Despite the fact that immunoglobulin G (IgG) is the major class of immunoglobulins and the protein with the longest serum half-life in all mammals, extremely little information is available on the role of IgG and the way it is managed in mucosal tissues. Intimately related to the function and fate of IgG is the neonatal Fc receptor for IgG (FcRn). FcRn manages both the transport of IgG across epithelial barriers and is the major factor responsible for the protection of IgG from catabolism and thus accounts for the long-lived nature of IgG in the serum. In addition, in light of our recent observation that FcRn is also expressed beyond the epithelium and endothelium in professional antigen-presenting cells (APC), it can be predicted that FcRn has significant functions beyond the simple passive transfer and protection of IgG and may also be involved in regulating antigen presentation. Our grant proposal, therefore, aims to define the cell biologic behavior of hFcRn in epithelial cells and APCs including dendritic cells (DC) and the related functions of FcRn in immune protection and inflammation. We therefore propose the following specific aims: 1) Define how FcRn transport of IgG bi-directionally occurs across polarized epithelial cell barriers by identifying the major structural components of FcRn that regulate its trafficking using a chimeric model system in which the extracellular, transmembrane and/or cytoplasmic tail domains of FcRn are fused to human CD4 and to identify the intracellular itinerary for the outwardly- and inwardly-directed transcytotic pathways of IgG with a special focus on the apical recycling endosome as a site of differentiation between these two pathways. These studies will be performed in transfected Madin-Darby canine kidney cells;2) Define how FcRn mediated transport of IgG interacts with bacteria and regulates anti-bacterial responses in a Citrobacter rodentium model system, an epithelial-associated pathogen that is regulated by IgG;3) Determine whether FcRn regulates antigen presentation by DC by examining DC from FcRn-deficient mice and mutant IgG fragments that are disabled in their ability to bind to FcRn, and;4) Determine whether FcRn regulates intestinal inflammation due to barrier disruption of the epithelium in dextran-sodium sulfate-mediated colitis as well as determine whether DC modulate intestinal inflammation in a hapten-mediated colitis model. These studies will gain a composite view of FcRn behavior in mucosal tissues. In addition, however, they will hopefully identify a role for IgG in mucosal inflammation that may be a target for therapeutic intervention. Recently, FcRn has been shown to regulate the development of immune-mediated diseases such as rheumatoid arthritis and bullous pemphigoid. This raises the possibility that blockade of FcRn function may be of therapeutic utility in colitis if our studies support an involvement of FcRn in inflammation.
Showing the most recent 10 out of 164 publications
