Nanoparticles Displaying Allergen and Siglec-8 Ligands Suppress IgE-FcεRI-Mediated Anaphylaxis and Desensitize Mast Cells to Subsequent Antigen Challenge.
Nanoparticles Displaying Allergen and Siglec-8 Ligands Suppress IgE-FcεRI-Mediated Anaphylaxis and Desensitize Mast Cells to Subsequent Antigen Challenge.
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DOI：
10.4049/jimmunol.1901212
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发表时间：
2021-05-15
期刊：
影响因子：
--
通讯作者：
Paulson JC
中科院分区：
文献类型：
--
作者：
Duan S;Arlian BM;Nycholat CM;Wei Y;Tateno H;Smith SA;Macauley MS;Zhu Z;Bochner BS;Paulson JC
Siglec-8是表达在嗜酸性粒细胞和肥大细胞上的抑制性受体。在这里，我们利用一种新的Siglec-8转基因小鼠模型来评估使用脂质体平台调节IgE依赖的肥大细胞脱颗粒和过敏反应的影响，以显示有或没有Siglec-8的合成多糖配体(Sig8L)的过敏原。假设Siglec-8重新聚集到ε-Fc IgE RI受体复合体将抑制变应原诱导的肥大细胞脱颗粒。过敏原和Sig8L在脂质体上的共显示深刻地抑制了IgE介导的小鼠骨髓来源的肥大细胞或表达Siglec-8的大鼠嗜碱性白血病细胞的脱颗粒。相反，仅显示Sig8L的脂质体对抗原脂质体诱导的脱颗粒没有明显的抑制作用，这表明只有当抗原和Sig8L位于同一颗粒上时，Siglec-8才具有抑制活性。在过敏反应的小鼠模型中，在抗原脂质体上展示Sig8L可以完全抑制表达Siglec-8的肥大细胞转基因小鼠的IgE介导的过敏反应，但对不表达Siglec-8的小鼠没有保护作用。此外，防止过敏反应的小鼠对随后的过敏原攻击仍然不敏感，这是由于细胞表面抗原特异性IgE的丢失和血液中IgE的加速清除。因此，虽然人Siglec-8在小鼠肥大细胞上的表达本身并不调节Ig E-FcεRI介导的细胞激活，但Sig8L修饰的抗原脂质体将Siglec-8强制募集到FcεRI受体上，导致抑制脱颗粒和对后续抗原暴露的脱敏。
Siglec-8 is an inhibitory receptor expressed on eosinophils and mast cells. Here we took advantage of a novel Siglec-8 transgenic mouse model to assess the impact of modulating IgE dependent mast cell degranulation and anaphylaxis using a liposomal platform to display an allergen with or without a synthetic glycan ligand for Siglec-8 (Sig8L). The hypothesis is that recruitment of Siglec-8 to the IgE-FcεRI receptor complex will inhibit allergen induced mast cell degranulation. Co-display of both allergen and Sig8L on liposomes profoundly suppresses IgE-mediated degranulation of mouse bone marrow derived mast cells or rat basophilic leukemia cells expressing Siglec-8. In contrast, liposomes displaying only Sig8L have no significant suppression of antigenic liposome-induced degranulation, demonstrating that the inhibitory activity by Siglec-8 occurs only when antigen and Sig8L are on the same particle. In mouse models of anaphylaxis, display of Sig8L on antigenic liposomes completely suppresses IgE-mediated anaphylaxis in transgenic mice with mast cells expressing Siglec-8, but has no protection in mice that do not express Siglec-8. Furthermore, mice protected from anaphylaxis remain desensitized to subsequent allergen challenge due to loss of antigen specific IgE from the cell surface and accelerated clearance of IgE from the blood. Thus, while expression of human Siglec-8 on murine mast cells does not by itself modulate IgE-FcεRI mediated cell activation, the enforced recruitment of Siglec-8 to the FcεRI receptor by Sig8L decorated antigenic liposomes results in inhibition of degranulation and desensitization to subsequent antigen exposure.
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DOI：
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发表时间：
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期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
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DOI：
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发表时间：
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期刊：
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