Composition of the immunoglobulin classic antigen-binding site regulates allergic airway inflammation in a murine model of experimental asthma.
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.
Kerzel
S
S
Department of Pediatrics, Zentrum für Kinder- und Jugendmedizin, Philipps-University Marburg, Marburg, Germany. kerzel@med.uni-marburg.de
Wagner
J
J
Rogosch
T
T
Yildirim
A-O
AO
Sikula
L
L
Fehrenbach
H
H
Garn
H
H
Maier
R F
RF
Schroeder
H W
HW
Zemlin
M
M
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
D000485:Allergens; D022801:Complementarity Determining Regions; D016207:Cytokines; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007073:Immunoglobulin E; D010047:Ovalbumin