Department of Rheumatology, Immunology and Allergology, University Hospital Bern, Bern, Switzerland; Department of BioMedical Research, University of Bern, Bern, Switzerland.
Department of Dermatology, Zurich University Hospital, Schlieren, Switzerland.
J Allergy Clin Immunol. 2020 Jan;145(1):301-311.e4. doi: 10.1016/j.jaci.2019.07.045. Epub 2019 Aug 19.
Type I hypersensitivity is mediated by allergen-specific IgE, which sensitizes the high-affinity IgE receptor FcεRI on mast cells and basophils and drives allergic inflammation upon secondary allergen contact. CD23/FcεRII, the low-affinity receptor for IgE, is constitutively expressed on B cells and has been shown to regulate immune responses. Simultaneous binding of IgE to FcεRI and CD23 is blocked by reciprocal allosteric inhibition, suggesting that the 2 receptors exert distinct roles in IgE handling.
We aimed to study how free IgE versus precomplexed IgE-allergen immune complexes (IgE-ICs) target the 2 IgE receptors FcεRI and CD23, and we investigated the functional implications of the 2 pathways.
We performed binding and activation assays with human cells in vitro and IgE pharmacokinetics and anaphylaxis experiments in vivo.
We demonstrate that FcεRI preferentially binds free IgE and CD23 preferentially binds IgE-ICs. We further show that those different binding properties directly translate to distinct biological functions: free IgE initiated allergic inflammation through FcεRI on allergic effector cells, while IgE-ICs were noninflammatory because of reduced FcεRI binding and enhanced CD23-dependent serum clearance.
We propose that IgE-ICs are noninflammatory through reduced engagement by FcεRI but increased targeting of the CD23 pathway.
I 型超敏反应由过敏原特异性 IgE 介导，IgE 使肥大细胞和嗜碱性粒细胞上的高亲和力 IgE 受体 FcεRI 致敏，并在二次过敏原接触时驱动过敏炎症。CD23/FcεRII 是 IgE 的低亲和力受体，在 B 细胞上持续表达，并已被证明可调节免疫反应。IgE 同时与 FcεRI 和 CD23 的结合被反向变构抑制所阻断，这表明这 2 个受体在 IgE 处理中发挥不同的作用。
我们旨在研究游离 IgE 与预先形成的 IgE-变应原免疫复合物（IgE-IC）如何靶向 2 个 IgE 受体 FcεRI 和 CD23，并研究这 2 种途径的功能意义。
我们在体外用人细胞进行结合和激活测定，并在体内进行 IgE 药代动力学和过敏实验。
我们证明 FcεRI 优先结合游离 IgE，而 CD23 优先结合 IgE-IC。我们进一步表明，这些不同的结合特性直接转化为不同的生物学功能：游离 IgE 通过过敏效应细胞上的 FcεRI 引发过敏炎症，而 IgE-IC 由于 FcεRI 结合减少和增强的 CD23 依赖性血清清除而无炎症。
我们提出 IgE-IC 通过减少 FcεRI 的结合而不增加 CD23 途径的靶向作用是非炎症性的。
