Abstract
Allergic asthma is characterized by airway eosinophilia, increased mucin production and allergen-specific IgE. Fc gamma receptor IIb (FcγRIIb), an inhibitory IgG receptor, has recently emerged as a negative regulator of allergic diseases like anaphylaxis and allergic rhinitis. However, no studies to date have evaluated its role in allergic asthma. Our main objective was to study the role of FcγRIIb in allergic lung inflammation. We used a murine model of allergic airway inflammation. Inflammation was quantified by BAL inflammatory cells and airway mucin production. FcγRIIb expression was measured by qPCR and flow cytometry and the cytokines were quantified by ELISA. Compared to wild type animals, FcγRIIb deficient mice mount a vigorous allergic lung inflammation characterized by increased bronchoalveolar lavage fluid cellularity, eosinophilia and mucin content upon ragweed extract (RWE) challenge. RWE challenge in sensitized mice upregulated FcγRIIb in the lungs. Disruption of IFN-γ gene abrogated this upregulation. Treatment of naïve mice with the Th1-inducing agent CpG DNA increased FcγRIIb expression in the lungs. Furthermore, treatment of sensitized mice with CpG DNA prior to RWE challenge induced greater upregulation of FcγRIIb than RWE challenge alone. These observations indicated that RWE challenge upregulated FcγRIIb in the lungs by IFN-γ- and Th1-dependent mechanisms. RWE challenge upregulated FcγRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells. FcγRIIb deficient mice also exhibited an exaggerated RWE-specific IgE response upon sensitization when compared to wild type mice. We propose that FcγRIIb physiologically regulates allergic airway inflammation by two mechanisms: 1) allergen challenge mediates upregulation of FcγRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells by an IFN-γ dependent mechanism; and 2) by attenuating the allergen specific IgE response during sensitization. Thus, stimulating FcγRIIb may be a therapeutic strategy in allergic airway disorders.
Highlights
Allergic asthma is an airway inflammatory disease that is characterized by bronchial hyper-responsiveness, airway eosinophilia, goblet cell hyperplasia and production of allergen specific IgE
We assessed the biological role of FccRIIb in a murine model of allergic asthma
Since our studies suggested that FccRIIb inhibited allergic airway inflammation, we sought to determine whether its upregulation was Th1 or IFN-c dependent
Summary
Allergic asthma is an airway inflammatory disease that is characterized by bronchial hyper-responsiveness, airway eosinophilia, goblet cell hyperplasia and production of allergen specific IgE. Cross-linking of the high affinity IgE receptor (FceRI) on mast cells by IgE, in the presence of allergen activates Btk, PLC-gamma and PI3K [1,2,3,4]. This leads to production and release of pro-inflammatory substances like histamine, leukotrienes and cytokines that promote allergic inflammation. Cytokines produced by allergen specific Th2 cells such as IL4, IL5, IL9, IL13 and IL25 promote allergen-specific IgE production and allergic airway inflammation [5,6,7,8,9,10,11,12,13,14]. Relatively little is known about negative regulatory mechanisms that attenuate allergic inflammation
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