title: 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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Zentrum für Kinder- und Jugendmedizin, Philipps-University Marburg, Marburg, Germany. kerzel@med.uni-marburg.de
authors.forename: S
authors.initials: S
authors.lastname: Kerzel
authors.forename: J
authors.initials: J
authors.lastname: Wagner
authors.forename: T
authors.initials: T
authors.lastname: Rogosch
authors.forename: A-O
authors.initials: AO
authors.lastname: Yildirim
authors.forename: L
authors.initials: L
authors.lastname: Sikula
authors.forename: H
authors.initials: H
authors.lastname: Fehrenbach
authors.forename: H
authors.initials: H
authors.lastname: Garn
authors.forename: R F
authors.initials: RF
authors.lastname: Maier
authors.forename: H W
authors.initials: HW
authors.lastname: Schroeder
authors.forename: M
authors.initials: M
authors.lastname: Zemlin
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D022801:Complementarity Determining Regions / Q000097:blood / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D007073:Immunoglobulin E / Q000097:blood / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D007143:Immunoglobulin Heavy Chains / Q000097:blood / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010047:Ovalbumin / Q000276:immunology
chemical_list: D000485:Allergens; D022801:Complementarity Determining Regions; D016207:Cytokines; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007073:Immunoglobulin E; D010047:Ovalbumin