Composition of the immunoglobulin classic antigen‐binding site regulates allergic airway inflammation in a murine model of experimental asthma

Abstract

Background When bound to mast cell FcεRI, 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. Objective We sought to evaluate the contribution of the classic CDR-H3-centric antigen-binding site to the development of an allergic phenotype. Methods Using a murine model of experimental asthma, we characterized a gene targeted mouse strain expressing an altered range of CDR-H3s (ΔD-iD mice) in response to the hydrophobic allergen ovalbumin. Mutant and wildtype (wt) mice were sensitized intraperitoneally with ovalbumin; non-sensitized mice served as controls. Results 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 to wt animals, ΔD-iD mice showed a significantly less pronounced ovalbumin-induced rise in allergen-specific IgE levels and hence in total serum IgE levels. (ii) In addition, ΔD-iD mice demonstrated a significant reduction in eosinophilic airway inflammation, as well as in IL-4, IL-5, and IL-13 levels in BAL fluids. Conclusion 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.

Plasma Cells and Nonplasma B Cells Express Differing IgE Repertoires in Allergic Sensitization

“…Using a gene targeted mouse strain with a limited CDR-H3 repertoire, we revealed that allergic sensitization and airway inflammation highly depend on the predominant BCR repertoire (11). Therefore, we now sought to systematically characterize the composition of the murine IgE repertoire.…”

IgE Transcripts in the Circulation of Allergic Children Reflect a Classical Antigen-Driven B Cell Response and Not a Superantigen-Like Activation

“…A lthough several studies have addressed the characterization of the IgE repertoire (1), it is subject to ongoing discussion whether the IgE production in allergic disorders is due to an oligoclonally expanded B cell response (2). This is particularly interesting in the context of allergen-specific immunotherapy and the emerging anti-IgE therapy, which has redirected the spotlight in allergy treatment to the B cell (1).…”

A Single D_H Gene Segment Is Sufficient for the Establishment of an Asthma Phenotype in a Murine Model of Allergic Airway Inflammation

“…For nonsensitized controls, the dilutions were 1:10 (IgG 1 ) or 1:2 (IgE). OVA-specific IgE antibody levels were determined as previously described [10]. As standard, we used an OVA-specific murine IgE (Serotec, Oxford, UK).…”

“…IgE heavy chain transcripts were amplified and cloned as described previously [10]. Sequences were aligned with the ImMunoGeneTics (IMGT) VQUEST program (http://imgt.cines.fr) [17].…”

“…To test for this possibility in an IgE-dependent allergic reaction, we previously evaluated allergic sensitization in gene-targeted mice with a normal binding site for superantigens but a restricted repertoire of classical antigen-binding sites (ΔD-iD mice) [9]. In these mice with an altered CDR-H3 repertoire, the asthma phenotype was markedly alleviated compared to wild-type (WT) animals [10]. Following sensitization and aerosolic challenge with the hydrophobic allergen ovalbumin (OVA), ΔD-iD mice displayed significantly reduced allergen-specific IgE levels, eosinophilic airway inflammation and local T H 2 cytokine responses.…”