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首页> 外文期刊>EBioMedicine >Genetic restriction of antigen-presentation dictates allergic sensitization and disease in humanized mice
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Genetic restriction of antigen-presentation dictates allergic sensitization and disease in humanized mice

机译：抗原呈递的遗传限制决定了人源化小鼠的过敏性致敏和疾病

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Background Immunoglobulin(Ig)E-associated allergies result from misguided immune responses against innocuous antigens. CD4+ T lymphocytes are critical for initiating and perpetuating that process, yet the crucial factors determining whether an individual becomes sensitized towards a given allergen remain largely unknown. Objective To determine the key factors for sensitization and allergy towards a given allergen. Methods We here created a novel human T cell receptor(TCR) and human leucocyte antigen (HLA)-DR1 (TCR-DR1) transgenic mouse model of asthma, based on the human-relevant major mugwort ( Artemisia vulgaris ) pollen allergen Art v 1 to examine the critical factors for sensitization and allergy upon natural allergen exposure via the airways in the absence of systemic priming and adjuvants. Results Acute allergen exposure led to IgE-independent airway hyperreactivity (AHR) and T helper(Th)2-prone lung inflammation in TCR-DR1, but not DR1, TCR or wildtype (WT) control mice, that was alleviated by prophylactic interleukin(IL)-2-αIL-2 mAb complex-induced expansion of Tregs. Chronic allergen exposure sensitized one third of single DR1 transgenic mice, however, without impacting on lung function. Similar treatment led to AHR and Th2-driven lung pathology in 90% of TCR-DR1 mice. Prophylactic and therapeutic expansion of Tregs with IL-2-αIL-2 mAb complexes blocked the generation and boosting of allergen-specific IgE associated with chronic allergen exposure. Conclusions We identify genetic restriction of allergen presentation as primary factor dictating allergic sensitization and disease against the major pollen allergen from the weed mugwort, which frequently causes sensitization and disease in humans. Furthermore, we demonstrate the importance of the balance between allergen-specific T effector and Treg cells for modulating allergic immune responses.
机译：背景免疫球蛋白（Ig）E相关的过敏症是由针对无害抗原的错误免疫反应导致的。 CD4 + T淋巴细胞对于启动和维持该过程至关重要，但是决定个体是否对某种过敏原敏感的关键因素仍然未知。目的确定对给定过敏原致敏和过敏的关键因素。方法我们根据与人类有关的主要艾蒿（Artemisia vulgaris）花粉过敏原Art v 1建立了一种新型的人类T细胞受体（TCR）和人类白细胞抗原（HLA）-DR1（TCR-DR1）转基因小鼠哮喘模型在没有全身性引发剂和佐剂的情况下，检查通过气道暴露于自然过敏原后致敏和过敏的关键因素。结果急性过敏原暴露可导致TCR-DR1的IgE非依赖性气道高反应性（AHR）和T辅助（Th）2易发性肺部炎症，但不能预防DR1，TCR或野生型（WT）对照小鼠，预防性白介素可以缓解这种情况（ IL）-2-αIL-2mAb复合物诱导的Treg扩增。慢性过敏原暴露使单只DR1转基因小鼠的三分之一致敏，但不影响肺功能。相似的治疗导致> 90％的TCR-DR1小鼠出现AHR和Th2驱动的肺部病理。用IL-2-αIL-2mAb复合物预防和治疗Treg的扩展可阻止与慢性变应原接触相关的变应原特异性IgE的产生和增强。结论我们确定过敏原呈递的遗传限制是决定对杂草艾草的主要花粉过敏原致敏性致敏和疾病的主要因素，杂草艾蒿经常引起人类致敏性和疾病。此外，我们证明了变应原特异性T效应物和Treg细胞之间的平衡对于调节变态免疫反应的重要性。

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