Abstract
Mice sensitized to ovalbumin (OVA) develop allergic airway disease (AAD) with short-term daily OVA aerosol challenge; inflammation resolves with long-term OVA aerosol exposure, resulting in local inhalational tolerance (LIT). Cbl-b is an E3 ubiquitin ligase involved with CD28 signaling; Cbl-b−/− effector T cells are resistant to regulatory T cell-mediated suppression in vitro and in vivo. The present study utilized Cbl-b−/− mice to investigate the role of Cbl-b in the development of AAD and LIT. Cbl-b−/− mice exhibited increased airway inflammation during AAD, which failed to resolve with long-term OVA aerosol exposure. Exacerbation of inflammation in Cbl-b−/− mice correlated with increased proinflammatory cytokine levels and expansion of effector T cells in the BAL during AAD, but did not result in either a modulation of lymphocyte subsets in systemic tissues or in OVA-specific IgE in serum. These results implicate a role for Cbl-b in the resolution of allergic airway inflammation.
Highlights
Mouse models of allergic airway disease (AAD) are important tools for investigating the underlying mechanisms of allergic asthma in humans
At local inhalational tolerance (LIT), while both wild-type and Cbl-b−/− mice exhibited significant decreases in total bronchoalveolar lavage (BAL) white blood cells (WBCs) from their respective AAD levels (p < 0.05 for LIT vs. AAD) (Figure 1A), there remained a significant increase in total WBCs and eosinophils in the BAL of Cbl-b−/− mice as compared to wild-type mice
The results of these studies indicate that Cbl-b plays an integral role in regulating the intensity of an allergic airway response in mice, as Cbl-b−/− mice exhibit increased inflammation during acute and chronic stages of an OVA-induced AAD model. This exacerbation does not appear to be due to the inherent autoimmune phenotype of Cbl-b−/− mice [9], since age-matched (i.e., 18-week) naïve Cbl-b−/− mice did not develop airway inflammation. These results indicate that Cbl-b deficiency can influence the severity of AAD through the dysregulation of T cell responses
Summary
Mouse models of allergic airway disease (AAD) are important tools for investigating the underlying mechanisms of allergic asthma in humans. In both mice and humans, CD4+ T cells are essential for the initiation of airway inflammation in response to allergen exposure. These CD4+ T-helper type-2 (TH2) cells are responsible for providing the proper signals for B cells to produce immunoglobulin type-E (IgE) antibodies, which are primary mediators of allergic responses through their interactions with receptors on mast cells.
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