The mucosal immune system is critical for establishing healthy local and systemic immunity. The specific bidirectional transporter for IgG, the neonatal Fc receptor for IgG (FcRn), confers a unique function to this immunoglobulin by its ability to retrieve IgG-complex luminal antigens and deliver these to local dendritic cells (DC) which, in turn, utilize FcRn to prime effective CD4+ and CD8+ T cell responses. The current research proposal addresses the unanswered question of how FcRn [in antigen presenting cells (APC)] contributes to ho- meostatic and pathogenic mucosal immune responses. Our long-term goal is to understand how modulating these actions of FcRn can be applied to treat intestinal inflammation, as is found in inflammatory bowel disease (IBD), as well as enhancing immune surveillance to cancer. The objective of this research is to elucidate how, at both the molecular and physiological levels, FcRn within DC acts to establish homeostatic and pathological gut T cell responses. [Our central hypothesis is that multimeric ligation of FcRn within DC downstream of FcgR recruits a specific cohort of signaling and effectors proteins which drive antigen processing and promote Th1 cytokine production and cytotoxicity, capable of promoting intestinal inflammation but also of enabling immune- surveillance against cellular aberrations induced by viral infection and neoplasia.] This rationale is derived not only from the increasing evidence linking defects in mucosal homeostasis, including CD8+ T cell responses and IgG-receptor polymorphisms, to the development of IBD but also from the increasing development of therapeutics targeted at inhibition or exploitation of the IgG-FcRn interaction. Our central hypothesis will be tested with three specific aims: 1) [Determine the intracellular itinerary of FcRn in antigen presenting cells and elucidate its functional relationship with hFcgRIIa;an IBD risk gene];2) Determine the role of FcRn in the development of Th1/Th2 homeostasis and T cell memory at mucosal sites;3) Determine the role of FcRn in the development of inflammation and non-inflammation induced neoplasia at mucosal sites.
In Aim 1, we seek to define the intracellular mechanisms by which FcRn routes IgG IC,[define how this pathway intersects with hFcgRIIa, a genetic risk factor for IBD, and determine whether hFcgRIIa-induced inflammation is dependent upon FcRn as a final common pathway].
In Aim 2, we will determine how FcRn-mediated routing of IgG IC within DC leads to the establishment of Th1 and Tc1 effectors responses within the gut.
In Aim 3, we will demonstrate that the Th1 and Tc1 effectors responses enabled by FcRn-directed IgG IC trafficking leads to protection against neoplastic development at mucosal sites. Overall, this proposal is significant because it will promote our understanding of the role of FcRn and its relationship with hFcgRIIa within DC in coordinating mucosal immune responses required for intestinal homeostasis, inflammation and cancer prevention. In addition to identifying new therapeutic targets for the treatment of IBD and a host of other inflammatory diseases, this research will provide a firm basis upon which to extend the opportunities for FcRn-targeted therapies.
The proposed research is relevant to public health because understanding how FcRn coordinates antigen presentation at mucosal sites, which in turn regulates activation of the innate and adaptive branches of the immune system, will provide new insights into the mechanisms that either maintain mucosal homeostasis or drive active inflammatory responses and neoplasia. The proposed studies are relevant to the mission of the NIDDK because they are expected to identify new therapeutic strategies for inhibiting inflammation associated with inflammatory bowel disease or enhancing immunity in the treatment of cancers and infections.
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