Division of Immunology, Allergy and Rheumatology, Department of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio.
Department of Research, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio; Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
J Allergy Clin Immunol. 2018 Apr;141(4):1373-1381.e5. doi: 10.1016/j.jaci.2017.05.027. Epub 2017 Jun 15.
The inhibitory receptor FcγRIIB is expressed on human and murine bone marrow-derived cells and limits inflammation by suppressing signaling through stimulatory receptors.
We sought to evaluate the effects of K9.361, a mouse IgG alloantibody to mouse FcγRIIB, on murine anaphylaxis.
Wild-type and FcγR-deficient mice were used to study anaphylaxis, which was induced by injection of 2.4G2 (rat IgG mAb that binds both FcγRIIB and the stimulatory receptor FcγRIII), by actively immunizing IgE-deficient mice and then challenging with the immunizing antigen, and by passive immunization with IgG or IgE anti-2,4,6-trinitrophenyl mAb, followed by injection of 2,4,6-trinitrophenyl-ovalbumin. Pretreatment with K9.361 was assessed for its ability to influence anaphylaxis.
Unexpectedly, K9.361 injection induced mild anaphylaxis, which was both FcγRIIB and FcγRIII dependent and greatly enhanced by β-adrenergic blockade. K9.361 injection also decreased expression of stimulatory Fcγ receptors, especially FcγRIII, and strongly suppressed IgG-mediated anaphylaxis without strongly affecting IgE-mediated anaphylaxis. The F(ab') fragment of K9.361 did not induce anaphylaxis, even after β-adrenergic blockade, and did not deplete FcγRIII or suppress IgG-mediated anaphylaxis but prevented intact K9.361-induced anaphylaxis without diminishing intact K9.36 suppression of IgG-mediated anaphylaxis.
Cross-linking FcγRIIB to stimulatory FcγRs through the Fc domains of an anti-FcγRIIB mAb induces and then suppresses IgG-mediated anaphylaxis without affecting IgE-mediated anaphylaxis. Because IgG- and IgE-mediated anaphylaxis can be mediated by the same cell types, this suggests that desensitization acts at the receptor rather than cellular level. Sequential treatment with the F(ab') fragment of anti-FcγRIIB mAb followed by intact anti-FcγRIIB safely prevents IgG-mediated anaphylaxis.
抑制性受体 FcγRIIB 表达于人类和鼠骨髓来源的细胞上，通过抑制刺激受体的信号转导来限制炎症。
我们试图评估 K9.361（一种针对鼠 FcγRIIB 的鼠 IgG 同种抗体）对鼠过敏反应的影响。
使用野生型和 FcγR 缺陷型小鼠来研究过敏反应，该过敏反应是通过注射 2.4G2（一种结合 FcγRIIB 和刺激受体 FcγRIII 的大鼠 IgG mAb）、主动免疫 IgE 缺陷型小鼠然后用免疫原进行攻毒、以及用 IgG 或 IgE 抗 2,4,6-三硝基苯 mAb 进行被动免疫，随后注射 2,4,6-三硝基苯-卵清蛋白来诱导。评估 K9.361 的预处理是否能够影响过敏反应。
出乎意料的是，K9.361 注射诱导了轻度过敏反应，该反应既依赖于 FcγRIIB，也依赖于 FcγRIII，并且被β-肾上腺素能阻断大大增强。K9.361 注射还降低了刺激 Fcγ 受体的表达，尤其是 FcγRIII，并强烈抑制 IgG 介导的过敏反应，而对 IgE 介导的过敏反应影响不大。K9.361 的 F(ab') 片段即使在β-肾上腺素能阻断后也不会引起过敏反应，也不会耗尽 FcγRIII 或抑制 IgG 介导的过敏反应，但可以预防完整 K9.361 诱导的过敏反应，而不会减弱完整 K9.361 对 IgG 介导的过敏反应的抑制作用。
通过抗 FcγRIIB mAb 的 Fc 结构域交联 FcγRIIB 到刺激 FcγR 会诱导并随后抑制 IgG 介导的过敏反应，而不影响 IgE 介导的过敏反应。由于 IgG 和 IgE 介导的过敏反应可以由相同的细胞类型介导，这表明脱敏作用发生在受体而不是细胞水平。用抗 FcγRIIB mAb 的 F(ab') 片段进行序贯治疗，然后用完整的抗 FcγRIIB 治疗，可以安全地预防 IgG 介导的过敏反应。
