression level and FcεRI-mediated histamine release of 5 w-cultured MCs were significantly increased compared with those without addition of IgE, whereas the expression level of tryptase and number of MCs was not affected. Omalizumab significantly inhibited IgE-dependent enhancement of FcεRI expression level and FcεRI-mediated histamine release.
High levels of IgE in the microenvironment in vivo may upregulate the responsiveness of immature MCs to allergens. Omalizumab may inhibit the IgE-mediated responsiveness of not only mature MCs, but also immature MCs.
大量证据表明，奥马珠单抗治疗中重度过敏性哮喘具有临床疗效，这强调了 IgE 在过敏性哮喘发病机制中的重要性。我们假设 IgE 可加速“未成熟”人肥大细胞（MC）FcεRI 介导的反应性，奥马珠单抗可下调这种加速作用。
研究 MC 前体细胞在 FcεRI 聚集后获得脱颗粒能力的时间，IgE 是否加速 FcεRI 聚集后未成熟 MC 的反应性，以及奥马珠单抗是否调节这种加速作用。
使用微阵列和定量逆转录聚合酶链反应检测基因表达。使用流式细胞术检测蛋白表达。使用 EIA 检测组胺释放。
在分化和组胺实验中，对 Kit(+)分选细胞中与 MC 相关的基因（包括 FcεRI）的 mRNA 表达进行时间进程分析显示，5 周（w）培养的 MC 中 FcεRI 的表达水平不足以在 FcεRI 聚集后诱导脱颗粒，但 5 w 培养的 MC 对钙离子载体完全有反应。在培养物中添加 IgE 可显著增加 5 w 培养的 MC 中 FcεRI 的表达水平和 FcεRI 介导的组胺释放，而不添加 IgE 则没有影响，而类胰蛋白酶的表达水平和 MC 数量则不受影响。奥马珠单抗可显著抑制 IgE 依赖性增强的 FcεRI 表达水平和 FcεRI 介导的组胺释放。
体内微环境中 IgE 水平升高可能上调未成熟 MC 对过敏原的反应性。奥马珠单抗不仅可以抑制成熟 MC，还可以抑制未成熟 MC 的 IgE 介导的反应性。
