The prevalence of food allergy is increasing in the westernized world;however, the inciting factors leading to the development of this potentially severe disease remain unknown. The mechanism of food allergy disease, like all allergic disease, depends upon the development of Th2 cells and production of IgE antibodies against food allergens. Induction of both antigen-specific Th2 cells and IgE depends upon a sensitization phase mediated by dendritic cells (DC). The primary goal of this application is to understand the role gastrointestinal (GI) DC and viruses play in the development of food allergies, based upon previous findings in the lung where respiratory virus initiated a DC-dependent pathway culminating in the development of atopic disease. In the lung, viral infection induced expression of the high affinity receptor for IgE (FceRI) on DC. Cross-linking of this receptor led to release of a chemoattractant for Th2 cells. Exposure to a non-viral antigen during the viral infection induced IgE against the non-viral antigen. Therefore, these data support the hypothesis that IgE- mediated cross-linking of FceRI on DC leads to recruitment and differentiation of Th2 cells initiating IgE production against innocuous environmental antigens. If this mechanism operates in the GI tract, it would explain the production of IgE against food allergens and the development of food allergy. We have found that a GI viral infection induces FceRI on GI DC, in a manner similar to what we saw in the lung. Therefore, to test the hypothesis that GI viral infection initiates a DC-dependent pathway culminating in the development of food allergy, we propose the following two specific aims:
Aim I. Define the effect of GI dendritic cell FceRI cross-linking on dendritic cell function. In this aim in vitro approaches will be utilized to explore whether cross-linking FceRI on GI DC leads to release of a Th2 chemoattractant and skews T cells towards a Th2 phenotype.
Aim II. Characterize the link between GI dendritic cell FceRI expression and IgE. In this aim in vivo approaches will be utilized to explore the role of GI DC FceRI in the recruitment and development of Th2 cells, as well as generation of IgE against food allergens during a GI viral infection. The relevance of these studies is that they provide important knowledge on the mechanisms involved in the development of food allergies. Further, these studies provide the basis for an animal model in which new therapies may be developed to treat or prevent food allergy.
| Chen, Xiuxu; Leach, Daniel; Hunter, Desire A et al. (2011) Characterization of intestinal dendritic cells in murine norovirus infection. Open Immunol J 4:22-30 |
