Abstract：
BACKGROUND: Allergic diseases, such as anaphylaxis and urticaria, pose significant health concerns. The quest for improved prognostic outcomes in these diseases necessitates the exploration of novel therapeutic avenues. To address this need, we have developed a novel mouse model of anaphylaxis, denoted as anaphylaxis-dependent spotted distribution of immune complex in skin (ASDIS). ASDIS manifests as distinct dotted symptoms in the skin, detectable through in vivo imaging, resembling urticarial symptoms. In this study, we investigated the potential underlying mechanisms giving rise to these dotted symptoms, exploring the role of vascular permeability and characterizing the ASDIS model as a new urticaria model.
METHODS: We employed haired and hairless HR mice (BALB/c background) and hairless HR-1 mice (a commercially available hairless strain with an unidentified genetic background). ASDIS was induced by the simultaneous intravenous injection of anti-ovalbumin IgE and fluorescein isothiocyanate (FITC)-ovalbumin, along with Evans blue - a recognized vascular permeability indicator. Anaphylaxis and scratching behavior were monitored through rectal temperature decrease and optical observation, respectively. Histamine, platelet-activating factor, and compound 48/80 were injected with or without FITC-ovalbumin for comparative analysis. The effects of an α1 adrenergic receptor agonist applied to the skin were also examined.
RESULTS: In hairless mice, the simultaneous injection of histamine, compound 48/80, or IgE with FITC-ovalbumin induced comparable rectal temperature decreases and vascular permeability. However, only the combination of FITC-ovalbumin and IgE triggered ASDIS, specifically the dotted urticaria-like symptom. Evans blue visualization and optical observation of dotted swelling confirmed that the vascular permeability mediated the phenomenon. Hairless mice exhibited a more pronounced temperature decrease than their haired counterparts when exposed to histamine, platelet-activating factor, compound 48/80, and IgE with FITC-ovalbumin. The application of an α1 adrenergic receptor agonist to the skin attenuated the topical urticaria-like symptom.
CONCLUSIONS: Our experiments revealed four findings. The first is that ASDIS mirrors urticaria-like symptoms resulting from increased vascular permeability, akin to human urticaria. The second finding is that the development of dotted symptoms involves an IgE-induced, yet unidentified, mechanism not triggered by histamine or compound 48/80 alone. The third finding highlights the heightened susceptibility of hairless mice to ASDIS induction. The fourth finding demonstrates that the inhibition of ASDIS by the topical application of an α1 adrenergic receptor agonist hints at a potential anti-urticarial application for this vasoconstrictor. Further elucidation of these unidentified IgE-dependent mechanisms and the specific generation of dotted symptoms by IgE-immune complexes could provide novel insights into allergic response processes and therapeutic interventions for these conditions.
METHODS: We employed haired and hairless HR mice (BALB/c background) and hairless HR-1 mice (a commercially available hairless strain with an unidentified genetic background). ASDIS was induced by the simultaneous intravenous injection of anti-ovalbumin IgE and fluorescein isothiocyanate (FITC)-ovalbumin, along with Evans blue - a recognized vascular permeability indicator. Anaphylaxis and scratching behavior were monitored through rectal temperature decrease and optical observation, respectively. Histamine, platelet-activating factor, and compound 48/80 were injected with or without FITC-ovalbumin for comparative analysis. The effects of an α1 adrenergic receptor agonist applied to the skin were also examined.
RESULTS: In hairless mice, the simultaneous injection of histamine, compound 48/80, or IgE with FITC-ovalbumin induced comparable rectal temperature decreases and vascular permeability. However, only the combination of FITC-ovalbumin and IgE triggered ASDIS, specifically the dotted urticaria-like symptom. Evans blue visualization and optical observation of dotted swelling confirmed that the vascular permeability mediated the phenomenon. Hairless mice exhibited a more pronounced temperature decrease than their haired counterparts when exposed to histamine, platelet-activating factor, compound 48/80, and IgE with FITC-ovalbumin. The application of an α1 adrenergic receptor agonist to the skin attenuated the topical urticaria-like symptom.
CONCLUSIONS: Our experiments revealed four findings. The first is that ASDIS mirrors urticaria-like symptoms resulting from increased vascular permeability, akin to human urticaria. The second finding is that the development of dotted symptoms involves an IgE-induced, yet unidentified, mechanism not triggered by histamine or compound 48/80 alone. The third finding highlights the heightened susceptibility of hairless mice to ASDIS induction. The fourth finding demonstrates that the inhibition of ASDIS by the topical application of an α1 adrenergic receptor agonist hints at a potential anti-urticarial application for this vasoconstrictor. Further elucidation of these unidentified IgE-dependent mechanisms and the specific generation of dotted symptoms by IgE-immune complexes could provide novel insights into allergic response processes and therapeutic interventions for these conditions.
