Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA.
J Immunol. 2012 May 1;188(9):4360-8. doi: 10.4049/jimmunol.1003223. Epub 2012 Mar 26.
Anaphylaxis is a rapid, life-threatening hypersensitivity reaction. Until recently, it was mainly attributed to histamine released by mast cells activated by allergen crosslinking (XL) of FcεRI-bound allergen-specific IgE. However, recent reports established that anaphylaxis could also be triggered by basophil, macrophage, and neutrophil secretion of platelet-activating factor subsequent to FcγR stimulation by IgG/Ag complexes. We have investigated the contribution of Fyn and Lyn tyrosine kinases to FcγRIIb and FcγRIII signaling in the context of IgG-mediated passive systemic anaphylaxis (PSA). We found that mast cell IgG XL induced Fyn, Lyn, Akt, Erk, p38, and JNK phosphorylation. Additionally, IgG XL of mast cells, basophils, and macrophages resulted in Fyn- and Lyn-regulated mediator release in vitro. FcγR-mediated activation was enhanced in Lyn-deficient (knockout [KO]) cells, but decreased in Fyn KO cells, compared with wild-type cells. More importantly, Lyn KO mice displayed significantly exacerbated PSA features whereas no change was observed for Fyn KO mice, compared with wild-type littermates. Intriguingly, we establish that mast cells account for most serum histamine in IgG-induced PSA. Taken together, our findings establish pivotal roles for Fyn and Lyn in the regulation of PSA and highlight their unsuspected functions in IgG-mediated pathologies.
过敏反应是一种迅速且危及生命的超敏反应。直到最近，它主要归因于过敏原交联（XL）使 mast cells 激活后释放的组织胺（histamine），进而激活 FcεRI 结合的过敏原特异性 IgE。然而，最近的报告表明，过敏反应也可能由 basophil、macrophage 和嗜中性粒细胞在 IgG/Ag 复合物刺激 FcγR 后分泌血小板激活因子（platelet-activating factor）触发。我们研究了 Fyn 和 Lyn 酪氨酸激酶在 IgG 介导的被动全身性过敏反应（PSA）中的 FcγRIIb 和 FcγRIII 信号转导中的作用。我们发现，mast cell IgG XL 诱导了 Fyn 和 Lyn 的磷酸化，进而激活 Akt、Erk、p38 和 JNK。此外，mast cell、basophil 和 macrophage 的 IgG XL 导致体外介质释放受到 Fyn 和 Lyn 调控。与野生型细胞相比，Lyn 缺陷（敲除 [KO]）细胞中的 FcγR 介导的激活增强，而 Fyn KO 细胞中的激活减弱。更重要的是，与野生型同窝仔相比，Lyn KO 小鼠的 PSA 特征明显加重，而 Fyn KO 小鼠没有变化。有趣的是，我们发现 mast cell 是 IgG 诱导的 PSA 中血清组织胺的主要来源。总之，我们的研究结果确立了 Fyn 和 Lyn 在 PSA 调节中的关键作用，并强调了它们在 IgG 介导的病理中的意想不到的功能。
