Our understanding of the pathology of IgE-antigen-dependent immune responses in the gastrointestinal (Gl) tract is rather limited, despite increasing concerns about the rising numbers of food allergic reactions and associated chronic intestinal inflammatory responses in children and adults. A major limitation of murine allergy models is the fact that the murine Gl tract has a different cellular distribution of IgE-binding structures than the human Gl tract. Human dendritic cells (DCs) express a trimeric isoform of the high affinity receptor for IgE, i.e. Fc-epsilon receptor I (FceRI). Due to the absence of FceRI on DCs in the rodent system little is known about its function and in vivo relevance. This proposal describes a 3-year experimental strategy to investigate the consequences of FceRI expression on DCs for the elicitation of IgE-mediated immune events at the mucosal surface of the Gl tract. Since mice do not express FceRI on DCs, Aim 1 proposes to asses the impact of FceRI-mediated antigen uptake by DCs to immune responses in the Gl tract using a transgenic knock-in mouse model. In this in vivo model, murine DCs are """"""""humanized"""""""" with respect to IgE-binding sites by expressing FceRloc under the DC-specific promoter CD11c. After the characterization of FceRI expression on DCs in the Gl tract, IgE/antigen transport of FceRI knock-in mice will be compared with wild type animals and IgE-mediated immune activation will be studied. This set of experiments should prove the hypothesis that DCs of the Gl tract process lumenal antigens by FceRI-lgE mediated uptake, thereby affecting intestinal inflammatory responses and type I hypersensitivity.
Aim 2 proposes to study FceRI-mediated DC function in vitro. A newly established DC line model will be applied to asses DC activation/maturation upon FceRlay2 engagement. The in vitro model will also allow a detailed analysis of the signaling properties of trimeric FceRlay2 complexes, which are specific for human DCs. In summary, the proposed experiments will advance our understanding of the mechanisms that control FceeRIIgE-mediated activation of the immune system in the Gl tract and thus, they are relevant with respect to the development of new treatment strategies for allergy and antigen-induced mucosal inflammation in the Gl tract.
The immune system in the gastrointestinal tract must balance the ability to respond to pathogens while remaining unresponsive to food and environmental substances. Rising numbers of individuals suffer from food allergies and chronic intestinal inflammation. The proposed research will lead to a better understanding of these allergic and inflammatory responses in the gastrointestinal tract and point towards new treatment strategies.
