Immunotherapy-induced neutralizing antibodies disrupt allergen binding and sustain allergen tolerance in peanut allergy.
Immunotherapy-induced neutralizing antibodies disrupt allergen binding and sustain allergen tolerance in peanut allergy.
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DOI：
10.1172/jci164501
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发表时间：
2023-01-17
影响因子：
15.9
通讯作者：
Patil, Sarita U.
中科院分区：
文献类型：
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作者：
LaHood, Nicole A.;Min, Jungki;Keswani, Tarun;Richardson, Crystal M.;Amoako, Kwasi;Zhou, Jingjia;Marini-Rapoport, Orlee;Bernard, Herve;Hazebrouck, Stephane;Shreffler, Wayne G.;Love, J. Christopher;Pomes, Anna;Pedersen, Lars C.;Mueller, Geoffrey A.;Patil, Sarita U.
在ige介导的食物过敏中，接触过敏原会激活全身过敏反应。口服免疫疗法（OIT）通过增加口服过敏原暴露来治疗食物过敏。然而，OIT仅在一小部分个体中诱导持续的临床耐受性和降低的嗜碱性粒细胞敏感性，尽管在所有治疗个体中循环过敏原特异性IgG增加。因此，我们检查了2组有持续和短暂反应的OIT患者的过敏原特异性抗体。在这里，我们比较了来自持续或短暂反应的个体的抗体，并发现了中和抗体识别的免疫优势过敏原Ara h2的特异性耐受性相关构象表位。首先，我们使用重组抗体的x射线晶体学确定了我们认为以前未知的构象，螺旋内表位。然后，我们确定了仅在持续耐受性中识别的表位。最后，识别耐受相关表位的抗体有效中和过敏原，抑制ige介导的效应细胞活化。我们的研究结果通过定义这些抗体如何破坏ige -过敏原相互作用以防止过敏反应，证明了抗体介导的保护在ige介导的食物过敏中的分子基础。我们研究中和抗体的结构和功能基础的方法证明了特异性抗体克隆在抗体介导的耐受性中的临床相关性。我们预计我们的发现将为使用中和抗体和低过敏原治疗花生过敏奠定基础。
In IgE-mediated food allergies, exposure to the allergen activates systemic allergic responses. Oral immunotherapy (OIT) treats food allergies through incremental increases in oral allergen exposure. However, OIT only induces sustained clinical tolerance and decreased basophil sensitivity in a subset of individuals despite increases in circulating allergen-specific IgG in all treated individuals. Therefore, we examined the allergen-specific antibodies from 2 OIT cohorts of patients with sustained and transient responses. Here, we compared antibodies from individuals with sustained or transient responses and discovered specific tolerance-associated conformational epitopes of the immunodominant allergen Ara h 2 recognized by neutralizing antibodies. First, we identified what we believe to be previously unknown conformational, intrahelical epitopes using x-ray crystallography with recombinant antibodies. We then identified epitopes only recognized in sustained tolerance. Finally, antibodies recognizing tolerance-associated epitopes effectively neutralized allergen to suppress IgE-mediated effector cell activation. Our results demonstrate the molecular basis of antibody-mediated protection in IgE-mediated food allergy, by defining how these antibodies disrupt IgE-allergen interactions to prevent allergic reactions. Our approach to studying the structural and functional basis for neutralizing antibodies demonstrates the clinical relevance of specific antibody clones in antibody-mediated tolerance. We anticipate that our findings will form the foundation for treatments of peanut allergy using neutralizing antibodies and hypoallergens.