Pathophysiological roles of basophils and mast cells in allergic inflammations

肥大细胞和嗜碱性粒细胞上的高亲和力ε受体(Fc-IgE RI)通过脱颗粒诱导预先形成的炎性介质的释放，以及炎性细胞因子的从头合成和分泌，导致一系列急性和慢性过敏症状。两个SLP-76家族适配器SLP-76和MIST在肥大细胞和嗜碱性粒细胞中都有表达，并且两者都参与FcεRI信号转导。然而，SLP-76和MIST在这一过程中的功能冗余和/或特异性仍不清楚。在本研究中，我们试图通过使用MIST和/或SLP-76基因缺陷的小鼠来阐明SLP-76和MIST在FcεRI介导的过敏反应中的功能冗余和/或特异性。FcεRI诱导的脱颗粒在MIST和SLP-76缺陷的肥大细胞中分别略低于和显著低于野生型细胞。在SLP-76缺陷细胞中检测到的残留脱颗粒通过引入雾缺陷被完全消除。T…为了更深入地了解SLP-76和MIST在FcεRI信号转导中功能差异的分子基础，我们研究了这两个接头的分子相互作用模式和膜靶向性。SLP-76与She(Gads)下游的Grb2相关接头相关，而Mist不与之相关。然而，当MIST中的Grb2结合基序被SLP-76中的高亲和力RXXK SH3结合基序取代时，该突变体(MIST-GBF)获得了与Gads结合的能力。虽然野生型云雾在抗原接触部位的募集和聚集形成弱于观察到的SLP-76，但在FcεRI诱导的这些变化方面，Mist Gbf突变体表现出与SLP-76相似的表现。此外，MIST-GBF在肥大细胞中的表达增强了FcεRI介导的脱颗粒，其水平与表达SLP-76的细胞中观察到的水平相当，这表明在FcεRI介导的肥大细胞激活中，GADS结合基序(RXXK)的存在决定了SLP-76在FcεRI介导的肥大细胞激活中的功能优势。由于SLP-76是结构性的，而MIST在肥大细胞和嗜碱性粒细胞中都可以诱导表达，这两个SLP-76家族适配器在过敏反应中分别作为FCεRI介导的肥大细胞激活的基本调节因子和放大器。较少

Engagement of the high-affinity IgE receptor (FcεRI) on mast cells as well as basophils induces the release of preformed inflammatory mediators by degranulation and also the de novo synthesis and secretion of inflammatory cytokines, leading to an array of acute and chronic allergic symptoms. Two SLP-76 family adaptors, SLP-76 and MIST, are expressed in both mast cells and basophils, and both are involved in FcεRI -signaling. However, the functional redundancy and/or specificity of SLP-76 and MIST in this process remain unclear. In the present study, we intended to clarify the functional redundancy and/or specificity of SLP-76 and MIST in FcεRI-mediated allergic reactions by using mice deficient in MIST and/or SLP-76.FcεRI-induced degranulation was slightly and profoundly reduced in MIST- and SLP-76-deficient mast cells than in wild type cells, respectively. The residual degranulation detected in SLP-76-deficient cells was completely abrogated by the introduction of a MIST-deficiency. T … More o gain insight into the molecular basis for the functional difference between SLP-76 and MIST in FcεRI-signaling, we examined the mode of molecular interactions and membrane targeting of these two adaptors. SLP-76 associated with Grb2-related adaptor downstream of She (Gads) whereas MIST did not. However, when the Grb2-binding motif in MIST was replaced with a high-affinity RXXK SH3-binding motif from SLP-76, this mutant (MIST-GBF) gained the ability to associate with Gads. Although recruitment and cluster formation of wild type MIST at the antigen contact site were weaker than that observed for SLP-76, the MIST GBF mutant behaved like SLP-76 in terms of these FcεRI-induced changes. Furthermore, expression of MIST-GBF in mast cells enhanced FcεRI-mediated degranulation to a level comparable to that observed in SLP-76-expressing cells, indicating that the presence of the Gads-binding motif (RXXK) determines the functional dominance of SLP-76 over MIST in FcεRI-mediated mast cell activation.Since SLP-76 is constitutively but MIST is inducibly expressed in mast cells and basophils, these two SLP-76 family adaptors function as a basal essential regulator and an amplifier of FcεRI-mediated mast cell activation, respectively, in allergic reactions. Less