The objective of this proposal is to test the hypothesis that FceRI can function as a receptor for antigen surveillance when expressed by dendritic cells (DC). Gastrointestinal (Gl) tract DC may process lumenal antigens by FceRI-lgE-mediated uptake, thereby implicating this receptor in the regulation of mucosal immune homeostasis. FcERI, the high affinity receptor for IgE, is expressed as a tetramer in mast cells and basophils of humans and rodents. In these cells, FceRI is centrally involved in the induction of IgE-mediated allergic responses (type I hypersensitivity). A trimeric isoform of FceRI is expressed constitutively in human antigen presenting cells. Due to the lack of constitutive expression of this trimeric receptor in the rodent system, little is known about its function in human health or disease. We have humanized the expression pattern of FceRI on murine DC. This has allowed investigation of the antigen uptake function of trimeric FceRI and elucidation of the role of this receptor in the presentation and cross-presentation of antigens, as proposed in Aim 1. These studies are clinically relevant because expression of FceRI on Gl tract DC may be a potential mechanism of host exposure to lumenal allergens. CD23, the low affinity receptor for IgE, is expressed by the Gl epithelium and has been established as a receptor for IgE transport across the epithelial barrier. Because FceRI is also present in the Gl tract, Aim 2 proposes to examine the role of FceRI in the transepithelial transport of IgE. The potential involvement of FceRI in IgE transport has significant implications for the maintenance of intestinal immune homeostasis and IgE-mediated events in the Gl tract and at other mucosal surfaces. ? HUMAN
Allergic disorders are progressively on the rise in industrialized countries and are one of the largest groups of clinical diseases that require medical intervention. The studies proposed here are thus, clinically relevant to our understanding of IgE-mediated immunity, the maintenance of mucosal immune homeostasis, and the development of allergic responses. Our results may provide new insights into the design of therapeutic interventions for allergy. ? ? ?
