Monomer hapten and hapten-specific IgG inhibit mast cell activation evoked by multivalent hapten with different mechanisms.
Monomer hapten and hapten-specific IgG inhibit mast cell activation evoked by multivalent hapten with different mechanisms.
复制标题
单体半抗原和半抗原特异性 IgG 以不同的机制抑制多价半抗原引起的肥大细胞活化。
DOI：
10.1002/eji.201847973
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发表时间：
2019
期刊：
影响因子：
5.4
通讯作者：
Hirashima N
中科院分区：
文献类型：
--
作者：
Suzuki R;Inoh Y;Yokawa S;Suzuki R;Furuno T;Hirashima N
多价抗原结合高亲和IgE受体（FcεRI）的IgE聚集可诱导肥大细胞活化。据报道，聚集的FcεRI的分解立即终止了脱粒，并且FcεRI和低亲和力IgG受体FcγRIIB的共连接形成通过含有SH2的肌醇5 ' -磷酸酶1 （SHIP1）磷酸化通过抑制信号阻断了脱粒。然而，它们抑制肥大细胞活化的分子机制尚不清楚。在此，我们发现在多价抗原（TNP‐OVA）激活的大鼠嗜碱性白血病细胞和小鼠骨髓来源的肥大细胞中添加过量的单体半抗原（TNP‐丙氨酸）可诱导立即和短暂的Syk去磷酸化，而之前Syk被TNP‐OVA磷酸化。Syk去磷酸化与细胞内Ca2+浓度（[Ca2+]i）的迅速降低、脱颗粒的终止以及通过抑制Akt和ERK磷酸化抑制细胞因子的产生相关。在活化的肥大细胞中加入半抗原特异性IgG单克隆抗体（抗TNP IgG1）可诱导SHIP1易位至质膜并磷酸化，这表明FcεRI聚集后，FcεRI与FcγRIIB的共连接可导致SHIP1活化。SHIP1磷酸化导致[Ca2+]i逐渐降低，对脱颗粒的抑制较弱，对细胞因子产生的抑制较强。我们的研究结果清楚地揭示了激活肥大细胞中Fc受体交联对细胞功能的抑制机制。
Aggregation of IgE bound to high affinity IgE receptor (FcεRI) by multivalent antigen induces mast cell activation. Reportedly, disaggregation of aggregated FcεRI immediately terminated degranulation, and formation of co‐ligated FcεRI and low affinity IgG receptor FcγRIIB blocked degranulation by inhibitory signal via SH2‐containing inositol 5’‐phosphatase 1 (SHIP1) phosphorylation. However, their molecular mechanisms to inhibit mast cell activation have been unclear in detail. Herein, we found that addition of excess monomeric hapten (TNP‐alanine) to multivalent antigen (TNP‐OVA)‐activated rat basophilic leukemia cells and mouse bone marrow‐derived mast cells induced immediate and transient Syk dephosphorylation, which was previously phosphorylated by TNP‐OVA addition. Syk dephosphorylation correlated to rapidly decreased intracellular Ca2+concentrations ([Ca2+]i), terminated degranulation, and suppressed cytokine production through inhibition of Akt and ERK phosphorylation. Addition of hapten‐specific IgG monoclonal antibody (anti‐TNP IgG1) to activated mast cells induced translocation of SHIP1 to the plasma membrane and its phosphorylation, indicating that co‐ligation of FcεRI and FcγRIIB after FcεRI aggregation can lead to SHIP1 activation. SHIP1 phosphorylation led to gradually decreased [Ca2+]i, weak inhibition of degranulation, and strong inhibition of cytokine production. Our findings clearly show the inhibitory mechanism of cell function in activated mast cells by operating Fc receptor crosslinking.