Kerzel S, Wagner J, Rogosch T, Yildirim A-O, Sikula L, Fehrenbach H, Garn H, Maier R F, Schroeder H W, Zemlin M
Department of Pediatrics, Zentrum für Kinder- und Jugendmedizin, Philipps-University Marburg, Marburg, Germany.
Clin Exp Allergy. 2009 Apr;39(4):591-601. doi: 10.1111/j.1365-2222.2008.03178.x. Epub 2009 Feb 3.
When bound to mast cell FcepsilonRI, IgE serves as antigen receptor for allergic reactions, permitting specific identification of the allergen. Although the core of the classic antigen-binding site is heavy chain complementarity determining region 3 (CDR-H3), recent studies suggest that allergens might also bind IgE in a superantigen-like fashion outside the classic antigen-binding site.
We sought to evaluate the contribution of the classic CDR-H3-centric antigen-binding site to the development of an allergic phenotype.
Using a murine model of experimental asthma, we characterized a gene-targeted mouse strain expressing an altered range of CDR-H3s (DeltaD-iD mice) in response to the hydrophobic allergen ovalbumin (OVA). Mutant and wild-type (wt) mice were sensitized intraperitoneally with OVA; non-sensitized mice served as controls.
We found the composition of the classic CDR-H3-centric antigen-binding site to be critical for the development of characteristic aspects of allergic asthma. (i) Compared with wt animals, DeltaD-iD mice showed a significantly less pronounced OVA-induced rise in allergen-specific IgE levels and hence in total serum IgE levels. (ii) In addition, DeltaD-iD mice demonstrated a significant reduction in eosinophilic airway inflammation, as well as in interleukin-4 (IL-4), IL-5 and IL-13 levels in BAL fluids.
Allergic sensitization and airway inflammation depend on the composition of the predominant CDR-H3 repertoire, suggesting that the classic CDR-H3-centric antigen-binding site plays a crucial role in creating the immunological interface between allergen and IgE. Our results further emphasize a central role of IgE, not only in mediating but also in regulating the allergic immune response.
当与肥大细胞FcepsilonRI结合时，IgE作为过敏反应的抗原受体，允许特异性识别过敏原。尽管经典抗原结合位点的核心是重链互补决定区3（CDR-H3），但最近的研究表明，过敏原也可能以超抗原样方式在经典抗原结合位点之外与IgE结合。
我们试图评估以经典CDR-H3为中心的抗原结合位点对过敏表型发展的贡献。
使用实验性哮喘的小鼠模型，我们对一种基因靶向小鼠品系进行了表征，该品系表达了针对疏水性过敏原卵清蛋白（OVA）的一系列改变的CDR-H3（DeltaD-iD小鼠）。突变型和野生型（wt）小鼠用OVA进行腹腔致敏；未致敏的小鼠作为对照。
我们发现以经典CDR-H3为中心的抗原结合位点的组成对于过敏性哮喘特征性方面的发展至关重要。（i）与wt动物相比，DeltaD-iD小鼠显示OVA诱导的过敏原特异性IgE水平以及总血清IgE水平的升高明显不那么显著。（ii）此外，DeltaD-iD小鼠的嗜酸性气道炎症以及BAL液中的白细胞介素-4（IL-4）、IL-5和IL-13水平显著降低。
过敏致敏和气道炎症取决于主要CDR-H3库的组成，这表明以经典CDR-H3为中心的抗原结合位点在创建过敏原与IgE之间的免疫界面中起关键作用。我们的结果进一步强调了IgE的核心作用，不仅在介导而且在调节过敏免疫反应中。
