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Clin Exp Allergy ; 39(4): 591-601, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19220320

ABSTRACT

BACKGROUND: 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. 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 (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. 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 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. 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.


Subject(s)
Asthma/immunology , Complementarity Determining Regions/immunology , Immunoglobulin E/immunology , Immunoglobulin Heavy Chains/immunology , Inflammation/immunology , Mast Cells/immunology , Allergens/immunology , Animals , Asthma/metabolism , Bronchoalveolar Lavage Fluid/immunology , Complementarity Determining Regions/blood , Complementarity Determining Regions/genetics , Cytokines/analysis , Cytokines/immunology , Disease Models, Animal , Eosinophils/immunology , Eosinophils/metabolism , Immunoglobulin E/blood , Immunoglobulin E/genetics , Immunoglobulin G/blood , Immunoglobulin Heavy Chains/blood , Immunoglobulin Heavy Chains/genetics , Inflammation/metabolism , Lung/immunology , Lung/pathology , Mast Cells/metabolism , Mice , Mice, Mutant Strains , Ovalbumin/immunology
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