Yuasa T, Ono M, Watanabe T, Takai T
Department of Experimental Immunology and the Core Research for Evolutional Science and Technology (CREST) Program of Japan Science and Technology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
J Exp Med. 2001 Mar 5;193(5):563-72. doi: 10.1084/jem.193.5.563.
The Src family kinase Lyn initiates intracellular signal transduction by associating with a variety of immune receptors such as antigen receptor on B cells and high-affinity Fc receptor (FcR) for immunoglobulin Ig(E) (FcepsilonRI) on mast cells. Involvement of Lyn in the IgE-mediated immediate-type hypersensitivity is well documented, but the physiological significance of Lyn in IgG-dependent, type III low-affinity FcR for IgG (FcgammaRIII)-mediated responses is largely unknown. In this study, we generated a double-mutant mouse strain deficient in both type II FcR for IgG (FcgammaRIIB) and Lyn to exclude any involvement of inhibitory signaling by FcgammaRIIB, which otherwise downregulates FcgammaRIII-mediated cellular responses. FcgammaRIIB-deficient but Lyn-sufficient mice served as controls. The Lyn deficiency attenuated IgG-mediated systemic anaphylaxis in vivo, and significantly reduced calcium mobilization and degranulation responses of bone marrow-derived mast cells (BMMCs) in vitro. However, we found that either interleukin 4 or tumor necrosis factor alpha release by BMMCs was comparable to that from Lyn-deficient and control mice, and the reverse-passive Arthus reaction was equally induced in both mutant mice, indicating that Lyn is not involved in the onset of the IgG-mediated, FcgammaRIII-dependent late phase responses of mast cells. These findings provide us with insight into distinct signaling mechanisms in mast cells underlying the development of diverse pathologies as well as a therapeutic potential for selective treatment of allergic disorders.
Src家族激酶Lyn通过与多种免疫受体结合来启动细胞内信号转导，这些受体如B细胞上的抗原受体以及肥大细胞上的免疫球蛋白IgE高亲和力Fc受体（FcR）（FcεRI）。Lyn参与IgE介导的速发型超敏反应已有充分记录，但Lyn在IgG依赖性、IgG低亲和力Fc受体（FcγRIII）介导的反应中的生理意义在很大程度上尚不清楚。在本研究中，我们构建了一种双突变小鼠品系，其缺乏IgG的II型FcR（FcγRIIB）和Lyn，以排除FcγRIIB抑制性信号传导的任何参与，否则FcγRIIB会下调FcγRIII介导的细胞反应。缺乏FcγRIIB但Lyn充足的小鼠作为对照。Lyn缺陷减弱了体内IgG介导的全身过敏反应，并显著降低了体外骨髓来源肥大细胞（BMMC）的钙动员和脱颗粒反应。然而，我们发现BMMC释放的白细胞介素4或肿瘤坏死因子α与Lyn缺陷小鼠和对照小鼠的相当，并且在两种突变小鼠中均同等诱导了反向被动Arthus反应，表明Lyn不参与肥大细胞IgG介导的、FcγRIII依赖性晚期反应的发生。这些发现为我们深入了解肥大细胞中不同病理发展背后的独特信号传导机制以及过敏性疾病的选择性治疗潜力提供了见解。