摘要：
背景：过敏性疾病，如过敏反应和荨麻疹，构成重大健康问题。寻求改善这些疾病的预后结果需要探索新的治疗途径。为了满足这一需求，我们开发了一种新的小鼠过敏反应模型，表示为皮肤中免疫复合物的过敏反应依赖性斑点分布(ASDIS)。ASDIS表现为皮肤明显的点状症状，可通过体内成像检测，类似荨麻疹症状。在这项研究中,我们调查了导致这些点状症状的潜在潜在潜在机制，探索血管通透性的作用，并将ASDIS模型描述为一种新的荨麻疹模型。
方法:我们采用了有毛和无毛HR小鼠(BALB/c背景)和无毛HR-1小鼠(具有未鉴定的遗传背景的市售无毛品系)。通过同时静脉注射抗卵清蛋白IgE和异硫氰酸荧光素（FITC）-卵清蛋白诱导ASDIS，与伊文思蓝-公认的血管通透性指标。通过直肠温度下降和光学观察来监测过敏反应和刮擦行为，分别。组胺,血小板活化因子,和化合物48/80注射或不注射FITC-卵清蛋白用于比较分析。还检查了应用于皮肤的α1肾上腺素能受体激动剂的作用。
结果：在无毛小鼠中，同时注射组胺,化合物48/80或含有FITC-卵清蛋白的IgE引起相当的直肠温度降低和血管通透性。然而,只有FITC-卵清蛋白和IgE的组合引发ASDIS，特别是点状的荨麻疹样症状。伊文思蓝可视化和点状肿胀的光学观察证实了血管通透性介导的现象。当暴露于组胺时，无毛小鼠比它们的毛发小鼠表现出更明显的温度下降，血小板活化因子,化合物48/80和含有FITC-卵清蛋白的IgE。将α1肾上腺素能受体激动剂应用于皮肤可减轻局部荨麻疹样症状。
结论：我们的实验揭示了四个发现。首先是ASDIS反映了血管通透性增加导致的荨麻疹样症状，类似于人类荨麻疹。第二个发现是点状症状的发展涉及IgE诱导的，但身份不明，机制不是由组胺或化合物48/80单独触发。第三个发现强调了无毛小鼠对ASDIS诱导的敏感性增加。第四个发现表明，局部应用α1肾上腺素能受体激动剂对ASDIS的抑制作用暗示了该血管收缩剂的潜在抗荨麻疹应用。进一步阐明这些未鉴定的IgE依赖性机制以及IgE-免疫复合物对点状症状的特异性产生可以为这些病症的过敏反应过程和治疗干预提供新的见解。
方法:我们采用了有毛和无毛HR小鼠(BALB/c背景)和无毛HR-1小鼠(具有未鉴定的遗传背景的市售无毛品系)。通过同时静脉注射抗卵清蛋白IgE和异硫氰酸荧光素（FITC）-卵清蛋白诱导ASDIS，与伊文思蓝-公认的血管通透性指标。通过直肠温度下降和光学观察来监测过敏反应和刮擦行为，分别。组胺,血小板活化因子,和化合物48/80注射或不注射FITC-卵清蛋白用于比较分析。还检查了应用于皮肤的α1肾上腺素能受体激动剂的作用。
结果：在无毛小鼠中，同时注射组胺,化合物48/80或含有FITC-卵清蛋白的IgE引起相当的直肠温度降低和血管通透性。然而,只有FITC-卵清蛋白和IgE的组合引发ASDIS，特别是点状的荨麻疹样症状。伊文思蓝可视化和点状肿胀的光学观察证实了血管通透性介导的现象。当暴露于组胺时，无毛小鼠比它们的毛发小鼠表现出更明显的温度下降，血小板活化因子,化合物48/80和含有FITC-卵清蛋白的IgE。将α1肾上腺素能受体激动剂应用于皮肤可减轻局部荨麻疹样症状。
结论：我们的实验揭示了四个发现。首先是ASDIS反映了血管通透性增加导致的荨麻疹样症状，类似于人类荨麻疹。第二个发现是点状症状的发展涉及IgE诱导的，但身份不明，机制不是由组胺或化合物48/80单独触发。第三个发现强调了无毛小鼠对ASDIS诱导的敏感性增加。第四个发现表明，局部应用α1肾上腺素能受体激动剂对ASDIS的抑制作用暗示了该血管收缩剂的潜在抗荨麻疹应用。进一步阐明这些未鉴定的IgE依赖性机制以及IgE-免疫复合物对点状症状的特异性产生可以为这些病症的过敏反应过程和治疗干预提供新的见解。
