EMORY UNIVERSITY
The Role of JAM-A in Regulation of Intestinal Antigen Presenting Cells and Inflammation Numerous observations have suggested that inflammatory bowel disease is a multifactorial process encompassing at least three major interacting elements: environmental conditions, altered mucosal immune function, and genetic susceptibility factors. Due to the fact that genetic factors and the environment are incredibly difficult to investigate in a controlled manner, attention and research investigation has focused on understanding mucosal immune responses with the working hypothesis being that intestinal inflammation results from a breakdown in immune tolerance to normal intestinal microbiota. While there is increasing understanding of the factors that contribute to the pathogenesis of intestinal inflammation, there is an urgent need for more thoroughly understanding protective factors that control inflammation in order to design more efficacious treatments. An important challenge remains gaining insight into the critical balance between enforcing tolerance to normal commensal bacteria, while simultaneously allowing for appropriate mucosal immune responses to pathogenic microbes. Mucosal resident antigen presenting cells (APCs), particularly dendritic cells (DCs) and macrophages, hold great promise in this regard because they can uptake enteric bacteria, viruses, and protozoa and induce distinct types of immune responses, for example pro-inflammatory (Th1/Th17) versus regulatory (Treg/Tr1/Th3) T cells responses. In essence, mucosal APCs are sentinels situated just beneath the epithelial barrier and are capable of initiating and orchestrating intestinal immune responses. Importantly, mucosal DC and macrophage functions are closely integrated with overlying intestinal epithelial cells and alterations in the integrity of the intestinal epithelial barrier can have a profound impact on intestinal disease susceptibility. While there are associations between increased intestinal epithelial permeability predating the onset of intestinal inflammation, little is known about how the epithelial barrier regulates innate and adaptive immune cells in the underlying lamina propria. We have recently demonstrated a role for Junctional Adhesion Molecule-A (JAM-A) in regulating mucosal permeability and intestinal inflammation, yet it remains unknown how JAM-A regulates intestinal innate and adaptive immune cells. Thus, a clear understanding of the consequences of increased intestinal epithelial permeability, as a result of JAM-A deficiency, on the function of intestinal APCs (Specific Aim 1) and detailed analysis of the outcome of permeability increases in regulation of immune responses during intestinal inflammation (Specific Aim 2) would represent major advancements toward the understanding mucosal tolerance and immunity. The central hypothesis driving this research is that enhanced epithelial permeability as a result of JAMA deficiency disturbs the tolerogenic functions of intestinal lamina propria macrophages and DCs, while promoting pro-inflammatory responses that contribute to the pathogenesis of intestinal inflammation. This hypothesis will be addressed by completing the following two Specific Aims. In Specific Aim 1 we will explore the consequences of increased intestinal epithelial permeability created by JAM-A deficiency on the function of lamina propria DCs and macrophages. In Specific Aim 2 the outcome of JAM-A deficiency in regulation of immune responses and intestinal inflammation will be investigated.